Chemical Duodenum Jejunum Ileum IBS Type(s) 1 X O O O B 2 O X O O C 3 X X O O C, B 4 O O X O C 5 X O X O C, B 6 O X X O C 7 X X X O C, B 8 O O O X D 9 X O O X D, B 10 O O X X D 11 X O X X D, B 12 O X X X D 13 X X X X D, B 14 O X O X A 15 X X O X A, B

Table 4. Summary of the four types and fifteen forms of IBS produced when

Any fault that disrupts sensory input from the small intestine to the brain or motor output from the brain to the small intestine will cause IBS symptoms. The section(s) of the intestine that are affected will not be the same as when a neurotransmitter is deficient. The first faulty section will cause an IBS Barrier to form at the start of the following brain controlled section. Subsequent defects will have little effect, except that diarrhoea symptoms will occur when a section that terminates the intestine is faulty. IBS-B cannot be produced by damage to the

If you compare two subjects with the same type of IBS, the symptoms that they each suffer

When the enteric nervous system controls movement of food soup in the small intestine, the transport speed varies according to the types of food eaten. Some foods cause very fast

More force is used to achieve very fast speeds, and the brain creates a stronger Barrier to stop the flow. A strong Barrier produces a complete transport halt for long periods, and

from can be different. The following factors explain how this variation occurs.

neurotransmitter deficiencies occur in the primary controller.

**4. Variation in the expression of IBS symptoms** 

**3.7 Primary control fault summary** 

Legend: X = defective and O = functioning

**3.8 Other primary control faults** 

duodenum walls.

**4.1 Food variables** 

speeds and others slower speeds.

Primary controller

Some fibre types stimulate fast speeds in the small intestine when the secondary controller is active. Fast speeds cause slight to moderate IBS symptoms and very fast speeds cause severe IBS symptoms. Other types of fibre stimulate slower speeds. Data on the transport speed of different foods, when the enteric nervous system is in control of the small intestine, is in Table 5.


Table 5. Speed of food types when transported by the enteric nervous system.

The outer coat of legumes and most cereals contain the fibre types that stimulate fast speeds in the small intestine. This fibre can be classed as insoluble, but not all types of insoluble fibre stimulate fast speeds.

### **4.1.2 Examination of fibre from cereals and legumes**


### **4.1.3 Insoluble fibre**

Currently all insoluble fibre is treated the same. This research has identified three distinct types of insoluble fibre;


3. *Corn grits…* this food causes no IBS symptoms. Insoluble fibre was extracted by boiling coarse corn meal (machine ground) in 3% hydrochloric acid for several hours. At 40x magnification the fibre consisted of three dimensional amorphous clumps and fragments (see Figure 5). The fibre appears to be tangled clumps of soft fibrils at 400x

4. *Split yellow peas…* this food causes no IBS symptoms. Insoluble fibre was extracted from hulled & split yellow peas by soaking overnight, crushing, and then boiling in 3% hydrochloric acid for several hours. The insoluble material was obloid and spherical lumps, 0.1 to 0.3 mm in diameter (see Figures 7 & 8). Sharp edges were not

5. *Haricot bean endosperm (internal portion)…* this food causes no IBS symptoms. Insoluble fibre was extracted by soaking whole beans overnight, removing the external coat, and boiling the crushed endosperm in 3% hydrochloric acid for several hours. The insoluble material was obloid and spherical lumps, 0.1 to 0.2 mm in diameter (see Figures 9 & 10).

6. *Haricot bean external coat…* this food causes severe IBS symptoms. Insoluble fibre was extracted by soaking whole beans overnight, removing the external coat, crushing it and boiling in 3% hydrochloric acid for several hours. The fibre consisted of flat two dimensional fragments about 1 to 5 mm in size (see Figure 11). At 400x magnification the material is seen to be composed of densely packed crystalline rods, about 0.03mm long and 0.01mm in diameter (see Figure 12). The rods are orientated at 90 degrees to

7. *Moong bean endosperm…* this food causes no IBS symptoms. Insoluble fibre was extracted by soaking whole beans overnight, removing the external coat, and boiling the crushed endosperm in 3% hydrochloric acid for several hours. The fibre consisted of obloid to spherical lumps, 0.1 to 0.2 mm in diameter (see Figure 13). Sharp edges were

8. *Moong bean external coat…* this food causes moderate IBS symptoms. Insoluble fibre was extracted by soaking beans overnight, removing the skin, crushing and then boiling it in 3% hydrochloric acid for several hours. The fibre is fragments of light coloured coat with dark veins (see Figure 14). The dark veins contain crystalline rods orientated like the sleepers on a railway track (see Figure 15). Figure 16 shows 0.05mm by 0.01mm rods

Currently all insoluble fibre is treated the same. This research has identified three distinct

1. *Cereal bran…* sharp edged, two dimensional flakes present in most cereals. It causes

2. *Legume micro-crystalline fibre...* these tiny, hard, crystalline rods are found in the external

3. *Soft insoluble fibre…* Soft amorphous material from corn, legumes, fruits, vegetables,

coats of legumes. In high numbers they trigger severe IBS symptoms.

magnification (see Figure 6).

Sharp edges were not visible.

the surface of the endosperm.

removed from the dark veins.

severe IBS symptoms when present in quantity.

nuts, seeds & animal foods. It caused no IBS symptoms.

visible.

not visible.

**4.1.3 Insoluble fibre** 

types of insoluble fibre;

Fig. 1. Insoluble fibre from whole meal wheat flour x 40. Image 3mm wide.

Fig. 2. Insoluble fibre from whole meal wheat flour x 160. Image 0.75mm wide

Fig. 3. Insoluble fibre from whole meal wheat flour x 400. Image 0.3mm wide

Fig. 4. Insoluble fibre from whole white rice x 400. Image 0.3mm wide

Fig. 3. Insoluble fibre from whole meal wheat flour x 400. Image 0.3mm wide

Fig. 4. Insoluble fibre from whole white rice x 400. Image 0.3mm wide

Fig. 5. Insoluble fibre extracted from corn grits x 40. Image 3mm wide.

Fig. 6. Insoluble fibre extracted from corn grits x 400. Image 0.3mm wide.

Fig. 7. Insoluble fibre from split yellow peas x 40. Image 3mm wide.

Fig. 8. Insoluble fibre from split yellow peas x 400. Image 0.3mm wide.

Fig. 7. Insoluble fibre from split yellow peas x 40. Image 3mm wide.

Fig. 8. Insoluble fibre from split yellow peas x 400. Image 0.3mm wide.

Fig. 9. Insoluble fibre from haricot bean endosperm x 40. Image 3mm wide.

Fig. 10. Insoluble fibre from haricot bean endosperm x 400. Image 0.3mm wide.

Fig. 11. Insoluble fibre from haricot bean external coat x 40. Image 3mm wide.

Fig. 12. Insoluble fibre from haricot bean external coat x 400. Image 0.3mm wide.

Fig. 11. Insoluble fibre from haricot bean external coat x 40. Image 3mm wide.

Fig. 12. Insoluble fibre from haricot bean external coat x 400. Image 0.3mm wide.

Fig. 13. Insoluble fibre from moong bean endosperm x 400. Image 0.3mm wide.

Fig. 14. Insoluble fibre from moong bean external coat x 40. Image 3mm wide.

Fig. 15. Insoluble fibre from moong bean external coat x 400. Image 0.3mm wide.

Fig. 16. Insoluble fibre from moong bean external coat x 400. Image 0.3mm wide.

Fig. 15. Insoluble fibre from moong bean external coat x 400. Image 0.3mm wide.

Fig. 16. Insoluble fibre from moong bean external coat x 400. Image 0.3mm wide.

### **4.1.4 Foods that slow the digestive system**

Some foods reduce the speed of the digestive system. This allows more time for dehydration to occur. Their effects are not seen when cereals and whole legumes are eaten. The foods are…


### **4.1.5 Trace minerals and depression**

When a high starch, low fat, cooked protein diet is eaten, trace minerals are supplied by the bacteria that digest residual starch & protein in the colon. These bacteria transform inorganic trace minerals into absorbable organic trace mineral complexes. However in IBS-A & IBS-D, colonic bacteria are regularly expelled and no longer supply trace minerals. Lack of these minerals causes depression.

### **4.2 Cholesterol**

The human body manages circulating cholesterol with the ileum. Cholesterol is used to make bile salts which are then stored in the gall bladder. This removes cholesterol from circulation. Bile salts are used to emulsify fats in the first and second sections of the small intestine and later on they can be reabsorbed in the third section (ileum). The ileum brain controller manages this recycling process. When cholesterol level is low, most bile salts are recycled. When cholesterol level is high, more bile salts are allowed to escape via the stool.


### **4.2.1 Symptoms of cholesterol deficit & excess**

When the ability to eliminate cholesterol via the digestive process is compromised, a high level of cholesterol causes the brain to display characteristic symptoms. When excessive amounts of bile salts are lost because of a defective ileum, a low cholesterol level causes similar symptoms. They are…


### **4.3 Variable level of the autonomic nervous system**

The level of the autonomic nervous system is high on arising and when environmental stress occurs. Overnight it usually declines. This variation coincides with levels of adrenal hormones in the body. Now the small intestine is controlled by five divisions of the autonomic nervous system. Variation in the activity level of this system thus affects control of the small intestine. IBS symptoms are worst early in the morning. The characteristic IBS-A & D symptom of the 'morning rush' occurs when the enteric nervous system relaxes the valve terminating the ileum, moves the contents of the ileum prematurely into the colon, and evacuates the colon in response to the presence of raw enzymes and/or fat. The characteristic IBS-C & A symptom of bloating is worst on eating breakfast. The control speed set by the enteric nervous system is higher, and the strength of the Barrier is stronger.

### **4.4 Climate, age & constitution**


### **4.5 Progression of the illness**

A neurotransmitter deficiency (or deficiencies) in the small intestine brain controller, can develop over decades. IBS symptoms are mild and irregular at first, gradually become more frequent, then continuous.

### **4.6 Other causes of IBS**


### **5. Evidence for the model**

### **5.1 No visible damage**

Medical examination of most IBS patients shows no damage that can account for the symptoms. The automated controls of the digestive system are where the problems are likely to be.

### **5.2 Cereal and legume fibre**

When consumption of cereals and whole legumes is stopped, IBS symptoms are dramatically improved. These foods stimulate too fast speeds when the enteric nervous system regulates transport in the small intestine.

### **5.3 Difficulty digesting fats**

76 Constipation – Causes, Diagnosis and Treatment

The level of the autonomic nervous system is high on arising and when environmental stress occurs. Overnight it usually declines. This variation coincides with levels of adrenal hormones in the body. Now the small intestine is controlled by five divisions of the autonomic nervous system. Variation in the activity level of this system thus affects control of the small intestine. IBS symptoms are worst early in the morning. The characteristic IBS-A & D symptom of the 'morning rush' occurs when the enteric nervous system relaxes the valve terminating the ileum, moves the contents of the ileum prematurely into the colon, and evacuates the colon in response to the presence of raw enzymes and/or fat. The characteristic IBS-C & A symptom of bloating is worst on eating breakfast. The control speed set by the enteric nervous system is higher, and the strength of the Barrier is stronger.

Living at arctic latitudes worsens symptoms, at tropical latitudes they improve.

Some constitutions suffer more from IBS. Those that suffer most are thin and

A neurotransmitter deficiency (or deficiencies) in the small intestine brain controller, can develop over decades. IBS symptoms are mild and irregular at first, gradually become more

Severing of nerves during surgery to the abdomen will cause symptoms immediately.

Pressure on nerves in the neck area from misaligned vertebrae, will cause intermittent

Damage to intestinal nerves from pregnancy or childbirth, will result in immediate

Failure of nervous system development as an infant will cause symptoms to appear as

Medical examination of most IBS patients shows no damage that can account for the symptoms. The automated controls of the digestive system are where the problems are

When consumption of cereals and whole legumes is stopped, IBS symptoms are dramatically improved. These foods stimulate too fast speeds when the enteric nervous

Damage to the intestine from a toxic insult will cause symptoms immediately.

IBS is seldom severe in young people. IBS is often severe in old age.

underweight. Substantial constitutions cope better.

**4.3 Variable level of the autonomic nervous system** 

**4.4 Climate, age & constitution** 

**4.5 Progression of the illness** 

frequent, then continuous.

**4.6 Other causes of IBS** 

symptoms.

symptoms.

soon as solid foods are fed.

**5. Evidence for the model** 

**5.2 Cereal and legume fibre** 

system regulates transport in the small intestine.

**5.1 No visible damage** 

likely to be.

The model identifies three possible causes of fat in the stool (steatorrhea)…


### **5.4 Irritation around the anus**

Diarrhoea is often accompanied by irritation of the skin around the anus. When the ileum no longer efficiently recycles chemicals, bowel movements will contain raw protease enzymes. These attack the area around the anus.

### **5.5 Intestinal bloating**

IBS bloating starts on arising when adrenal hormones are released and breakfast is eaten. Stress during the day further increases it. Overnight it can disappear. The autonomic nervous system is at a high level in the morning, high in response to stress and low overnight. It is likely to be causing the bloating.

The symptom of bloating displays two degrees. It is either severe, or slight to moderate and hard to detect. The duodenum is short (25 cm). When the Barrier is at the start of the jejunum and the stomach continues to pump in food soup, bloating is severe (see Diagram 1). The jejunum is 2–3m long. When the Barrier is at the start of the ileum, it causes only slight to moderate bloating (see Diagram 2) that is hard to detect.

### **5.6 Intestinal cramping**


### **6. Suggestions for testing the model**

### **6.1 Three kinds of IBS-C**

Clinicians may be able to find the three kinds of neurotransmitter deficient IBS-C predicted by the hypothesis.


### **6.2 Three kinds of IBS-D**

The symptom of borborygmi may allow the clinician to find the three kinds of neurotransmitter deficient IBS-D predicted by the theory. If IBS-B occurs, this may cause borborygmi that will obscure the diagnosis.


### **7. Coping with IBS symptoms**

### **7.1 Key symptoms for diagnosis**

The often confusing collection of symptoms that IBS presents, can be made sense of by using the key diagnostic criteria presented in Table 6.


Table 6. Diagnostic criteria for IBS

Diagnosis of IBS-B may cause problems, as steatorrhea can also be caused by continual diarrhoea that empties the gall bladder & pancreas, and by backpressure in the duodenum. If diarrhoea & severe bloating are absent, and steatorrhea is present, then IBS-B is indicated. The presence of severe symptoms is also indicative of IBS-B. However dietary trials are likely to be needed to find out if IBS-B is definitely present.

### **7.2 Healing the symptoms**

78 Constipation – Causes, Diagnosis and Treatment

1. The duodenum brain controller is deficient. When a breakfast containing cereal is eaten, the symptoms are immediate severe bloating and possibly cramping. **Constipation** and

2. The jejunum brain controller is deficient. When a breakfast containing cereal is eaten, symptoms are borborygmi, and hard to detect, slight to moderate bloating, both delayed by a few minutes. **Constipation** occurs. Cramping and steatorrhea are possible. 3. Both the duodenum and jejunum brain controllers are deficient. When a breakfast containing cereal is eaten, symptoms are immediate borborygmi, and immediate slight to moderate bloating that is hard to detect. **Constipation** occurs. Cramping and

The symptom of borborygmi may allow the clinician to find the three kinds of neurotransmitter deficient IBS-D predicted by the theory. If IBS-B occurs, this may cause

1. The ileum brain controller is malfunctioning. Borborygmi will start several hours after a breakfast containing cereal is eaten. Diarrhoea occurs immediately food reaches the end of the ileum, or on arising the next morning. Cramping and steatorrhea are possible. 2. Both the ileum and jejunum brain controllers are malfunctioning. Borborygmi will begin a few minutes after starting to eat a breakfast containing cereal. Diarrhoea occurs immediately food reaches the end of the ileum, or on arising the next morning.

3. The ileum, jejunum, and duodenum brain controllers are malfunctioning. Borborygmi will begin immediately after starting to eat a breakfast containing cereal. Diarrhoea occurs immediately food reaches the end of the ileum, or on arising the next morning.

The often confusing collection of symptoms that IBS presents, can be made sense of by using

*IBS Type Identifying diagnostic symptoms*  IBS-A Diarrhoea AND bloating

IBS-B Steatorrhea often accompanied by

IBS-C **Constipation** but NO diarrhoea IBS-D Diarrhoea but NO bloating.

severe symptoms of IBS-A, C, or D.

steatorrhea occur.

steatorrhea are possible.

borborygmi that will obscure the diagnosis.

Cramping and steatorrhea are possible.

Cramping and steatorrhea are possible.

the key diagnostic criteria presented in Table 6.

**7. Coping with IBS symptoms 7.1 Key symptoms for diagnosis** 

Table 6. Diagnostic criteria for IBS

**6.2 Three kinds of IBS-D** 

IBS symptoms are dramatically reduced by removing cereals and whole legumes from the diet (Dobson, 2011; Sinclair 2003). Most remaining symptoms can be removed with Relaxation Therapies. When stress releases adrenal hormones, the autonomic nervous system moves to a higher level, and IBS symptoms become worse. A cascade occurs…

Stress → IBS → more Stress → severe IBS etc…

Relaxation Therapies (Blanchard 1993, 2001; Dobson 2011), keep the level of adrenal hormones lower and the autonomic nervous system operates at a lower level. The enteric nervous system then moves food soup slower, the Barrier diminishes, and the valve into the colon is harder to open.

### **8. Future research**

The author is currently developing a range of diets to treat IBS. The hypothesis presented here, together with the diets and relaxation therapies, will eventually be published in a book written so that all can understand.

More research…


### **9. Acknowledgement**

Thanks to Wai, Carol, Robert, Brenda, Bill, Pat, Celine, Janette, Andrea, Alwyn, Mark, Amanda, Paul, Lois, Alice, Miao, Carlos, Don Juan, Sw. Satyananda, & Elsevier, for their assistance. The facilities of the University of Auckland have also been very helpful.

### **10. References**


Dobson B.C., (2011), *IBS Explained*, Brian C. Dobson, Retrieved from www.ibsexplained.com


## **6**

### **Opioid Induced Constipation**

Caterina Aurilio, Maria Caterina Pace, Vincenzo Pota and Pasquale Sansone *Department of Anesthesiological, Surgical and Emergency Science, Second University of Naples, Naples, Italy* 

### **1. Introduction**

80 Constipation – Causes, Diagnosis and Treatment

Dobson B.C., (2011), *IBS Explained*, Brian C. Dobson, Retrieved from www.ibsexplained.com Drossman D.A. ed., (2007), *The functional gastrointestinal disorders ROME III. 3rd ed*., pp. 490,

Fasano A. & Shea-Donohue T., (2005), The role of intestinal barrier function in the

Rehfeld J.F., (2004), Cholecystokinin, *Bailliere's Clinical Endocrinology and Metabolism*, Vol. 18,

Schwetz I., Lin Chang, (2004), *Encyclopedia Gastroenterology,* pp. 467, Elsevier, ISBN: 978-0-12-

*Gastroenterology & Hepatology*, Vol. 2, No. 9, pp 416, ISSN: 1759-5045

Sinclair C, (2003) *The IBS low starch diet*, Ninox Publishing, ISBN: 0-9582529-0-4,

pathogenesis of gastrointestinal autoimmune diseases, *Nature Clinical Practice* 

www.degnon.org ISBN: 0-9656837-5-3.

No. 4, pp. 569, ISSN: 0950-351X

386860-2

www.lowstarchdiet.net

The prevalence of chronic pain in the adult population ranges from2 to 40 (1–3). The chronic use of opioids for the treatment of non-cancer pain is commonly encountered in clinical practice.

The American Society of the Interventional Pain Physicians has issued guidelines for appropriate use of opioids (4).

With the increased use of opioids, there are more patients presenting with opioid induced constipation (OIC) or opioid bowel dysfunction (OBD) (5,6).

The definitions of constipation include a reference to infrequent, difficult or incomplete bowel evacuation that may lead to pain and discomfort; with stools that can range from small, hard 'rocks', to a large bulky mass. Constipation may be debilitating among those who require chronic analgesia (7); OIC or OBD affected an average of 41 % patients taking an oral opioid for up to 8 weeks in a meta-analysis of 11 placebo-controlled, randomized studies in non-malignant pain (14). In a survey of patients taking opioid therapy for pain of non-cancer origin, who required laxative therapy, only 46 % of opioid-treated patients reported achieving the desired treatment results > 50 % of the time, in contrast to the reported satisfaction in 84 % of control subjects (8).

The prevalence of constipation was 46.9 % and chronic abdominal pain 58.2 % among 100 ambulatory patients with moderate-to-severe chronic non-cancer pain.

In the United States and European survey of 322 patients taking daily oral opioids and laxatives, 45 % of patients reported < 3 bowel movements per week, 81 % reported constipation, and 58 % straining, symptoms were most oft en reported as severe, had at least a moderate negative impact on overall quality of life and activities of daily living. The objectives of this narrative review are to summarize essential aspects of the epidemiology of opiateinduced constipation (OIC), summarize the effects of opiates on gastrointestinal functions that lead to constipation, evaluate pharmacological approaches to treat or prevent OIC.

### **2. Pathophysiology of opioid induced constipation**

The opioid receptors identified as having effects on human gastrointestinal function are δ -, κ -, and μ -receptors. They all belong to the family of G-protein-coupled receptors, and inhibit adenylate cyclase. The m-receptors are the principal mediators of the analgesic action of endogenous and exogenous opioids as well as of the major side-effects, ie, sedation, bowel dysfunction, respiratory depression, and dependence. At the membrane level, they reduce neuronal excitability and neurotransmitter (acetylcholine) release (9) with an overall inhibitory effect on the neuron.

Opioid receptors are widely distributed in the central and peripheral nervous system, the intestinal musculature, and other tissues. In the gastrointestinal tract, μ-receptors are widely distributed in the submucosa (10), as well as in the ileal mucosa. They influence ion transport changes (11). While μ – and κ -opiate receptors are more representative in stomach and proximal colon (12).

The cause of constipation in opiate users is multi-factorial (13). Opioids interfere with normal gastrointestinal motility by delaying transit, stimulating non-propulsive motility, segmentation and tone, and stimulation of sphincters such as the pylorus and ileocecal sphincter (13) through their effects on enteric neurons (14). They can also stimulate the absorption of fluids, mainly by delayed transit, and by stimulating mucosal sensory receptors that activate a reflex arc that facilitates further fluid absorption (15,16). These multiple effects lead to OIC.

### **3. Pharmacological approach to OIC**

### **3.1 μ-opioid receptor agonists**

### **Tapentadol**

Tapentadol HCI is a μ -opioid agonist that also inhibits norepinephrine reuptake (17). The analgesic effect is so a combination of two different mechanism. In different trials norepinephrine reuptake inhibition (e.g., with venlafaxine (18) and the α 2-adrenergic agonist clonidine (19, 20) are associated with reduced colonic or rectal sensation in response to distension. Moreover it seems that, because of the combined analgesic action of tapentadol , the pain control can be achieved with a relatively lower level of μ-opioid agonism, which therefore reduces the gastrointestinal adverse effects such as constipation. As an analgesic tapentadol has a more favorable gastrointestinal side-effect profile than the classic μ-opioid receptor agonist oxycodone (21).

However, there were substantially lower incidences of gastrointestinal-related adverse effects with tapentadol extended release than with oxycodone controlled release (22). Similarly, tapentadol extended release, 100– 250 mg b.i.d., effectively relieved moderate-tosevere chronic low back pain over 15 weeks with a better gastrointestinal tolerability than oxycodone HCl controlled release, 20 – 50 mg b.i.d. (23). Studies of the pharmacodynamic effects of tapentadol on gastric emptying and colonic transit would be of significant interest.

### **3.2 μ-opioid receptor antagonists**

The main problem in using opioid antagonist for reversing the gastrointestinal adverse effects of opioid that the dose efficaciousness in reversing OIC may inhibit the analgesic effect of opioids, causing either opiate withdrawal symptoms or reversal of desirable analgesia.

### **Naloxone**

82 Constipation – Causes, Diagnosis and Treatment

inhibit adenylate cyclase. The m-receptors are the principal mediators of the analgesic action of endogenous and exogenous opioids as well as of the major side-effects, ie, sedation, bowel dysfunction, respiratory depression, and dependence. At the membrane level, they reduce neuronal excitability and neurotransmitter (acetylcholine) release (9) with an overall

Opioid receptors are widely distributed in the central and peripheral nervous system, the intestinal musculature, and other tissues. In the gastrointestinal tract, μ-receptors are widely distributed in the submucosa (10), as well as in the ileal mucosa. They influence ion transport changes (11). While μ – and κ -opiate receptors are more representative in stomach

The cause of constipation in opiate users is multi-factorial (13). Opioids interfere with normal gastrointestinal motility by delaying transit, stimulating non-propulsive motility, segmentation and tone, and stimulation of sphincters such as the pylorus and ileocecal sphincter (13) through their effects on enteric neurons (14). They can also stimulate the absorption of fluids, mainly by delayed transit, and by stimulating mucosal sensory receptors that activate a reflex arc that facilitates further fluid absorption (15,16). These

Tapentadol HCI is a μ -opioid agonist that also inhibits norepinephrine reuptake (17). The analgesic effect is so a combination of two different mechanism. In different trials norepinephrine reuptake inhibition (e.g., with venlafaxine (18) and the α 2-adrenergic agonist clonidine (19, 20) are associated with reduced colonic or rectal sensation in response to distension. Moreover it seems that, because of the combined analgesic action of tapentadol , the pain control can be achieved with a relatively lower level of μ-opioid agonism, which therefore reduces the gastrointestinal adverse effects such as constipation. As an analgesic tapentadol has a more favorable gastrointestinal side-effect profile than the

However, there were substantially lower incidences of gastrointestinal-related adverse effects with tapentadol extended release than with oxycodone controlled release (22). Similarly, tapentadol extended release, 100– 250 mg b.i.d., effectively relieved moderate-tosevere chronic low back pain over 15 weeks with a better gastrointestinal tolerability than oxycodone HCl controlled release, 20 – 50 mg b.i.d. (23). Studies of the pharmacodynamic effects of tapentadol on gastric emptying and colonic transit would be of significant interest.

The main problem in using opioid antagonist for reversing the gastrointestinal adverse effects of opioid that the dose efficaciousness in reversing OIC may inhibit the analgesic effect of opioids, causing either opiate withdrawal symptoms or reversal of desirable

inhibitory effect on the neuron.

and proximal colon (12).

multiple effects lead to OIC.

**3.1 μ-opioid receptor agonists** 

**Tapentadol** 

analgesia.

**3. Pharmacological approach to OIC** 

classic μ-opioid receptor agonist oxycodone (21).

**3.2 μ-opioid receptor antagonists** 

Naloxone is a competitive antagonist at opioid receptors with much greater affinity for μ than for κ - or δ -receptors. Naloxone blocks opioid intestinal receptors and has low systemic bioavailability (2%) due to a marked hepatic first-pass effect. In patients with chronic pain, oral naloxone improved symptoms of laxation (24), but because of its very narrow therapeutic index, doses that reverse gut symptoms can often cause reversal of analgesia (25). However, there has been a resurgence of interest in naloxone in a prolonged-release preparation, which shows evidence of analgesic efficacy and safety when used in combination with oxycodone (prolonged release) for moderate-to-severe chronic pain (26) and improved bowel function when compared with oral oxycodone (prolonged release) alone (27). This effiacy continues for up to 52 weeks in patients with non-cancer chronic pain (28).

### **Naltrexone extended release**

There one open-label study that evaluated the safety of a combination of extended-release pellets of morphine sulfate with a sequestered naltrexone core (administered once or twice daily) in patients with chronic, moderate to-severe pain. The pain-relieving objectives of treatment were achieved using dosages of the combination that could be adjusted in accordance with the investigator' s best medical judgment. The median average daily dose of morphine over the course of study in the safety population was 58.6 mg. 465 patients received one or more doses, 160 completed the 12-month study: 30% of the discontinuations occurred in the first month, most often because of adverse events (23.7 %), nausea (5.4 %), constipation in (3.4 %), and vomiting in (2.6 %). Most of the 465 patients (81.3 %) experienced one or more adverse events, most commonly constipation (31.8%) or nausea (25.2%). Opiate withdrawal symptoms were mild and affected < 5% of patients during each week of the study (29). Form these data the authors concluded that combination does not resolve OBD.

### **3.3 Association of opioid agonist and antagonist**

### **Oxycodone/Naloxone**

A new oral formulation (oxycodone/naloxone, OXN) that combines prolonged-release oxycodone (PRO) and prolonged-release naloxone (PRN) was devel- oped. The ratio of 2:1 PRO to PRN was chosen for the new tablets, which have different strengths: 5/2.5 mg, 10/5 mg, 20/10 mg and 40/20 mg [30,31]. The aim of this formulation is to counteract opioidinduced con- stipation (OIC) development [32] through naloxone local antagonist effect on the opioid receptors in the gut wall [33] while maintain analgesia [35] due to the high systemic oxycodone availability after oral ad- ministration (60–87%)

Meissner et al. [30] reported a randomized, double- blind study that assessed analgesic efficacy and, impact on the OIC of OXN and identified the optimal dose ratio of oxycodone and naloxone. Two hundred and two patients with chronic pain (most non-malignant, 2.5% cancerrelated pain) and stable oxycodone dose (40, 60 or 80 mg per day) were randomized into groups that received 10, 20, and 40 mg per day naloxone or placebo. After 4 weeks of the maintenance phase, patients received oxycodone for two weeks. Pain intensity was evaluated by the NRS, and bowel function was assessed by the bowel function index (BFI). No loss of analgesia with naloxone was observed. Na- loxone at doses of 20 and 40 mg improved bowel function in comparison to placebo (p < 0.05). The combination was well tolerated with no unexpected adverse effects. A trend towards an increase in diarrhea with the higher naloxone doses was observed. The 2:1 oxyco- done/naloxone ratio was identified as the most suitable.

### **3.4 Peripherally restricted μ- opiate receptor antagonists**

### **Methylnaltrexone**

Methylnaltrexone is a quaternary ammonium derivative of naltrexone, an opioid antagonist similar to naloxone, but it is less lipid soluble, so, less likely to cross the blood–brain barrier (36). Methylnaltrexone blocks acute morphine-induced delay in orocecal transit time without affecting analgesia or causing central opiate withdrawal symptoms.

Intravenous methylnaltrexone infusion reversed methadone induced constipation, increasing stool frequency and decreasing orocecal transit times (37,38). Orally administered methylnaltrexone showed the same results (39) with plasma drug levels were very low, suggesting a local site of action in the gut.

Several studies evaluated the effect of methylnaltrexone on apin and OIC. Methylnaltrexone, 0.45 mg / kg intravenously (i.v.), reversed the effects of 0.05 and 0.1 mg/kg morphine on orocecal transit in healthy volunteers (40)

Methylnaltrexone (at a dose of 0.15 mg / kg subcutaneously (s.c.), every other day for 2 weeks) was tested for OIC in advanced illness in 133 patients who had received opioids for 2 or more weeks and had received stable doses of opioids and laxatives for 3 or more days without relief of OIC (41). Methylnaltrexone s.c. has been approved by the US Food and Drug Administration, Health Canada and the European Medicines Agency (42). The approved indication is OIC in patients with advanced illness receiving palliative care after failing laxative therapy, and the usual dosing schedule is 1 dose every other day, as needed, but no more frequently than 1 dose in a 24-h period. The recommended dose of methylnaltrexone is 8 mg for patients weighing 38– 62 kg or 12 mg for patients weighing 62 – 114 kg. Patients whose weight falls outside of these ranges should be dosed at 0.15 mg / kg (43).

#### **Alvimopan**

Alvimopan is an orally administered, peripherally acting μ -opioid receptor antagonist that does not cross the blood – brain barrier at clinically relevant dosages (44) and does not reverse analgesia or cause opioid withdrawal symptoms. At the moment, Alvimopan is not approved for treatment of OIC. However, there is already significant literature about its potential in OIC associated with chronic opioid therapy.

In a study of 522 subjects reporting < 3 spontaneous bowel movements (SBMs) per week and a pain treatment with ≥ 30 mg oral morphine equivalent unit / day, were evaluated the efficacy of alvimapan on OIC. (45) Participants were randomized to receive alvimopan, 0.5 mg b.i.d., 1 mg once daily, 1 mg b.i.d., or placebo for 6 weeks (45). There was a significant increase in mean SBM / week over the initial 3 weeks of treatment with all 3 doses of alvimopan tested, as well as improvements in straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, which were sustained over 6 weeks. The most frequent adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5 mg b.i.d. dose demonstrated the best benefit-to-risk profile for managing OBD, with a side-effect profile similar to that of placebo (45). There was no evidence of opioid analgesia antagonism.

### **NKTR-118**

84 Constipation – Causes, Diagnosis and Treatment

function in comparison to placebo (p < 0.05). The combination was well tolerated with no unexpected adverse effects. A trend towards an increase in diarrhea with the higher naloxone doses was observed. The 2:1 oxyco- done/naloxone ratio was identified as the most suitable.

Methylnaltrexone is a quaternary ammonium derivative of naltrexone, an opioid antagonist similar to naloxone, but it is less lipid soluble, so, less likely to cross the blood–brain barrier (36). Methylnaltrexone blocks acute morphine-induced delay in orocecal transit time

Intravenous methylnaltrexone infusion reversed methadone induced constipation, increasing stool frequency and decreasing orocecal transit times (37,38). Orally administered methylnaltrexone showed the same results (39) with plasma drug levels were very low,

Several studies evaluated the effect of methylnaltrexone on apin and OIC. Methylnaltrexone, 0.45 mg / kg intravenously (i.v.), reversed the effects of 0.05 and 0.1

Methylnaltrexone (at a dose of 0.15 mg / kg subcutaneously (s.c.), every other day for 2 weeks) was tested for OIC in advanced illness in 133 patients who had received opioids for 2 or more weeks and had received stable doses of opioids and laxatives for 3 or more days without relief of OIC (41). Methylnaltrexone s.c. has been approved by the US Food and Drug Administration, Health Canada and the European Medicines Agency (42). The approved indication is OIC in patients with advanced illness receiving palliative care after failing laxative therapy, and the usual dosing schedule is 1 dose every other day, as needed, but no more frequently than 1 dose in a 24-h period. The recommended dose of methylnaltrexone is 8 mg for patients weighing 38– 62 kg or 12 mg for patients weighing 62 – 114 kg. Patients whose

Alvimopan is an orally administered, peripherally acting μ -opioid receptor antagonist that does not cross the blood – brain barrier at clinically relevant dosages (44) and does not reverse analgesia or cause opioid withdrawal symptoms. At the moment, Alvimopan is not approved for treatment of OIC. However, there is already significant literature about its

In a study of 522 subjects reporting < 3 spontaneous bowel movements (SBMs) per week and a pain treatment with ≥ 30 mg oral morphine equivalent unit / day, were evaluated the efficacy of alvimapan on OIC. (45) Participants were randomized to receive alvimopan, 0.5 mg b.i.d., 1 mg once daily, 1 mg b.i.d., or placebo for 6 weeks (45). There was a significant increase in mean SBM / week over the initial 3 weeks of treatment with all 3 doses of alvimopan tested, as well as improvements in straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, which were sustained over 6 weeks. The most frequent adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5 mg b.i.d. dose

without affecting analgesia or causing central opiate withdrawal symptoms.

**3.4 Peripherally restricted μ- opiate receptor antagonists** 

mg/kg morphine on orocecal transit in healthy volunteers (40)

weight falls outside of these ranges should be dosed at 0.15 mg / kg (43).

potential in OIC associated with chronic opioid therapy.

suggesting a local site of action in the gut.

**Methylnaltrexone** 

**Alvimopan** 

NKTR-118 is an oral PEGylated naloxol conjugate that blocks peripheral μ -opioid receptors in the gut. PEGylation of naloxone alters its distribution, reducing central nervous system penetration and metabolism (reduced first-pass effect) while retaining its opioid antagonist properties peripherally (46).

In human pharmacodynamic studies, NKTR-118 normalized morphine-induced delay in orocecal transit (47), while central effects were maintained with uninhibited pupillary constriction.

In a phase 2, placebo-controlled clinical trial of NKTR-118 in OIC patients ( < 3 SBM/ week, on a stable opioid dose of 30– 1,000 morphine-equivalent unit / day for ≥ 2 weeks), 208 patients were randomized into three sequential cohorts of 5, 25, or 50 mg for 4 consecutive weeks aft er a 1-week placebo run-in phase. Patients receiving 25 mg or 50 mg (but not 5 mg) NKTR-118 had significantly increased (over baseline) number of SBM during the first week of treatment (primary end point) and over the 28-day treatment period, compared with placebo. There was no evidence of opioid withdrawal, reversal of analgesia, or increase in opioid use at any dose tested. Most frequent side eff ects were abdominal cramping, diarrhea, nausea, and vomiting, which were more frequent in the 50 mg cohort. *TD-1211*  TD-1211 is an orally administered, peripherally selective, multivalent inhibitor of the μ opioid receptor. It has high affinity for human μ - and δ -receptors, and guinea-pig μ -opioid receptors, with > 6,000-fold selectivity for the μ –opioid receptor over non-opioid receptors, ligand-gated ion channels, enzymes, ion channels (including hERG), and transporters. It inhibits loperamide-induced reduction in gastric emptying and attenuation of castor oilinduced diarrhea following acute oral dosing to conscious rats.

### **3.5 Prucalopride, a prokinetic 5-HT 4 receptor agonist**

Prucalopride is a new, selective 5-HT 4 agonist with efficacy in relief of chronic constipation and safety from a cardiovascular perspective. In a phase 2, double-blind, placebo-controlled study 196 patients with OIC were randomized to receive placebo, prucalopride 2 or 4 mg for 4 weeks. The increase from baseline of ≥ 1 spontaneous complete bowel movements (SCBM) per week (weeks 1 – 4, primary end point) was greater in the prucalopride groups (35.9 % (2 mg) and 40.3% (4 mg) than placebo (23.4%), reaching statistical significance in week 1. Prucalopride, 4 mg, significantly improved patient-rated severity of constipation and effectiveness of treatment vs. placebo, and improved Patient Assessment of Constipation - Symptom (PAC-SYM) total scores and Patient Assessment of Constipation-Quality of Life (PAC-QOL) total and satisfaction subscale scores. The most common adverse events were abdominal pain and nausea.

### **Lubiprostone**

Lubiprostone is a chloride channel activator that induces intestinal secretion.

Lubiprostone, in vitro, stimulates chloride secretion that was suppressed by morphine. *In vivo*, instead, s.c. lubiprostone increased fecal wet weight and numbers of pellets expelled in guinea-pig and mouse (48) reduced by Morphine.

Injection of lubiprostone, 30 min after morphine, reversed morphine-induced suppression of fecal wet weight. The data suggest that lubiprostone, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium (48).

### **4. Conclusion**

The management of patients with OIC is an increasingly relevant problem with the extensive use of opioids for the relief of chronic pain, often associated with benign conditions. Several novel pharmacological approaches are being developed, including assessment of promotility and secreta- gogue agents that have efficacy in chronic idiopathic constipation. Other approaches are directed at the reversal of peripheral opiate effects in the gut while maintaining the desired analgesic efficacy. Several new approaches are promising, including tapentadol, combination of opioids with prolonged release naloxone, NKTR-118, and TD-1211. An evidence-based management approach for OIC will be more feasible after the new generation of drugs is formally and thoroughly studied in large, high-quality clinical trials.

### **5. References**


Injection of lubiprostone, 30 min after morphine, reversed morphine-induced suppression of fecal wet weight. The data suggest that lubiprostone, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium (48).

The management of patients with OIC is an increasingly relevant problem with the extensive use of opioids for the relief of chronic pain, often associated with benign conditions. Several novel pharmacological approaches are being developed, including assessment of promotility and secreta- gogue agents that have efficacy in chronic idiopathic constipation. Other approaches are directed at the reversal of peripheral opiate effects in the gut while maintaining the desired analgesic efficacy. Several new approaches are promising, including tapentadol, combination of opioids with prolonged release naloxone, NKTR-118, and TD-1211. An evidence-based management approach for OIC will be more feasible after the new generation

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### **Drugs in Development for Opioid-Induced Constipation**

Kelly S. Sprawls, Egilius L.H. Spierings and Dustin Tran *MedVadis Research Corporation USA* 

### **1. Introduction**

88 Constipation – Causes, Diagnosis and Treatment

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Opioids induce gastrointestinal side effects indirectly through an effect on the central nervous system and directly through an effect on the gastrointestinal tract. Related to the indirect effect, it has been shown that intrathecal administration of opioids decreases gastrointestinal motility and intestinal secretion (Anderson, 2007). The direct effect is mediated through mu-opioid receptors in the neuronal plexi, located between the longitudinal and circular muscle layers (myenteric plexus) and within the submucosa (submucosal plexus). Within the myenteric plexus, the opioids induce relaxation of the longitudinal smooth-muscle layer and increase tonicity in the circular smooth-muscle layer. These effects are thought to be mediated through inhibition of acetylcholine release and inhibition of vasoactive intestinal peptide and nitric oxide release, respectively. The result of this differential effect on the longitudinal and circular intestinal smooth muscles is an increase in segmental contraction and a decrease in peristaltic activity.

Normal peristalsis in the small bowel occurs every 90 minutes in order to move the luminal contents from the duodenum to the ileum. Mass movements in the large bowel occurs less often, one to three times per day, sweeping its contents over longer distances. As a result of the reduced peristalic activity, the transit time is significantly prolonged. The food stays in the stomach longer and the stool resides in the small and large bowel. The former causes gastric distension, resulting in nausea and gastric reflux, and the latter contributes to the constipation by allowing more time for fluid absorption, a predominant function of the large bowel in particular. A decrease in bowel-movement frequency is the primary symptom of constipation, with secondary symptoms being hard, dry stool, the need for straining with bowel movements, and a sense of incomplete evacuation. Tertiary symptoms are abdominal bloating/distension, discomfort, and pain from stool or gas, borborygmi, flatulence, and dyspnea from interference of the abdominal stool and gas content with diaphragmatic contraction aiding inspiration. Aside from these physiologic effects exuded by the opioid analgesics themselves, the lifestyle of patients in chronic pain typically intensifies their condition. Chronic pain patients are often inactive and deconditioned. They are more likely to be overweight, have a poor diet, and get little to no exercise, exacerbating their constipation.

### **2. Prevalence**

In 2010, it was estimated that approximately 250 million prescriptions were written for opioids in the United States (IMS Health 2010) and many studies indicate that a high percentage of patients receiving opioids experience gastrointestinal side effects. A systematic review was performed of 11 randomized, double-blind, placebo-controlled studies of oral opioids in the treatment of chronic non-cancer pain, given for periods ranging from 4 days to 8 weeks (Kalso et al., 2004). The opioids were morphine in five studies, morphine or methadone in one study, and oxycodone in four studies; all studies used inactive placebo except two in which benztropine was given as active placebo. Of the 1,025 subjects randomized, 674 subjects completed the study they were in and 698 subjects were evaluable. Adverse events and lack of efficacy were the most frequent reasons for discontinuation during both opioid and placebo treatment. The mean final daily doses of the oral opioids varied from 30 to 120 mg for morphine, 20 to 45 mg for oxycodone (30 to 68.5 mg morphine equivalents), and 15 mg for methadone (45 mg morphine equivalents).

Constipation was the most common adverse event in the opioid-treated subjects, reported by 41% of the subjects in comparison to 11% of those treated with placebo, followed by nausea (32% *versus* 12%). The actual occurrence of constipation with oral opioid treatment in the range of 30 to 120 mg morphine equivalents per day is probably higher. The enriched nature of the studies excluded subjects from randomization who did not tolerate the medication or who did not find it effective in relieving their pain. The subjects who were not randomized because of the latter reason would also have discontinued the medication in practice; however, the subjects who were not randomized because of tolerability reasons would possibly have continued the treatment if the adverse event was constipation and this was effectively treated.

### **3. Available treatments**

In 2008, the Food and Drug Administration approved a peripherally-acting mu-opioidreceptor antagonist (PAMORA), subcutaneous methylnaltrexone (Relistor®), for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care when response to traditional laxative therapy has been inadequate. Another peripherally-acting mu-opioid-receptor antagonist, alvimopan, was being studied as well but cardiovascular safety concerns, consisting of an increased risk of myocardial infarction, halted drug development. However, the Food and Drug Administration approved the medication in 2008 with a Risk Evaluation and Mitigation Strategy (REMS) for the indication of accelerating the time to upper and lower gastrointestinal recovery, following partial small- or large-bowel resection with primary anastomosis. The Risk

constipation, with secondary symptoms being hard, dry stool, the need for straining with bowel movements, and a sense of incomplete evacuation. Tertiary symptoms are abdominal bloating/distension, discomfort, and pain from stool or gas, borborygmi, flatulence, and dyspnea from interference of the abdominal stool and gas content with diaphragmatic contraction aiding inspiration. Aside from these physiologic effects exuded by the opioid analgesics themselves, the lifestyle of patients in chronic pain typically intensifies their condition. Chronic pain patients are often inactive and deconditioned. They are more likely to be overweight, have a poor diet, and get little to no exercise, exacerbating their constipation.

In 2010, it was estimated that approximately 250 million prescriptions were written for opioids in the United States (IMS Health 2010) and many studies indicate that a high percentage of patients receiving opioids experience gastrointestinal side effects. A systematic review was performed of 11 randomized, double-blind, placebo-controlled studies of oral opioids in the treatment of chronic non-cancer pain, given for periods ranging from 4 days to 8 weeks (Kalso et al., 2004). The opioids were morphine in five studies, morphine or methadone in one study, and oxycodone in four studies; all studies used inactive placebo except two in which benztropine was given as active placebo. Of the 1,025 subjects randomized, 674 subjects completed the study they were in and 698 subjects were evaluable. Adverse events and lack of efficacy were the most frequent reasons for discontinuation during both opioid and placebo treatment. The mean final daily doses of the oral opioids varied from 30 to 120 mg for morphine, 20 to 45 mg for oxycodone (30 to 68.5

mg morphine equivalents), and 15 mg for methadone (45 mg morphine equivalents).

Constipation was the most common adverse event in the opioid-treated subjects, reported by 41% of the subjects in comparison to 11% of those treated with placebo, followed by nausea (32% *versus* 12%). The actual occurrence of constipation with oral opioid treatment in the range of 30 to 120 mg morphine equivalents per day is probably higher. The enriched nature of the studies excluded subjects from randomization who did not tolerate the medication or who did not find it effective in relieving their pain. The subjects who were not randomized because of the latter reason would also have discontinued the medication in practice; however, the subjects who were not randomized because of tolerability reasons would possibly have continued the treatment if the adverse event was constipation and this was effectively treated.

In 2008, the Food and Drug Administration approved a peripherally-acting mu-opioidreceptor antagonist (PAMORA), subcutaneous methylnaltrexone (Relistor®), for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care when response to traditional laxative therapy has been inadequate. Another peripherally-acting mu-opioid-receptor antagonist, alvimopan, was being studied as well but cardiovascular safety concerns, consisting of an increased risk of myocardial infarction, halted drug development. However, the Food and Drug Administration approved the medication in 2008 with a Risk Evaluation and Mitigation Strategy (REMS) for the indication of accelerating the time to upper and lower gastrointestinal recovery, following partial small- or large-bowel resection with primary anastomosis. The Risk

**2. Prevalence** 

**3. Available treatments** 

Evaluation and Mitigation Strategy restricts the use of the medication to short-term (15 doses) treatment in hospitalized patients and only in hospitals that have registered with the program and have met all the requirements.

Lubiprostone and tegaserod are Food and Drug Administration approved for the treatment of chronic idiopathic constipation in adults and can, of course, be used off label for this condition as well. Lubiprostone is an activator of the CIC-2 chloride channel, increasing water secretion in the lumen of the gastrointestinal tract, and tegaserod is a non-selective serotonin-4-receptor agonist. However, in 2007, upon request from the Food and Drug Administration, alleging increased risk of cardiovascular and cerebrovascular events, Novartis withdrew tegaserod from the market. Prior to its withdrawal, tegaserod was being studied for opioid-induced constipation. A prokinetic medication could be used as well, although not approved by the Food and Drug Administration for (opioid-induced) constipation, such as cisapride, a non-selective serotonin-4-receptor agonist, domperidone, a peripherally-acting dopamine-receptor antagonist, or metoclopramide, a dopamine-2 receptor antagonist and mixed serotonin-3-receptor antagonist/serotonin-4-receptor agonist. However, cisapride was withdrawn from the market because of long QT syndrome predisposing to arrhythmias, domperidone is not on the market in the United States, and the long-term, daily use of metoclopramide is not recommended because of potential extrapyramidal side effects, particularly tardive dyskinesia. Misoprostol, a synthetic prostaglandin E1 analogue, approved by the Food and Drug Administration for the prevention of gastric ulcers caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs), also increases colonic transit and can be used off label as well.

Another strategy that is used to treat opioid-induced constipation is to switch to an opioid that, in general, causes less constipation as a side effect. From a constipation perspective and according to our experience, morphine, codeine, and hydrocodone tend to be worse and, for example, oxycodone and fentanyl better. Opioids that produce analgesia through other mechanisms, such as tramadol and tapentadol, which apart from being mu-opioid-receptor agonists also inhibit the presynaptic uptake of noradrenaline, tend to cause less constipation.

Over the counter constipation products in general can also be used for opioid-induced constipation, such as bulking agents (cellulose, psyllium), stool softeners (docusate), osmotic agents (lactulose, sorbitol, magnesium citrate, polyethylene glycol), and laxatives (senna, bisacodyl). Although traditional laxatives have proved efficacious at inducing bowel movments, they are a temporary, quick fix and frequently induce undesired side effects. For many patients a successful bowel movement requires a cumbersome combination of stool softeners, bowel stimulants, and osmotic agents. The unpredictable nature of stimulant laxatives are unappealing for patients as well. Aggressive laxative use does not come without the risk of serious side effects, including metabolic abnormalities, and the long term safety and relief of abdominal symptoms has yet to be revealed. One exception is Miralax (polyethylene glycol) which demonstrated sustained efficacy in long-term studies. Furthermore, traditional laxatives are not specifically approved by the Food and Drug Administration (FDA) for opioid-induced constipation.

### **4. Drug development**

Given the paucity of FDA-approved medications and the sub-optimal efficacy of over the counter options for the treatment of opioid-induced constipation, a new drug class, peripherally-acting mu-opioid receptor antagonists (PAMORAs), has evolved that directly targets the mechanism of opioid-induced constipation. The first two drugs to enter the market were subcutanous methylnaltrexone (Relistor®) in April 2008 and an oral formulation of alvimopan (Entereg®) in May 2008. However, both drugs were FDAapproved in a specific sub-population, palliative care patients and post-surgical patients, respectively. Thus, the treatment for the general population with opioid-induced constipation reamined limited. Since 2008, several pharmaceutical companies have developed peripherally-acting mu-opioid receptor antagonists that are now undergoing various phases of clinical studies with the specific indication of opioid-induced constipation in chronic pain patients.

Peripherally-acting mu opioid-receptor antagonists are an improvement to the traditional non-specific opioid-antagonists, naloxone and naltrexone. The novelty behind the new class resides with its restricted activity to the peripheral mu-opioid receptors in the enteric system and increased specificity to the mu-receptors versus the kappa- and delta-receptors. As a result, the constipating effects of opioids on gastrointestinal function and motility are inhibited without crossing the blood-brain barrier and reversing the central analgesic effects of opioids.

Amoung the drugs currently being developed, the oral formulation is the most popular. While subcutaneous methylnaltrexone (Relistor) has already been approved by the Food and Drug Administration, clinical studies with the oral formulation are underway. Other oral, peripherally-acting mu-opioid receptor antagonists in development for opioid-induced constipation are ADL5945 (Adolor), ALKS37 (Alkermes), NKTR-118 (AstraZeneca), S-297995 (Shionogi), and TD-1211 (Theravance). Lubiprostone, already FDA-approved for other types of constipation, is undergoing development for opioid-induced constipation as well. Medications that are in development for chronic constipation and may ultimately also be developed for opioid-induced constipation are the selective serotonin-4-receptor agonist, prucalopride (Johnson & Johnson), and the guanylate-cyclase C-receptor agonists, linaclotide (Ironwood) and plecanatide (Synergy).

### **4.1 Methylnaltrexone**

Methylnaltrexone is a quaternary derivative of naltrexone, synthesized by adding a methyl group to the nitrogen atom of the molecule. Quaternary opioid antagonists are constructed to have more polarity and, therefore, less lipid solubility than their parent compounds. The reduced ability to penetrate the blood-brain barrier allows the medications to block opioidinduced constipation peripherally, without antagonizing the centrally-mediated opioid analgesia or causing central opioid withdrawal.

Methylnaltrexone was initially tested in an intravenous formulation. A laxation response was seen in 11 subjects with methadone-induced constipation who were treated with methylnaltrexone IV, compared to no laxation response in the 11 subjects in the placebo group (P<0.001)2. Along with the 100% response rate in the methylnaltrexone recipients, no central opioid withdrawal was observed and no significant adverse events were reported. At the same time, the oral-cecal transit time was decreased by 77.7 minutes from baseline in the methylnaltrexone group, while only by 1.4 minutes in the placebo group (p<0.001). Subsequently, subcutaneous administration was studied, potentially enlarging the target population for this treatment.

peripherally-acting mu-opioid receptor antagonists (PAMORAs), has evolved that directly targets the mechanism of opioid-induced constipation. The first two drugs to enter the market were subcutanous methylnaltrexone (Relistor®) in April 2008 and an oral formulation of alvimopan (Entereg®) in May 2008. However, both drugs were FDAapproved in a specific sub-population, palliative care patients and post-surgical patients, respectively. Thus, the treatment for the general population with opioid-induced constipation reamined limited. Since 2008, several pharmaceutical companies have developed peripherally-acting mu-opioid receptor antagonists that are now undergoing various phases of clinical studies with the specific indication of opioid-induced constipation

Peripherally-acting mu opioid-receptor antagonists are an improvement to the traditional non-specific opioid-antagonists, naloxone and naltrexone. The novelty behind the new class resides with its restricted activity to the peripheral mu-opioid receptors in the enteric system and increased specificity to the mu-receptors versus the kappa- and delta-receptors. As a result, the constipating effects of opioids on gastrointestinal function and motility are inhibited without crossing the blood-brain barrier and reversing the central analgesic effects

Amoung the drugs currently being developed, the oral formulation is the most popular. While subcutaneous methylnaltrexone (Relistor) has already been approved by the Food and Drug Administration, clinical studies with the oral formulation are underway. Other oral, peripherally-acting mu-opioid receptor antagonists in development for opioid-induced constipation are ADL5945 (Adolor), ALKS37 (Alkermes), NKTR-118 (AstraZeneca), S-297995 (Shionogi), and TD-1211 (Theravance). Lubiprostone, already FDA-approved for other types of constipation, is undergoing development for opioid-induced constipation as well. Medications that are in development for chronic constipation and may ultimately also be developed for opioid-induced constipation are the selective serotonin-4-receptor agonist, prucalopride (Johnson & Johnson), and the guanylate-cyclase C-receptor agonists,

Methylnaltrexone is a quaternary derivative of naltrexone, synthesized by adding a methyl group to the nitrogen atom of the molecule. Quaternary opioid antagonists are constructed to have more polarity and, therefore, less lipid solubility than their parent compounds. The reduced ability to penetrate the blood-brain barrier allows the medications to block opioidinduced constipation peripherally, without antagonizing the centrally-mediated opioid

Methylnaltrexone was initially tested in an intravenous formulation. A laxation response was seen in 11 subjects with methadone-induced constipation who were treated with methylnaltrexone IV, compared to no laxation response in the 11 subjects in the placebo group (P<0.001)2. Along with the 100% response rate in the methylnaltrexone recipients, no central opioid withdrawal was observed and no significant adverse events were reported. At the same time, the oral-cecal transit time was decreased by 77.7 minutes from baseline in the methylnaltrexone group, while only by 1.4 minutes in the placebo group (p<0.001). Subsequently, subcutaneous administration was studied, potentially enlarging the target

in chronic pain patients.

**4.1 Methylnaltrexone** 

population for this treatment.

linaclotide (Ironwood) and plecanatide (Synergy).

analgesia or causing central opioid withdrawal.

of opioids.

In a double-blind, randomized, placebo-controlled study in healthy volunteers, oral-cecal transit time was significantly reduced after 0.3 mg/kg subcutaneous methylnaltrexone plus morphine, compared with placebo plus morphine (P<0.05) ((Yuan et al, 2002). As an intervention for opioid-induced constipation in advanced illness, 0.15 mg/kg subcutaneous methylnaltrexone caused a laxation response within 4 hours in 48% of 62 subjects in the methylnaltrexone group, compared to 15% of the 71 subjects in the placebo group (p<0.001). Fifty two percent of the subjects had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared to 8% in the placebo group (P<0.001) ((Thomas et al, 2008). The treatment did not affect centrally-mediated analgesia and did not precipitate opioid withdrawal. Abdominal pain and flatulence were the most common adverse events.

A similar study in opioid-induced constipation in advanced illness used a single subcutaneous injection of methylnaltrexone, 0.15 mg/kg or 0.3 mg/kg, or placebo (Slatkin et al, 2009). Sixty two percent and 58% of the subjects treated with methylnaltrexone 0.15 mg/kg and 0.3 mg/kg, respectively, had a laxation response within 4 hours, compared to 14% of the subjects in the placebo group (P<0.0001; each dose *versus* placebo). Adverse events were slightly more common in the subjects treated with 0.15 mg/kg than in those treated with 0.3 mg/kg, particularly abdominal pain, flatulence, nausea, and dizziness. Due to a comparable efficacy profile, the results suggest the lower dose, 0.15 mg/kg, to be most optimal.

Methylnaltrexone in a dose of 12 mg subcutaneous was given once daily or every other day for 28 days in a randomized, double-blind, placebo-controlled study, which involved a total of 469 subjects with opioid-induced constipation (Slatkin et al, 2009). Compared to placebo, the medication given once daily significantly improved rectal symptoms (P<0.05), stool symptoms (P<0.001), and global constipation scores (P<0.001), while given every other day significantly improved stool symptoms (P<0.05) and global constipation scores (P<0.05). The changes from baseline in abdominal symptoms and pain scores between the two methylnaltrexone groups and placebo were not significant.

Although the intravenous and subcutaneous formulations produced promising results, they are impractical for the general population. An intravenous administration can only be administered under the supervision of health care professionals, and while the subcutaneous injections are more safe and convenient, they either require selfadministration or frequent assistance. An oral formulation is the most favorable as a pill is generally more convenient and affordable. Fortunately, phase 3 studies have commenced, assessing the safety and efficacy of oral methylnaltrexone for opioid-induced constipation in chronic pain patients.

### **4.2 ADL5945**

ADL5945 is an oral peripherally-acting mu-opioid-receptor antagonist in development by Adolor with two randomized, double-blind, placebo-controlled studies recently completed in subjects with chronic non-cancer pain and opioid-induced constipation. In the first study, two doses of ADL5945 (0.10 mg and 0.25 mg) were given twice daily *versus* placebo to 130 subjects (43 per treatment arm) over 4 weeks. The second study was of similar design, with the exception that only one dose of ADL5945 (0.25 mg) was given and only once daily *versus*

placebo to 80 patients (40 per treatment arm). The primary endpoint in both studies was the change from baseline in the mean number of spontaneous bowel movements per week over the 4-week treatment period. The results demonstrated a statistically significant and clinically relevant effect of the 0.25 mg dose in particular, without tolerability issues and evidence of central opioid withdrawal or reversal of opioid analgesia. Adolor's backup compound for opioid-induced constipation is the peripherally-acting mu-opioid-receptor antagonist, ADL7745, which recently successfully completed preclinical studies.

### **4.3 ALKS37**

ALKS 37 (RDC-1036) is an oral peripherally-acting mu-opioid-receptor antagonist in development by Alkermes for the treatment of opioid-induced constipation, with a randomized, double-blind, placebo-controlled, multi-dose study recently completed (Alkermes website, 2011). The study treated opioid-induced constipation in subjects with chronic non-cancer pain with doses of 1 to 100 mg taken once daily. Subjects were eligible to participate in the study if they were taking opioid analgesics at doses of 30 mg or more morphine equivalents per day and had fewer than three spontaneous bowel movements per week.

The primary endpoint was a change from baseline in the average number of spontaneous bowel movements per week. A clear dose-response relationship was demonstrated with a statistically significant increase in the average number of spontaneous bowel movements per week in the subjects receiving 100 mg of the medication once daily, compared to those receiving placebo (4.5 *versus* 0.7) (p = 0.006). The results also demonstrated a statistically significant increase in the average number of complete spontaneous bowel movements per week, compared to subjects receiving placebo (3.5 *versus* 0.8) (p = 0.007). Overall, ALKS 37 was well tolerated and the most commonly reported adverse events were gastrointestinal in nature, including abdominal pain (25%) and diarrhea (22%), mostly occurring in the higher and most effective doses (30 mg and 100 mg). There was no indication of reversal of opioid analgesia, that is, there was no increase in average daily pain score or opioid use (Alkermes Press Release, 2011).

### **4.4 NKTR-118**

NKTR-118, also known as PEG-naloxol, is a combination of naloxol, a derivative of the opioid antagonist, naloxone, and a polyethylene glycol moiety. The purpose of the PEGylation is twofold, that is: 1. altering its metabolism, thereby reducing the first-pass effect and increasing its bioavailability, and 2. modifying its distribution to reduce penetration into the central nervous system. A randomized, double-blind, placebocontrolled, multiple-dose study was performed, evaluating the safety and efficacy of NKTR-118 in subjects with opioid-induced constipation (Webster, L., 2009). Eligible subjects were defined as having opioid-induced constipation with fewer than three spontaneous bowel movements per week and on a stable analgesic opioid regimen of 30 mg to 1000 mg morphine equivalents per day for a minimum of 2 weeks. A total of 208 subjects were randomized to NKTR-118 or placebo in three sequential cohorts. The first week they received a once daily dose of single-blind placebo, followed by 4 weeks of NKTR-118 once daily in doses of 5, 25, or 50 mg, or placebo.

The primary endpoint was achieved in both the 25-mg and 50-mg treatment groups, with a significant increase in the mean number of spontaneous bowel movements per week over the first week. Subjects receiving 25 mg NKTR-118 had an average of 5.0 spontaneous bowel movements during the first week (1.4 at baseline) *versus* 3.1 in the placebo group (1.2 at baseline)(p = 0.002). Subjects receiving 50 mg NKTR-118 had an average of 6.0 spontaneous bowel movements during the first week (1.6 at baseline) *versus* 3.3 in the placebo group (1.3 at baseline)(p = 0.0001). The increase in bowel movements was sustained at a statistically significant level throughout the 4 weeks in both dose groups (p = 0.002 and p<0.0001, respectively). The medication was well tolerated and adverse events were dose-dependent, occurring most frequently in the 50-mg group, and were primarily gastrointestinal in nature, particularly abdominal pain, cramps, diarrhea, and nausea. The majority of the adverse events were rated as mild or moderate in intensity. Reversal of opioid analgesia was not observed in the study, as measured by numerical pain rating and opioid requirement.

### **4.5 S-297995**

94 Constipation – Causes, Diagnosis and Treatment

placebo to 80 patients (40 per treatment arm). The primary endpoint in both studies was the change from baseline in the mean number of spontaneous bowel movements per week over the 4-week treatment period. The results demonstrated a statistically significant and clinically relevant effect of the 0.25 mg dose in particular, without tolerability issues and evidence of central opioid withdrawal or reversal of opioid analgesia. Adolor's backup compound for opioid-induced constipation is the peripherally-acting mu-opioid-receptor

ALKS 37 (RDC-1036) is an oral peripherally-acting mu-opioid-receptor antagonist in development by Alkermes for the treatment of opioid-induced constipation, with a randomized, double-blind, placebo-controlled, multi-dose study recently completed (Alkermes website, 2011). The study treated opioid-induced constipation in subjects with chronic non-cancer pain with doses of 1 to 100 mg taken once daily. Subjects were eligible to participate in the study if they were taking opioid analgesics at doses of 30 mg or more morphine equivalents per day and had fewer than three spontaneous bowel movements per

The primary endpoint was a change from baseline in the average number of spontaneous bowel movements per week. A clear dose-response relationship was demonstrated with a statistically significant increase in the average number of spontaneous bowel movements per week in the subjects receiving 100 mg of the medication once daily, compared to those receiving placebo (4.5 *versus* 0.7) (p = 0.006). The results also demonstrated a statistically significant increase in the average number of complete spontaneous bowel movements per week, compared to subjects receiving placebo (3.5 *versus* 0.8) (p = 0.007). Overall, ALKS 37 was well tolerated and the most commonly reported adverse events were gastrointestinal in nature, including abdominal pain (25%) and diarrhea (22%), mostly occurring in the higher and most effective doses (30 mg and 100 mg). There was no indication of reversal of opioid analgesia, that is, there was no increase in average daily pain score or opioid use (Alkermes

NKTR-118, also known as PEG-naloxol, is a combination of naloxol, a derivative of the opioid antagonist, naloxone, and a polyethylene glycol moiety. The purpose of the PEGylation is twofold, that is: 1. altering its metabolism, thereby reducing the first-pass effect and increasing its bioavailability, and 2. modifying its distribution to reduce penetration into the central nervous system. A randomized, double-blind, placebocontrolled, multiple-dose study was performed, evaluating the safety and efficacy of NKTR-118 in subjects with opioid-induced constipation (Webster, L., 2009). Eligible subjects were defined as having opioid-induced constipation with fewer than three spontaneous bowel movements per week and on a stable analgesic opioid regimen of 30 mg to 1000 mg morphine equivalents per day for a minimum of 2 weeks. A total of 208 subjects were randomized to NKTR-118 or placebo in three sequential cohorts. The first week they received a once daily dose of single-blind placebo, followed by 4 weeks of NKTR-118 once

antagonist, ADL7745, which recently successfully completed preclinical studies.

**4.3 ALKS37** 

week.

Press Release, 2011).

daily in doses of 5, 25, or 50 mg, or placebo.

**4.4 NKTR-118** 

Shionogi has developed an oral peripherally-acting mu-opioid-receptor antagonist, S-297995. Initially, it was designed to alleviate a spectrum of opioid-induced side effects (constipation, nausea, and vomiting) but the more recent studies have focused primarily on its effects on opioid-induced constipation. S-297995 may prove more favorable than existing treatments, given its efficacy at lower doses in alleviating not just opioid-induced constipation but also nausea and vomiting (Shionogi website, 2011).

In 2011, a randomized, double-blind, placebo-controlled, single-ascending dose study was completed to evaluate the safety and efficacy of S-297995 in opioid-induced constipation. Subjects were eligible to participate in the study if they had chronic pain requiring 90 mg or more morphine equivalents daily for a minimum of 3 months, opioid-induced constipation, and physical opioid dependence. Seventy five subjects were randomized to one of six S-297995 cohorts (0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 1.0 mg, or 3.0 mg). Preliminary results demonstrate a statistically significant and dose-dependent increase from baseline in the number of spontaneous bowel movements at 24 hours post-dose, starting at doses of 0.3 mg (p = 0.0011 in the 0.3-mg group and p<0.001 in both the 1.0-mg and 3.0-mg groups). The medication was generally well tolerated with predominantly mild or moderate gastrointestinal adverse events. There was no evidence of central opioid withdrawal and there was no impact on the analgesic effect of the opioids or a change in pupil size (Shionogi Annual Report, 2011).

### **4.6 TD-1211**

TD-1211 is a multivalent compound designed by Theravance to block the effects of opioids on the gastrointestinal mu-opioid receptors, without mitigating their central analgesic properties. In preclinical studies, the medication demonstrated oral bioavailability with no evidence of activity in the central nervous system. A randomized, double-blind, placebo-controlled, doseescalation study assessed the efficacy and safety of the medication in subjects with non-cancer pain and opioid-induced constipation (Theravance Press Release, 2011). The latter was defined as fewer than five spontaneous bowel movements during a 2-week baseline period and at least one additional symptom of constipation. A total of 70 subjects were randomized to receive oral 0.25, 0.75, 2.0, 5.0, and 10.0 mg doses of TD 1211 daily, or placebo.

The primary endpoint was the change from baseline in the average spontaneous bowel movements per week over the 2-week treatment period. Proof of efficacy was achieved in a dose-dependent fashion, specifically with the 5 and 10 mg doses. In the subjects who received the 5 mg dose, the mean number of spontaneous bowel movements increased by 3.2 (from 1.1 at baseline to 4.3 over the 2-week treatment period; confidence interval: 1.5-5.0). Similarly, in the subjects who received the 10 mg dose, the mean number of spontaneous bowel movements increased by 4.9 (from 1.4 at baseline to 6.3 over the 2-week treatment period; confidence interval: 3.1-6.7). However, in the placebo-treated group, the increase in the mean number of spontaneous bowel movements was not statistically significant (from 1.7 at baseline to 3.3 over the 2-week treatment period; confidence interval: 0.6-2.5).

Regarding the median time to first spontaneous bowel movement after the first dose of TD-1211, a dose-dependent reduction was observed in the subjects receiving the 5 and 10 mg doses, with the time reduced to 8.6 and 3.6 hours, respectively, *versus* 28.7 hours in the placebo group. Overall, TD-1211 was well tolerated with the majority of the gastrointestinal adverse events mild or moderate in intensity, occurring early in treatment and resolving within days. There was no evidence of central opioid withdrawal with the medication or reversal of opioid analgesia.

### **4.7 Lubiprostone**

Lubiprostone is an activator of the CIC-2 chloride channel, increasing water secretion in the lumen of the gastrointestinal tract, approved by the Food and Drug Administration for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome (IBS). It is in development for opioid-induced constipation and two randomized, doubleblind, placebo-controlled studies with this indication have been completed (Sucampo website, 2009). The two studies are identical phase 3 trials in which a total of 875 subjects with opioid-induced bowel dysfunction were randomized to 12-week treatment with lubiprostone, 24 mcg twice daily. The subjects were taking opioid medications for chronic non-cancer pain, including fentanyl, methadone, morphine, and oxycodone, for at least 30 days prior to screening and continued to take these medications for the duration of the study. During the 2-week baseline period before randomization, they were required to have fewer than three spontaneous bowel movements per week. The overall adverse-event rate for the combined studies was 54.9% for lubiprostone and 51.6% for placebo, with nausea being most common (15.0% *versus* 7.5%), followed by diarrhea (8.5% *versus* 3.7%).

The primary endpoint of the studies was the change from baseline in the frequency of spontaneous bowel movements at week 8 of treatment, which was met in one of the studies (OBD0631) but not in the other (OBD0632). The change from baseline in the frequency of spontaneous bowel movements in the first study was from 1.42 to 4.54 for lubiprostone and from 1.46 to 3.81 for placebo; in the second study, these changes were from 1.60 to 4.10 for lubiprostone and from 1.60 to 3.95 for placebo. An interesting post-hoc sub-analysis revealed that subjects taking methadone and randomized to lubiprostone experienced a lower increase in the frequency of spontaneous bowel movements than lubiprostone-treated subjects on other opioids. Methadone was subsequently found to interfere with the mode of action of lubiprostone at the level of the CIC-2 chloride channel. A third randomized, double-blind, placebo-controlled study with the exclusion of methadone users is currently being conducted.

### **5. Conclusion**

96 Constipation – Causes, Diagnosis and Treatment

The primary endpoint was the change from baseline in the average spontaneous bowel movements per week over the 2-week treatment period. Proof of efficacy was achieved in a dose-dependent fashion, specifically with the 5 and 10 mg doses. In the subjects who received the 5 mg dose, the mean number of spontaneous bowel movements increased by 3.2 (from 1.1 at baseline to 4.3 over the 2-week treatment period; confidence interval: 1.5-5.0). Similarly, in the subjects who received the 10 mg dose, the mean number of spontaneous bowel movements increased by 4.9 (from 1.4 at baseline to 6.3 over the 2-week treatment period; confidence interval: 3.1-6.7). However, in the placebo-treated group, the increase in the mean number of spontaneous bowel movements was not statistically significant (from

1.7 at baseline to 3.3 over the 2-week treatment period; confidence interval: 0.6-2.5).

reversal of opioid analgesia.

**4.7 Lubiprostone** 

being conducted.

Regarding the median time to first spontaneous bowel movement after the first dose of TD-1211, a dose-dependent reduction was observed in the subjects receiving the 5 and 10 mg doses, with the time reduced to 8.6 and 3.6 hours, respectively, *versus* 28.7 hours in the placebo group. Overall, TD-1211 was well tolerated with the majority of the gastrointestinal adverse events mild or moderate in intensity, occurring early in treatment and resolving within days. There was no evidence of central opioid withdrawal with the medication or

Lubiprostone is an activator of the CIC-2 chloride channel, increasing water secretion in the lumen of the gastrointestinal tract, approved by the Food and Drug Administration for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome (IBS). It is in development for opioid-induced constipation and two randomized, doubleblind, placebo-controlled studies with this indication have been completed (Sucampo website, 2009). The two studies are identical phase 3 trials in which a total of 875 subjects with opioid-induced bowel dysfunction were randomized to 12-week treatment with lubiprostone, 24 mcg twice daily. The subjects were taking opioid medications for chronic non-cancer pain, including fentanyl, methadone, morphine, and oxycodone, for at least 30 days prior to screening and continued to take these medications for the duration of the study. During the 2-week baseline period before randomization, they were required to have fewer than three spontaneous bowel movements per week. The overall adverse-event rate for the combined studies was 54.9% for lubiprostone and 51.6% for placebo, with nausea

being most common (15.0% *versus* 7.5%), followed by diarrhea (8.5% *versus* 3.7%).

The primary endpoint of the studies was the change from baseline in the frequency of spontaneous bowel movements at week 8 of treatment, which was met in one of the studies (OBD0631) but not in the other (OBD0632). The change from baseline in the frequency of spontaneous bowel movements in the first study was from 1.42 to 4.54 for lubiprostone and from 1.46 to 3.81 for placebo; in the second study, these changes were from 1.60 to 4.10 for lubiprostone and from 1.60 to 3.95 for placebo. An interesting post-hoc sub-analysis revealed that subjects taking methadone and randomized to lubiprostone experienced a lower increase in the frequency of spontaneous bowel movements than lubiprostone-treated subjects on other opioids. Methadone was subsequently found to interfere with the mode of action of lubiprostone at the level of the CIC-2 chloride channel. A third randomized, double-blind, placebo-controlled study with the exclusion of methadone users is currently Opioid-induced gastrointestinal dysfunction results predominantly from the effect of opioids on the mu-opioid receptors in the gastrointestinal tract. Constipation and nausea are its most common symptoms, probably occurring in at least half of the patients treated with oral opioids. The constipation in particular is not an uncommon reason for patients to discontinue the medication or to take it at a dose that is much lower than required for adequate pain relief. In addition, it can further decrease the quality of life in patients whose quality of life is generally already significantly impaired by chronic pain. With the exception of subcutaneous methylnaltrexone for a subset of patients, there are no medications on the market for the general population with opioid-induced constipation. Prospective treatments are in developement and will undoubtedly obtain marketing approval from the Food and Drug Administration within the next several years. With the emergence of these novel medications that specifically target the pathophysiology of OIC, there is hope for patients who suffer not only from chronic pain but the adverse effects of their opioid pain medication.

### **6. Acknowledgements**

I would like to thank Dr. Spierings for his support and guidance while writing this manuscript.

### **7. References**

Adolor Clinical Pipeline. n.d. *Website*. September 2011, Available from:


### **Constipation Treatment in Neurological Disorders**

Gallelli Luca, Pirritano Domenico, Palleria Caterina and De Sarro Giovambattista *School of Medicine, University of Catanzaro, Italy* 

### **1. Introduction**

98 Constipation – Causes, Diagnosis and Treatment

Kalso, E., Edwards, J. & Moore, R. (2004). Opioids in chronic non-cancer pain: systematic review of efficacy and safety. *Pain*, Vol. 112, No. 3, (December 2004), pp. 372-380.

Sucampo website. n.d. *Website*. July 2009, Available from: <http://investor.sucampo.com> Theravance Announces Positive Results from Phase 1 and Phase 2 Clinical Studies with TD-

Thomas, J., Karver, S. & Cooney, G. (2008). Methylnaltrexone for Opioid-Induced

Webster, L. (2009) NKTR-118 Significantly Reverses Opioid-Induced Constipation: *Poster, 20th AAPM Annual Clinical Meeting,* September 2011, Available from: <http://nektar.com/pdf/pipeline/NKTR-118/Nektar\_poster118AAPM.pdf> Yuan, C., Foss, J. & O'Conner, M. (2000). Methylnaltrexone for Reversal of Constipation Due

Yuan, C., Wei, G. & Foss, J. (2002). Effects of Subcutaneous Methylnaltrexone on Morphine-

Controlled Trial. JPET, Vol.300, No. 1, (January 2002), pp. 118-123.

Induced Constipation in Advanced Illness Patients. J. Support Oncol, Vol. 7, No. 1,

1211 in Development for Opioid-Induced Constipation. n.d. *Press Release*,

<http://files.shareholder.com/downloads/THERA/1186849209x0x411447/9eac04

Constipation in Advanced Illness. NEJM, Vol. 358, No. 22, (May 2008), pp. 2332-

to Chronic Methadone Use: A Randomized Controlled Trial. *JAMA*,Vol. 283, No.3,

Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-

Research and Development. n.d. *Shionogi website*, September 2011. Available from: <http://www.shionogi.co.jp/ir\_en/explanatory/pdf/e\_p110310.pdf> Shionogi Annual Report 2011. n.d. *Shionogi website*, September 2011. Available from: <http://www.shionogi.co.jp/ir\_en/report/pdf\_11/business11.pdf> Slatkin, N., Thomas, J. & Lipman, A. (2009). Methylnaltrexone for Treatment of Opioid-

(January 2009), pp. 39-46.

2343.

September 2011. Available from:

(January 2000), pp. 367-372.

a8-c982-4ef5-a92d-ff3520f44ccd/PUMA\_TD1211.pdf>

Bowel dysfunction is common in patients with neurological diseases. Its prevalence ranges from 30% to 60% in patients with cerebrovascular diseases and new-onset constipation occurs in 55% of patients after a stroke (Su et al., 2009; Harari et al., 2004; Robain et al., 2002; Bracci et al., 2007). In Multiple Sclerosis (MS) constipation is a frequent bowel symptom and it has been observed in up to 73% of patients (Crayton et al., 2004; Gulick et al., 2011; Wiesel et al., 2000). In Parkinson's disease (PD) constipation is one of the most frequent non-motor features, believed to occur in over 50% of patients (Wood et al., 2010; Pfeiffer et al., 2003; Wolters et al., 2009). Disorders of the anorectal sphincters consist of incontinence or difficulty in expelling faeces. Constipation is almost always associated with slowed bowel transit. It may be due to sphincter incoordination in relation to the detrusor mechanism or to detrusor weakness causing loss of propulsive force (Swash et al., 2001). Constipation may have a significant impact on quality of life and would restrict patient's social activities, increasing levels of anxiety and depression, so that symptoms' management is critically important (Ng et al., 2005). This review describes the possible pathogenesis of constipation in neurological disorders, pharmacological therapies available for constipation and management approaches that may increase the likelihood of satisfactory treatment outcomes.

### **2. Constipation in stroke**

Constipation is defined as two or fewer bowel movements per week, the need to manipulate the rectum digitally to facilitate defecation all or most of the time, and/or use of laxatives, enemas or suppositories more than once a week (Hinds et al., 1990). Medical complications after acute stroke are common, ranging from 28% to 96% (Hong et al., 2008). Bowel dysfunction are the most frequent gastrointestinal complaints with a negative impact on patients' quality of life, restricting their social activities (Bracci et al., 2007; Su et al., 2009). The prevalence of constipation after stroke varies from 30% to 60% (Harari et al., 2004). New-onset constipation is seen in 55% of patients within a month after first stroke, strongly relating to disability. Its development may predict a poor outcome at 12 weeks in patients with moderately severe stroke (Su et al., 2009).

New onset constipation occurs in 30% of hemiplegic patients and has no relationship with the hemispheric side or with the severity of stroke even if a trend of reduced risk of constipation is described in patients with ischemic event and less widespread lesion (Bracci et al., 2007). Risk factors for constipation among stroke patients include use of a number of different drugs, dehydration, older age and immobility (Bracci et al., 2007; Su et al., 2009; Kumar et al., 2010). For the elderly, acute hospitalization is at higher risk to develop constipation than in other age groups (Cardin et al., 2010). The highest risk of new-onset constipation occurs on one week after stroke, so that early intervention may prevent the development of bowel dysfunction (Su et al., 2009). Treatment with nitrates and antithrombotics represents an independent risk factor for developing chronic constipation. Nitrates may cause constipation due to the inhibitory role in gut motility secondary to the release of nitric oxide. Antithrombotic drugs, such as acetyl salicylic acid (ASA), indobufen and ticlopidine, have been reported to be associated with bowel dysfunction. ASA and NSAID are more frequently associated with constipation probably via inhibition of the propulsive activity by preventing the release of prostaglandins. Indobufen and ticlopidine are usually associated with diarrhea. No significant association has been described between new onset constipation and ACE inhibitors or anticoagulants (Bracci et al., 2007). Anticholinergic drugs, such as antipsychotics, tricyclic antidepressants or oxybutynin, significantly increase the risk of faecal incontinence in patients with stroke, decreasing gut motility and causing constipation with overflow incontinence (Kumar et al., 2010). The use of diuretics such as mannitol or furosemide is associated with new-onset constipation (Su et al., 2009).

Bed rest and immobility contribute to constipation onset. Hypovolemia, as a result of dysphagia and/or impaired thirst mechanisms, is another risk factor. Between 37% and 78% of patients with stroke develop dysphagia, with a restriction of oral intake of dietary fibre and a high risk of undernutrition and dehydration (Ullman et al., 1996; Kumar et al., 2010; Su et al., 2009).

It is well known that the central nervous system (CNS) takes part in the control of visceral functions and its damage can lead to gastrointestinal impairment (Bracci et al., 2007). Lesions affecting the pontine defecatory centre may disrupt the sequencing of sympatical and parasympathical components of defecation, and impair the coordination of the peristaltic wave and the relaxation of the pelvic floor and external sphincter (Ullman et al., 1996). Constipation could be a clinical manifestation of spinal cord stroke as a consequence of pelvic autonomic dysfunction (Sakakibara et al., 2008).

### **3. Constipation in MS**

Constipation may represent an early symptom of MS and large bowel impairment can precede the onset of MS by many years (Lawthom et al., 2003; Chellingsworth et al., 2003). Bowel dysfunctions are multifactorial and include neurological impairment, behavioural problems, inappropriate toilet facilities, side effects of drugs or coexistent disorders. A multidisciplinary approach is the best way to deal with this symptom. Bowel symptoms should be carefully treated because sometimes helping constipation can precipitate faecal incontinence. Certain patients would prefer to remain constipated if incontinence is thereby avoided (Wiesel et al., 2001). Gastrointestinal symptoms are common in patients with MS and are much more frequent than in the general population (Wiesel et al., 2001). The

New onset constipation occurs in 30% of hemiplegic patients and has no relationship with the hemispheric side or with the severity of stroke even if a trend of reduced risk of constipation is described in patients with ischemic event and less widespread lesion (Bracci et al., 2007). Risk factors for constipation among stroke patients include use of a number of different drugs, dehydration, older age and immobility (Bracci et al., 2007; Su et al., 2009; Kumar et al., 2010). For the elderly, acute hospitalization is at higher risk to develop constipation than in other age groups (Cardin et al., 2010). The highest risk of new-onset constipation occurs on one week after stroke, so that early intervention may prevent the development of bowel dysfunction (Su et al., 2009). Treatment with nitrates and antithrombotics represents an independent risk factor for developing chronic constipation. Nitrates may cause constipation due to the inhibitory role in gut motility secondary to the release of nitric oxide. Antithrombotic drugs, such as acetyl salicylic acid (ASA), indobufen and ticlopidine, have been reported to be associated with bowel dysfunction. ASA and NSAID are more frequently associated with constipation probably via inhibition of the propulsive activity by preventing the release of prostaglandins. Indobufen and ticlopidine are usually associated with diarrhea. No significant association has been described between new onset constipation and ACE inhibitors or anticoagulants (Bracci et al., 2007). Anticholinergic drugs, such as antipsychotics, tricyclic antidepressants or oxybutynin, significantly increase the risk of faecal incontinence in patients with stroke, decreasing gut motility and causing constipation with overflow incontinence (Kumar et al., 2010). The use of diuretics such as mannitol or furosemide is associated with new-onset constipation (Su et

Bed rest and immobility contribute to constipation onset. Hypovolemia, as a result of dysphagia and/or impaired thirst mechanisms, is another risk factor. Between 37% and 78% of patients with stroke develop dysphagia, with a restriction of oral intake of dietary fibre and a high risk of undernutrition and dehydration (Ullman et al., 1996; Kumar et al., 2010;

It is well known that the central nervous system (CNS) takes part in the control of visceral functions and its damage can lead to gastrointestinal impairment (Bracci et al., 2007). Lesions affecting the pontine defecatory centre may disrupt the sequencing of sympatical and parasympathical components of defecation, and impair the coordination of the peristaltic wave and the relaxation of the pelvic floor and external sphincter (Ullman et al., 1996). Constipation could be a clinical manifestation of spinal cord stroke as a consequence

Constipation may represent an early symptom of MS and large bowel impairment can precede the onset of MS by many years (Lawthom et al., 2003; Chellingsworth et al., 2003). Bowel dysfunctions are multifactorial and include neurological impairment, behavioural problems, inappropriate toilet facilities, side effects of drugs or coexistent disorders. A multidisciplinary approach is the best way to deal with this symptom. Bowel symptoms should be carefully treated because sometimes helping constipation can precipitate faecal incontinence. Certain patients would prefer to remain constipated if incontinence is thereby avoided (Wiesel et al., 2001). Gastrointestinal symptoms are common in patients with MS and are much more frequent than in the general population (Wiesel et al., 2001). The

of pelvic autonomic dysfunction (Sakakibara et al., 2008).

al., 2009).

Su et al., 2009).

**3. Constipation in MS** 

prevalence of constipation, alone or in association with faecal incontinence, ranges between 35% to 73%, depending on definitions and selection (Crayton et al., 2004; Gulick et al., 2011; Wiesel et al., 2000; Bakke et al., 1996). There is no difference between male and female patients regarding constipation frequency that presents a strong correlation with disability and disease duration (Hinds et al., 1990). Bladder and bowel dysfunctions have a significant role in psychosocial disability of MS patients, affecting quality of life (Wiesel et al., 2001).

Pathophysiology of constipation in MS is poorly understood. Central nervous system lesions, related to the disease process, may be responsible in some cases, affecting the extrinsic neurological control of gut and sphincter function. Autonomic nervous system impairment, specifically involving parasympathetic pathways, or some systemic mechanism not well known, similar to that which causes fatigue in MS, have been proposed (Fowler et al., 1997; De Seze et al., 2001; Guinet et al., 2011). Some authors have suggested a cerebral involvement or a motor spinal pathways failure as a cause of constipation in MS (Haldeman et al., 1982; Mathers et al., 1990). Abnormalities of colonic activity and prolonged colonic transit time have been demonstrated in some patients, and difficult defecation due to failure to relax the pelvic floor muscles has been found in others (Mark et al., 1999). Whether pelvic floor incoordination shown in some patients with MS should be regarded as a behavioural phenomenon, as in non-neurological constipation, or as related to the MS is yet unknown (Wiesel et al., 2000). Some authors associated large bowel dysfunction to demyelinating lesions of the conus medullaris, even if the role of more proximal lesions cannot be ruled out (Taylor et al., 1984). Other features connected to MS, compromising pelvic floor function and visceral motility, may contribute to constipation: muscle weakness, fatigue, spasticity and poor mobility. Also some medications, commonly used to manage different MS symptoms, such as anticholinergics, antidepressants, opiates and muscle relaxants, can affect bowel function (Wiesel et al., 2001; Fowler et al., 1997; Nordenbo et al., 1996; Gill et al., 1994). Finally, psychological factors or behavioural problems may also affect toileting (Wiesel et al., 2000).

### **4. Constipation in spinal cord injury**

Bowel dysfunction is one of the major sequelae of spinal cord injury (SCI), with a severe impact on long-term quality of life, also increasing anxiety and depression. The prevalence of constipation in subjects with SCI is 20-58% (Ng et al., 2005). It is well known that constipation in SCI is due to prolonged colonic transit time. In SCI the extrinsic neural control is lost with an altered sympathic function (Winge et al., 2003). There is a clear association between constipation and the presence of a higher level of injury, as demonstrated by a mouth-to-cecum transit time prolonged in quadriplegics rather than paraplegics (Rajendran et al., 1992). Patients with cauda equina lesions may have an atonic bowel and develop severe and chronic constipation (Winge et al., 2003).

The variation in constipation prevalence in patients with different levels of neurologic deficit are related to different factors, such as attenuated gastrocolonic reflex, weakness of abdominal and perineal musculature, anorectal dysfunction and body immobilization (Stark et al., 1999; Ng et al., 2005).

Treating constipation in SCI subjects can be demanding. The usual management is a combination of bulking agents and scheduled enemas. Bowel training is used to evacuate the colon at regular intervals and an adequate fiber and fluid intake maintains bowel movements in a soft and bulky form. Shortly after breakfast, a rectal suppository and digital stimulation of the anorectum are used to induce reflex evacuation. These treatments usually leads to a daily planned evacuation. When they fail, prokinetic agents, parasympathetic nerve stimulators or colostomy can be used (Stark et al., 1999). In selected patients, transanal irrigation improves bowel function, compared with conservative management (Christensen et al., 2006).

### **5. Constipation in Parkinson Diseases (PD)**

Bowel dysfunction is the most commonly observed non-motor feature of PD and it is a major factor in determining quality of life, progression of disability and nursing care (Hely et al., 2005). Some authors found constipation in 29% of patients (Edwards et al., 1991). However this symptom is under-recognised and under-treated but it has the potential to be more debilitating than motor features. The reason of this could be the patients' unawareness that these symptoms are linked to PD. Constipation is frequently reported as a prominent complaint before the onset of motor symptoms in about 50% of patients (Wood et al., 2010). Recently, an epidemiological study revealed an association between frequency of bowel movements and the risk of developing PD. Those patients with an initial finding of constipation were at a 3-fold increased risk of developing PD after 10 years from the initial report of constipation (Abbott et al., 2001). Bowel dysfunction can occur across all stages of PD but often occurs earlier during disease course and it might precede motor symptoms onset by more than a decade, correlating closely with the progression of Lewy pathology (Korczyn et al., 1990; Chaudhuri et al., 2009).

Bowel dysfunction can consist of both slowed colonic transit with consequent reduced bowel-movement frequency and difficulty with the act of defecation itself with excessive straining and incomplete emptying (anorectal dysfunction). Anorectal dysfunction is the more prevalent form of bowel impairment in PD Recognition can lead to earlier and potentially more effective therapeutic intervention (Pfeiffer et al., 2003).

An efficient and successful defecation requires the coordinated contraction and relaxation of several muscles. Defecography, anorectal manometry and analsphincter electromyography have been used to study defecation in PD, showing different abnormalities (Stocchi 2000). In a group of patients, anorectal dysfunction caused a paradoxical contraction of voluntary sphincters during defecation, which is believed to be a type of focal dystonia (Mathers et al., 1989).

Control of gastrointestinal function is complex and involves components of the central, autonomic, and enteric nervous systems (Pfeiffer et al., 2003). Changes in parasympathetic autonomic supply to the gut could certainly account for the impairment of gastrointestinal function in PD but abnormalities in the enteric nervous system within the gut itself have also been identified, including both Lewy-body formation and loss of dopaminergic neurons (Pfeiffer et al., 2003).

Lewy body pathology in the myenteric plexus, leading to colonic sympathetic denervation, has long been recognized in patients with PD. Such pathologic changes are associated with prolonged intestinal transit time and constipation, symptoms believed to occur in ~80% of patients with PD (Jost et al., 1997). Recently, Politis et al. have suggested a dopaminergic

the colon at regular intervals and an adequate fiber and fluid intake maintains bowel movements in a soft and bulky form. Shortly after breakfast, a rectal suppository and digital stimulation of the anorectum are used to induce reflex evacuation. These treatments usually leads to a daily planned evacuation. When they fail, prokinetic agents, parasympathetic nerve stimulators or colostomy can be used (Stark et al., 1999). In selected patients, transanal irrigation improves bowel function, compared with conservative management (Christensen

Bowel dysfunction is the most commonly observed non-motor feature of PD and it is a major factor in determining quality of life, progression of disability and nursing care (Hely et al., 2005). Some authors found constipation in 29% of patients (Edwards et al., 1991). However this symptom is under-recognised and under-treated but it has the potential to be more debilitating than motor features. The reason of this could be the patients' unawareness that these symptoms are linked to PD. Constipation is frequently reported as a prominent complaint before the onset of motor symptoms in about 50% of patients (Wood et al., 2010). Recently, an epidemiological study revealed an association between frequency of bowel movements and the risk of developing PD. Those patients with an initial finding of constipation were at a 3-fold increased risk of developing PD after 10 years from the initial report of constipation (Abbott et al., 2001). Bowel dysfunction can occur across all stages of PD but often occurs earlier during disease course and it might precede motor symptoms onset by more than a decade, correlating closely with the progression of Lewy pathology

Bowel dysfunction can consist of both slowed colonic transit with consequent reduced bowel-movement frequency and difficulty with the act of defecation itself with excessive straining and incomplete emptying (anorectal dysfunction). Anorectal dysfunction is the more prevalent form of bowel impairment in PD Recognition can lead to earlier and

An efficient and successful defecation requires the coordinated contraction and relaxation of several muscles. Defecography, anorectal manometry and analsphincter electromyography have been used to study defecation in PD, showing different abnormalities (Stocchi 2000). In a group of patients, anorectal dysfunction caused a paradoxical contraction of voluntary sphincters during defecation, which is believed to be a type of focal dystonia (Mathers et al.,

Control of gastrointestinal function is complex and involves components of the central, autonomic, and enteric nervous systems (Pfeiffer et al., 2003). Changes in parasympathetic autonomic supply to the gut could certainly account for the impairment of gastrointestinal function in PD but abnormalities in the enteric nervous system within the gut itself have also been identified, including both Lewy-body formation and loss of dopaminergic neurons

Lewy body pathology in the myenteric plexus, leading to colonic sympathetic denervation, has long been recognized in patients with PD. Such pathologic changes are associated with prolonged intestinal transit time and constipation, symptoms believed to occur in ~80% of patients with PD (Jost et al., 1997). Recently, Politis et al. have suggested a dopaminergic

potentially more effective therapeutic intervention (Pfeiffer et al., 2003).

et al., 2006).

1989).

(Pfeiffer et al., 2003).

**5. Constipation in Parkinson Diseases (PD)** 

(Korczyn et al., 1990; Chaudhuri et al., 2009).

contribution to several non-motor symptoms of PD, including autonomic dysfunction and constipation (Politis et al., 2008).

Apomorphine treatment can improve anorectal dysfunction in PD and suggests that abnormalities of defaecation and anorectal function could be a consequence of dopamine deficiency secondary to the pathological changes of PD (Chaudhuri et al., 2009).

Medications used to treat the motor symptoms of PD (levodopa, anticholinergics) have even been implicated in further slowing of gastrointestinal motility and exacerbation of gastrointestinal dysfunction (Wood et al., 2010).

### **6. Assessment of constipation**

A carefully taken history, including ongoing drugs and physical examination may be adequate in most cases. To perform more specific tests depend on single cases. It is possible to evaluate different aspects of bowel dysfunction. Measurement of whole gut transit time, swallowing a radio-opaque contrast medium, is the most widely used, non-invasive and inexpensive method to quantify large bowel function (Gill et al., 1994; Prokesch et al., 1999; Nicoletti et al., 1992; Evans et al., 1992). Anorectal function and pelvic floor incoordination can be assessed by anorectal testing, anorectal manometry and a balloon expulsion test. For instance, in this way it has been possible to demonstrate pelvic floor incoordination in MS patients (Diamant et al., 1999; et al., Weber 1987; Jameson et al., 1994; Chia et al., 1996). To evaluate distal colon innervation, electrical rectal sensory testing is a useful tool. It can distinguish between constipation connected to impaired central innervation of the gut or idiopathic form (Kamm et al., 1990).

### **7. Pharmacological therapies**

Several drugs are available for patients with chronic constipation, ranging from older overthe-counter laxatives to more recently developed prescription drugs (Lembo 2003; Longstreth 2006; Ramkumar et al., 2005; Rao et al., 2009; Tack et al., 2009; Tramonte et al., 1997). Laxatives stimulate defecation by decreasing stool consistency and/or by stimulating colon motility. There are different classes of laxative drugs with different mechanism of action: osmotic laxatives and stimulant laxatives, bulking agents, stool softeners (Ramkumar et al., 2005; Tramonte et al., 1997).

### **8. Fibers**

Fibers intake such as eating high-fiber foods (fruits, vegetables) or taking fiber/bulk supplements (bran, psyllium, methylcellulose or polycarbophil) is recommended during the initial treatment of constipation (Lembo et al., 2003; Locke et al., 2000). Unfortunately a long treatment (about 2-3 months) is required to obtain symptom relief. Despite the widespread use of fiber supplementation, this approach is effective in only a subset of patients and clinical trial supporting the use of increased fiber intake is limited.

### **9. Osmotic laxatives**

Osmotic laxatives (poorly absorbed/non-absorbed sugars, saline laxatives and polyethylene glycol [PEG]) cause intestinal water secretion and may be recommended when fiber therapy is ineffective (Lembo et al., 2003). Many osmotic laxatives require few days to be effective and can result in electrolyte and volume overload in patients with renal or cardiac failure (Lembo et al., 2003). Osmotic laxatives can induce abdominal cramping, bloating and flatulence.

Osmotic agents are ions or molecules that are poorly absorbed by intestine and therefore they cause water retention in the intestinal lumen. Small intestine and colon are not able to keep an osmotic gradient between luminal contents and plasma, in contrast to stomach. Osmotic agents include: incompletely absorbed salts such as magnesium, sulphate and phosphate salts; sugar alcohols such as sorbitol or mannitol; poorly absorbed disaccharides such as lactulose and polyethylene glycol (PEG).

These agents keep water in intestinal lumen, increasing stool frequency, softening their consistency and decreasing straining. Non-absorbable sugars induce little improvement in stool frequency and consistency, but they cause colonic fermentation and consequently bloating and abdominal distention. Sodium sulphate reduces water absorption, stimulating peristalsis.

Bisodic phosphate is partially absorbed into the small bowel and it is well tolerated even if hyperphosphatemia can be observed as a consequence of overdose.

Magnesium hydroxide and magnesium salts improve stool frequency and consistency. Their systemic absorption is limited and the most common side effects are electrolyte abnormalities (i.e. hypokalemia and sodium overload) and diarrhea. In this light, magnesium should be used with great care in patients with hearth or/and renal failure and in the elderly (Golzarian et al., 1994; Schiller et al., 2001; Spinzi et al., 2007).

Lactulose is a complex sugar that is not digested and metabolized by bowel bacteria to form lactic, acetic and formic acids. In this way, it causes acidification of intestinal lumen, water secretion, production of H2 and CO2, and colon distension. Lactulose is very effective but induces flatulence and borborygmuses; moreover, its use should be avoided in patients with lactose intolerance.

In a systematic review of controlled trials, PEG was more effective than lactulose (Lee-Robichaud et al., 2010). PEG preparations are available with or without electrolyte supplements, and at different doses.

Macrogol 3350 is a mixture of non-absorbable polymers with high molecular weight. It is not metabolized by bowel bacteria and it works as a pure osmotic agent by keeping water into colon, causing rehydration and softer stool. The amount of water and electrolytes carried by macromolecular structure of macrogol is related to dose. The presence of electrolytes reduces risk of electrolyte imbalance, increasing safety in patients with kidney diseases (Migeon-Duballet et al., 2006). Moreover, macrogol causes less flatulence compared to lactulose, and it is useful for treating chronic constipation and drug-induced constipation (Di Palma et al., 2007; Zangaglia et al., 2007). Preparations containing electrolytes can also be used with high water volumes intake, such as for colon cleansing prior to colonoscopy or surgery (Di Palma et al., 2002; Szojda et al., 2007).

Glycerine is a well tolerated laxative, available just for rectal use. It works mainly by osmotic mechanism and stimulates evacuation lubricating stool.

is ineffective (Lembo et al., 2003). Many osmotic laxatives require few days to be effective and can result in electrolyte and volume overload in patients with renal or cardiac failure (Lembo et al., 2003). Osmotic laxatives can induce abdominal cramping, bloating and

Osmotic agents are ions or molecules that are poorly absorbed by intestine and therefore they cause water retention in the intestinal lumen. Small intestine and colon are not able to keep an osmotic gradient between luminal contents and plasma, in contrast to stomach. Osmotic agents include: incompletely absorbed salts such as magnesium, sulphate and phosphate salts; sugar alcohols such as sorbitol or mannitol; poorly absorbed disaccharides

These agents keep water in intestinal lumen, increasing stool frequency, softening their consistency and decreasing straining. Non-absorbable sugars induce little improvement in stool frequency and consistency, but they cause colonic fermentation and consequently bloating and abdominal distention. Sodium sulphate reduces water absorption, stimulating

Bisodic phosphate is partially absorbed into the small bowel and it is well tolerated even if

Magnesium hydroxide and magnesium salts improve stool frequency and consistency. Their systemic absorption is limited and the most common side effects are electrolyte abnormalities (i.e. hypokalemia and sodium overload) and diarrhea. In this light, magnesium should be used with great care in patients with hearth or/and renal failure and

Lactulose is a complex sugar that is not digested and metabolized by bowel bacteria to form lactic, acetic and formic acids. In this way, it causes acidification of intestinal lumen, water secretion, production of H2 and CO2, and colon distension. Lactulose is very effective but induces flatulence and borborygmuses; moreover, its use should be avoided in patients with

In a systematic review of controlled trials, PEG was more effective than lactulose (Lee-Robichaud et al., 2010). PEG preparations are available with or without electrolyte

Macrogol 3350 is a mixture of non-absorbable polymers with high molecular weight. It is not metabolized by bowel bacteria and it works as a pure osmotic agent by keeping water into colon, causing rehydration and softer stool. The amount of water and electrolytes carried by macromolecular structure of macrogol is related to dose. The presence of electrolytes reduces risk of electrolyte imbalance, increasing safety in patients with kidney diseases (Migeon-Duballet et al., 2006). Moreover, macrogol causes less flatulence compared to lactulose, and it is useful for treating chronic constipation and drug-induced constipation (Di Palma et al., 2007; Zangaglia et al., 2007). Preparations containing electrolytes can also be used with high water volumes intake, such as for colon cleansing prior to colonoscopy or

Glycerine is a well tolerated laxative, available just for rectal use. It works mainly by osmotic

hyperphosphatemia can be observed as a consequence of overdose.

in the elderly (Golzarian et al., 1994; Schiller et al., 2001; Spinzi et al., 2007).

flatulence.

peristalsis.

lactose intolerance.

supplements, and at different doses.

surgery (Di Palma et al., 2002; Szojda et al., 2007).

mechanism and stimulates evacuation lubricating stool.

such as lactulose and polyethylene glycol (PEG).


Table 1. Classification of laxative drugs

Stimulant laxatives (diphenylmethane and anthraquinone derivatives) produce rhythmic bowel contractions and should be recommended when osmotic laxatives fail (Borum et al., 2001). These agents increase intestinal motility and secretion after few hours from ingestion, but they may cause severe side effects (e.g. abdominal cramps, rebound constipation, damage to intestinal smooth muscles or enteric nervous system, colorectal cancer risk, hyponatremia, hypokalemia, dehydration. (Borum et al., 2001; Lembo et al., 2003; Muller-Lissner et al., 2005).

Several drugs and herbal preparations induce defecation by different mechanisms and are called 'stimulant' laxatives because they are able to stimulate bowel motility (Geboes et al., 1993). It is now clear that they have effect on mucosal transport as well as motility (Schiller et al., 1997).

These agents include: surface active agents, such as docusate and bile acids; diphenylmethane derivatives, such as phenolphthalein and bisacodyl; ricinoleic acid; anthraquinones, such as senna and cascara. Senna and bisacodyl cause rhythmic contractions of intestinal muscles, increasing bowel motility; moreover they increase water secretion into bowel. Bisacodyl is hydrolyzed in both small intestine and colon into a freeform that inhibits water absorption, but it also has an effect on enteric nervous system, inducing peristaltic response. Therefore, it should be avoided in patients with suspected intestinal obstruction. It is not clear whether these laxatives can induce damage to myenteric plexus, whereas it is known that their chronic use is associated with colonic melanosis that is reversible with drug withdrawal (about 5-6 months).

Bisacodyl and picosulfate are both phenylmethane prodrugs, hydrolysed by colonic bacteria or brush border enzymes to their active metabolite bis-(p-hydroxyphenyl)- pyridyl-2 methane (BHPM) which stimulates peristalsis.

The cathartic activity of bisacodyl and sodium picosulphate may depend on their conversion to compounds with free diphenolic groups (Sund et al., 1981).

Phenolphthalein inhibits water absorption in small intestine and colon by effecting prostaglandins, kinins and the Na+K+-ATPase pump. Phenolphthalein is absorbed and can be undergone to an enterohepatic circulation which may prolong its effect. It has been withdrawn from sale in the United States because some studies in rodents suggested it may be carcinogenic (Garner et al., 2000; Josefson et al., 1997). Adverse reactions of derivatives of diphenylmethane are cramping and abdominal pain; high doses induce severe diarrhea, electrolyte depletion, damage to enterocytes, skin allergies and Stevens-Johnson syndrome (phenolphthalein).

Docusates are ionic detergents which were designed to allow water to interact more effectively with stool solids, thereby softening stools. Bile acids are natural detergents that have been used as components of proprietary laxative preparations. If exogenous bile acid is taken orally, normal ileal absorptive capacity may be enormous and sufficient bile acid may get to the colon to reduce water and electrolyte absorption or to stimulate water secretion.

Anthraquinones are a group of chemicals based on tricyclic anthracene nucleus. They are produced by different plants. Monoanthrones can form dianthrones and can be conjugated with sugars to yield glycosides. They are pro-drugs, not absorbed in small intestine and hydrolyzed by colon bacteria to active forms. The effects on water secretion with increased fecal water may appear about 6-8 hours after administration. These compounds are indicated to treat chronic constipation. Adverse drug reactions include allergies, loss of body fluid and electrolytes, reversible melanosis.

The laxative action of Castor oil is due to an irritant action on tenuous intestine by rinoleic acid released by hydrolysis of triglycerides by pancreatic lipase. It has several action mechanisms:


Castor oil is used to preparation bowel for diagnostic or surgical procedures. Adverse reactions include abdominal-cramps and intestinal wall damage (e.g. erosion of the mucosa and epithelial desquamation).

### **10. Stool softeners**

Laxatives which mostly soften or lubricate stools (e.g. sodium dioctyl sulfosuccinate and liquid paraffin) seem to be more effective than placebo to increase bowel movement frequency. Liquid paraffin, since it may interfere with absorption of fat-soluble vitamins, should be avoided in patients with oropharyngeal dysphagia (Gondouin et al., 1996).

### **11. Bulk lassatives**

106 Constipation – Causes, Diagnosis and Treatment

plexus, whereas it is known that their chronic use is associated with colonic melanosis that is

Bisacodyl and picosulfate are both phenylmethane prodrugs, hydrolysed by colonic bacteria or brush border enzymes to their active metabolite bis-(p-hydroxyphenyl)- pyridyl-2-

The cathartic activity of bisacodyl and sodium picosulphate may depend on their

Phenolphthalein inhibits water absorption in small intestine and colon by effecting prostaglandins, kinins and the Na+K+-ATPase pump. Phenolphthalein is absorbed and can be undergone to an enterohepatic circulation which may prolong its effect. It has been withdrawn from sale in the United States because some studies in rodents suggested it may be carcinogenic (Garner et al., 2000; Josefson et al., 1997). Adverse reactions of derivatives of diphenylmethane are cramping and abdominal pain; high doses induce severe diarrhea, electrolyte depletion, damage to enterocytes, skin allergies and Stevens-Johnson syndrome

Docusates are ionic detergents which were designed to allow water to interact more effectively with stool solids, thereby softening stools. Bile acids are natural detergents that have been used as components of proprietary laxative preparations. If exogenous bile acid is taken orally, normal ileal absorptive capacity may be enormous and sufficient bile acid may get to the colon to reduce water and electrolyte absorption or to stimulate water secretion. Anthraquinones are a group of chemicals based on tricyclic anthracene nucleus. They are produced by different plants. Monoanthrones can form dianthrones and can be conjugated with sugars to yield glycosides. They are pro-drugs, not absorbed in small intestine and hydrolyzed by colon bacteria to active forms. The effects on water secretion with increased fecal water may appear about 6-8 hours after administration. These compounds are indicated to treat chronic constipation. Adverse drug reactions include allergies, loss of

The laxative action of Castor oil is due to an irritant action on tenuous intestine by rinoleic acid released by hydrolysis of triglycerides by pancreatic lipase. It has several action mechanisms:

Castor oil is used to preparation bowel for diagnostic or surgical procedures. Adverse reactions include abdominal-cramps and intestinal wall damage (e.g. erosion of the mucosa

Laxatives which mostly soften or lubricate stools (e.g. sodium dioctyl sulfosuccinate and liquid paraffin) seem to be more effective than placebo to increase bowel movement frequency. Liquid paraffin, since it may interfere with absorption of fat-soluble vitamins, should be avoided in patients with oropharyngeal dysphagia (Gondouin et al., 1996).

conversion to compounds with free diphenolic groups (Sund et al., 1981).

reversible with drug withdrawal (about 5-6 months).

methane (BHPM) which stimulates peristalsis.

body fluid and electrolytes, reversible melanosis.


and epithelial desquamation).

**10. Stool softeners** 



(phenolphthalein).

Undigestible fibres attract water, causing larger and softer fecal mass, increasing bowel movements by 1.4 per week (Ramkumar et al., 2005; Tramonte et al., 1997). Fibres are usually well tolerated, although some symptoms, such as bloating, may get worse.

### **12. Neuromuscular agents**

Some patients with colonic inertia seem to have a reduction in cholinergic nerve activity. This could be due to a damage to the enteric nervous system or to agents with anticholinergic effects. In such instances it would be useful to increase cholinergic stimulation of colonic smooth muscle by supplying a cholinergic agonist agent. Bethanechol can be used for this purpose with good results in some patients. Neostigmine has recently been suggested as effective therapy for acute colonic pseudo-obstruction.

### **13. 5-HT4 receptor agonists**

Serotonin (5-HT) is a regulator of gastrointestinal motility, secretion and sensitivity. Through 5-HT4 receptors, mainly expressed in enteric neurons, 5-HT triggers and coordinates intestinal peristalsis (Gershon et al., 2007). Cisapride, a 5-HT4 receptor agonist, is used to stimulate gastrointestinal motility in patients with gastro-esophageal reflux disease, functional dyspepsia and gastroparesis; in 2000, it was withdrawn from sale because of the occurrence of fatal arrhythmia's through QT interval prolongation in patients with predisposing conditions (Tonini et al., 1999).

Tegaserod, a 5-HT4 receptor agonist is shown to be effective for treatment of irritable bowel syndrome with constipation (Al-Judaibi et al., 2010). In 2007, Tegaserod was withdrawn from the commerce because of increased risk of cardiovascular adverse events such as myocardial infarction, unstable angina and stroke ( De Maeyer et al., 2008).

Prucalopride, a 5-HT4 receptor agonist, is a highly selective compound. It enhances colonic transit in healthy control subjects and in patients with chronic constipation, in a dosedependent way (Bouras et al., 1999; Bouras et al., 2001; Camilleri et al., 2008; De Maeyer et al., 2008). It has been approved in Europe for the treatment of chronic constipation in women who do not respond to laxatives (2 mg). Recommended dose in elderly patients is 1 mg for a larger bio-availability (Müller-Lissner et al., 2010).

The misoprostol affects intestinal transit in healthy subjects and in patients with chronic constipation by stimulating water secretion and intestinal muscle contraction, especially in the left colon. Initial dosage should be 200 mcg twice/day, increased to 4/day, being sure it does not appear abdominal cramps.

### **14. Colonic secretagogues**

Lubiprostone, the last drug approved by FDA for treatment of adult patients with chronic idiopathic constipation (Bethesda et al., 2006), is a gastrointestinal system-targeted bicyclic functional fatty acid that acts as a selective chloride channel (ClC-2) activator in the apical membrane of gastrointestinal epithelium to increase intestinal water secretion (Orr et al., 2006; Winpenney et al., 2005). This enhanced secretion of chloride leads to an increased intraluminal fluid amount, which facilitates transit in the intestine and thereby stool passage (Camilleri et al., 2006).

Lubiprostone, approved by FDA in 2006, is not yet approved in Europe (Drossman et al., 2009). Nausea, diarrhea and headache represent the most common adverse events, but patients also reported abdominal distension, abdominal pain and flatulence. Nausea can be reduced taking lubiprostone with food (Bethesda et al., 2006).

Linaclotide is a 14-amino acid peptide analog of guanylin and acts as an agonist at the luminal guanylin receptor on enterocytes, the guanylate cyclase-C receptor, which induces intestinal chloride and fluid secretion through cyclic GMP production (Bharucha et al., 2010). It is not yet approved for treatment of chronic constipation (Kurtz et al., 2006).

The mixed 5-HT4 receptor agonist/5-HT3 receptor antagonist renzapride relieves symptoms of constipation by softening stool consistency and increasing colonic transit. It has been tested only in patients with irritable bowel syndrome and constipation (Camilleri et al., 2004). Other 5-HT4 agonists, such as norcisapride and mosapride (Cremonini et al., 2005), neurotrophic factors (Coulie et al., 2000) and probiotic agents (Koebnick et al., 2003; Ouwehand et al., 2002) are also under investigations. Additional works are needed to determine their role in the treatment of chronic constipation.

**Neurotrophins** stimulate the development, growth and function of the nervous system, and increase colonic transit when administered subcutaneously in healthy subjects and patients with chronic constipation (Coulie et al., 2000).

**Colchicine**, usually used in the treatment of acute gout, induces diarrhea through an unknown dose-dependent mechanism. Colchicine increases stool frequency and reduces number of rescue laxatives needed. In a controlled trial, colchicine (1 mg/day) improved constipation in patients with slow transit (Taghavi et al., 2010).

### **15. Opiate antagonists**

Opiate antagonists have also been suggested to treat constipation. These agents block opiate receptors in intestine avoiding mucosal absorption and inhibition of intestinal transit, caused by opiate. Thus mucosal absorption should be reduced and intestinal transit should be increase by the administration of drugs like naloxone and naltrexone. An early report suggested a role for this type of agent in idiopathic constipation, but a successive report denied it (Ragavan et al., 1983; Fotherby et al., 1987).

Opiate antagonists are useful in patients with opiate-induced constipation (Meissner et al., 2000; Yuan et al., 2000). The opiate antagonists methylnaltrexone and alvimopan are under investigation for the treatment of opiate-induced constipation and postoperative ileus, but unlike other opiate antagonists, they do not have any impact on central analgesia (Camilleri et al., 2005; Yuan et al., 2004). Their usefulness in treating non-opioid-induced constipation remains unclear.

### **16. Management of constipation in neurological disorders**

Managing bowel function is a main concern in neurological patients, having an impact equal to mobility impairment on quality of life (Norton et al., 2010). It is important to get

intraluminal fluid amount, which facilitates transit in the intestine and thereby stool passage

Lubiprostone, approved by FDA in 2006, is not yet approved in Europe (Drossman et al., 2009). Nausea, diarrhea and headache represent the most common adverse events, but patients also reported abdominal distension, abdominal pain and flatulence. Nausea can be

Linaclotide is a 14-amino acid peptide analog of guanylin and acts as an agonist at the luminal guanylin receptor on enterocytes, the guanylate cyclase-C receptor, which induces intestinal chloride and fluid secretion through cyclic GMP production (Bharucha et al.,

The mixed 5-HT4 receptor agonist/5-HT3 receptor antagonist renzapride relieves symptoms of constipation by softening stool consistency and increasing colonic transit. It has been tested only in patients with irritable bowel syndrome and constipation (Camilleri et al., 2004). Other 5-HT4 agonists, such as norcisapride and mosapride (Cremonini et al., 2005), neurotrophic factors (Coulie et al., 2000) and probiotic agents (Koebnick et al., 2003; Ouwehand et al., 2002) are also under investigations. Additional works are needed to

**Neurotrophins** stimulate the development, growth and function of the nervous system, and increase colonic transit when administered subcutaneously in healthy subjects and patients

**Colchicine**, usually used in the treatment of acute gout, induces diarrhea through an unknown dose-dependent mechanism. Colchicine increases stool frequency and reduces number of rescue laxatives needed. In a controlled trial, colchicine (1 mg/day) improved

Opiate antagonists have also been suggested to treat constipation. These agents block opiate receptors in intestine avoiding mucosal absorption and inhibition of intestinal transit, caused by opiate. Thus mucosal absorption should be reduced and intestinal transit should be increase by the administration of drugs like naloxone and naltrexone. An early report suggested a role for this type of agent in idiopathic constipation, but a successive report

Opiate antagonists are useful in patients with opiate-induced constipation (Meissner et al., 2000; Yuan et al., 2000). The opiate antagonists methylnaltrexone and alvimopan are under investigation for the treatment of opiate-induced constipation and postoperative ileus, but unlike other opiate antagonists, they do not have any impact on central analgesia (Camilleri et al., 2005; Yuan et al., 2004). Their usefulness in treating non-opioid-induced constipation

Managing bowel function is a main concern in neurological patients, having an impact equal to mobility impairment on quality of life (Norton et al., 2010). It is important to get

2010). It is not yet approved for treatment of chronic constipation (Kurtz et al., 2006).

reduced taking lubiprostone with food (Bethesda et al., 2006).

determine their role in the treatment of chronic constipation.

constipation in patients with slow transit (Taghavi et al., 2010).

**16. Management of constipation in neurological disorders** 

denied it (Ragavan et al., 1983; Fotherby et al., 1987).

with chronic constipation (Coulie et al., 2000).

**15. Opiate antagonists** 

remains unclear.

(Camilleri et al., 2006).

information on current bowel status in order to provide an effective treatment (Gulick et al., 2011). The frequent coexistence of faecal incontinence represents a challenge in the management of constipation (Hinds et al., 1990). On the other hand, treatment of constipation is essential, because constipation itself may worsen bladder symptoms (Hinds et al., 1989). Treatment of bowel dysfunction in MS patients is often empirical and there are a few studies comparing the efficacy of different measures such as high fibre diet, adequate intake of fluids, bowel habits, physical exercise and the use of medication (Winge et al., 2003).

Increasing dietary fibre may be useful in MS patients to soften faeces, but it is not helpful in patients with severe constipation, as observed in spinal cord injury (Cameron et al., 1996). Furthermore the need for adequate fluid intake when taking bulking agents should be strongly encouraged. Sufficient or additional fluid intake and the use of docusate stool softener (up to 600 mg/day) are simple ways to help maintain soft bowel movements (DasGupta et al., 2003). On the other hand, a high fibre diet or the use of bulking agents may produce increased symptoms connected to the presence of increased fermentable substrate if peristalsis is impaired (Winge et al., 2003; Muller et al., 1988).

Stimulant or osmotic laxatives are useful when transit is slow. Senna and bisacodyl are effective and their dose can be modulated in order to avoid faecal incontinence, an effect reported more frequently with osmotic laxatives (Gattuso et al., 1994; Schiller et al., 1999).

Rectal stimulants such as glycerine or bisacodyl suppository, sodium citrate micro-enema or phosphate enema, have the advantage of predictability in terms of time of response as observed in patients with spinal cord injury or stroke (House et al., 1997; Munchiando et al., 1993).

Pelvic floor incoordination has been observed in MS patients (Mathers et al., 1990; Weber et al., 1987; Chia et al., 1996). Behavioural therapies – the so called biofeedback - have an important role in the management of constipation in this group of patients and they are effective in subjects with mild to moderate disability and a non progressive disease course. Over a third of patients considered themselves to have benefited in the medium term, but long term effects of biofeedback are unknown. There are no physiological test that can predict the response to this treatment (Wiesel et al., 2000; Munteis et al., 2008). Biofeedback improves pelvic floor function, conditioning the voluntary striated muscle sphincter response and patient's consciousness of a stimulus distending the rectum (Wiesel et al., 2000; Storrie et al., 1997).

Recently, in a randomized controlled study, some authors have suggested a beneficial effect of abdominal massage on constipation symptoms in MS patients (McClurg et al., 2011). Abdominal massage decreases severity of constipation and abdominal pain, and increases bowel movements. In health subjects with constipation, the massage has a delayed effect that may occur first after a number of weeks so that it is considered a long-term treatment. It does not lead to decrease in laxative intake, so abdominal massage could be a complement to medication rather than a substitute (Lämås et al., 2009).

For selected patients with severe constipation, when there is a lack of response to conservative therapies, colostomy or the Malone appendicostomy can be contemplated (Wiesel et al., 2001; Hennessey et al., 1999; Krogh et al., 2009).

In stroke patients Early physical activity should be recommended for stroke patients to prevent new-onset constipation (Su et al., 2009). The establishment of dedicated stroke units with early mobilisation, rehydration and diet regulating measures have resulted in a remarkable reduction of the problems related to constipation in stroke patients (Winge et al., 2003; Cardin et al., 2010; Kumar et al., 2010). A systematic assessment of bowel habits by nursing staff with a simple practice-based approach towards bowel management and patient/caregiver education has been shown to be helpful in patients with stroke (Harari et al., 2004).

A step by step approach, from simple to more complex treatment measures, is strongly recommended also in PD patients. Increasing daily fibre and fluid intake is the first step, since it is deficient in many patients with PD. Fibre supplements with psyllium or methylcellulose is useful and it significantly increases stool frequency and weight. The second step is to add a stool softener, such as docusate. Then patient can use an osmotic laxative, such as lactulose or sorbitol. Also the regular use of polyethylene glycol electrolyte balanced solutions is effective. It would be better to avoid irritant laxatives and enemas, even if they could be useful in selected cases (Pfeiffer et al., 2003).

Intrajejunal infusion of duodopa in patients with advanced-stage PD determine an improvement in constipation and other bowel symptoms in addition to other non-motor symptoms (Chaudhuri et al., 2009). Treatment of defecatory dysfunction in PD is more demanding. Laxatives do not improve the impaired anorectal muscular coordination and may increase the problem. Dopaminergic drugs may be useful, being observed an improvement in anorectal manometric during "on" periods, with deterioration when "off"' (Pfeiffer et al., 2003). Also apomorphine therapy can improve anorectal dysfunction in PD (Chaudhuri et al., 2009). Botulinum-toxin injections into the puborectalis muscle have been used successfully in the treatment of parkinsonian defecatory dysfunction. Faecal incontinence is a potential complication. Behavioural treatment approaches such as biofeedback training have not been specifically investigated in PD (Pfeiffer et al., 2003).

### **17. Conclusions**

Bowel dysfunction is a frequent complication in neurological disorders and it can be due to neurological lesions or non-neurological causes. Owing to a complex physiopathology and to the involvement of autonomic system, a specific treatment is limited. A multimodal approach is needed to manage symptoms successfully and to provide individualized care for a particular patient. It is essential to determine realistic aims. Training bowel habits associated with physical activity, proper use of medication and biofeedback, just for selected patients, is an effective strategy to improve constipation in neurologic patients for some time, depending largely on disability level. Bowel management is still often empirical in neurological disorders and well-designed controlled trials are needed.

### **18. References**

[1] Abbott RD, Petrovich H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson's disease. *Neurology* 2001;57:456–62.

In stroke patients Early physical activity should be recommended for stroke patients to prevent new-onset constipation (Su et al., 2009). The establishment of dedicated stroke units with early mobilisation, rehydration and diet regulating measures have resulted in a remarkable reduction of the problems related to constipation in stroke patients (Winge et al., 2003; Cardin et al., 2010; Kumar et al., 2010). A systematic assessment of bowel habits by nursing staff with a simple practice-based approach towards bowel management and patient/caregiver education has been shown to be helpful in patients with stroke (Harari et

A step by step approach, from simple to more complex treatment measures, is strongly recommended also in PD patients. Increasing daily fibre and fluid intake is the first step, since it is deficient in many patients with PD. Fibre supplements with psyllium or methylcellulose is useful and it significantly increases stool frequency and weight. The second step is to add a stool softener, such as docusate. Then patient can use an osmotic laxative, such as lactulose or sorbitol. Also the regular use of polyethylene glycol electrolyte balanced solutions is effective. It would be better to avoid irritant laxatives and enemas,

Intrajejunal infusion of duodopa in patients with advanced-stage PD determine an improvement in constipation and other bowel symptoms in addition to other non-motor symptoms (Chaudhuri et al., 2009). Treatment of defecatory dysfunction in PD is more demanding. Laxatives do not improve the impaired anorectal muscular coordination and may increase the problem. Dopaminergic drugs may be useful, being observed an improvement in anorectal manometric during "on" periods, with deterioration when "off"' (Pfeiffer et al., 2003). Also apomorphine therapy can improve anorectal dysfunction in PD (Chaudhuri et al., 2009). Botulinum-toxin injections into the puborectalis muscle have been used successfully in the treatment of parkinsonian defecatory dysfunction. Faecal incontinence is a potential complication. Behavioural treatment approaches such as biofeedback training have not been specifically investigated in PD (Pfeiffer et al., 2003).

Bowel dysfunction is a frequent complication in neurological disorders and it can be due to neurological lesions or non-neurological causes. Owing to a complex physiopathology and to the involvement of autonomic system, a specific treatment is limited. A multimodal approach is needed to manage symptoms successfully and to provide individualized care for a particular patient. It is essential to determine realistic aims. Training bowel habits associated with physical activity, proper use of medication and biofeedback, just for selected patients, is an effective strategy to improve constipation in neurologic patients for some time, depending largely on disability level. Bowel management is still often empirical in

[1] Abbott RD, Petrovich H, White LR, et al. Frequency of bowel movements and the future

even if they could be useful in selected cases (Pfeiffer et al., 2003).

neurological disorders and well-designed controlled trials are needed.

risk of Parkinson's disease. *Neurology* 2001;57:456–62.

al., 2004).

**17. Conclusions** 

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### **Bowel Dysfunction in Persons with Multiple Sclerosis**

Elsie E. Gulick1 and Marie Namey2 *1Rutgers, The State University of New Jersey, 2Mellen Center for MS Treatment & Research Cleveland Clinic, USA* 

### **1. Introduction**

116 Constipation – Causes, Diagnosis and Treatment

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Information is presented pertaining to the characteristics of multiple sclerosis (MS) including bowel dysfunction that consists of constipation, fecal incontinence or both constipation and fecal incontinence. Bowel functions and its neural control, prevalence and symptoms of constipation and fecal incontinence that is characteristic of persons with MS together with a description of procedures for assessment and intervention strategies are presented. The outcomes of bowel interventions and their effects on the quality of life of persons with MS together with suggestions for further research are also presented.

### **2. Characteristics of Multiple Sclerosis**

Multiple Sclerosis (MS) is an inflammatory and demyelinating autoimmune disorder (Herndon, 2003) that affects approximately 2.5 million people worldwide (Moses, Picone & Smith, 2008) that has an approximately 2:1 female to male ratio (Willer, Dyment, Risch, Sadovnick, & Ebers, 2003). This disease of the central nervous system (CNS) affects nerve pathways in the brain and spinal cord. MS is thought to be acquired through the complex interaction of genetic and environmental factors (Goodin, 2010). Environmental influences are thought to include low levels of ultraviolet radiation and vitamin D, viruses, and non infectious agents such as smoking and psychological stress (Milo & Kahana, 2010; Sloka, Silva, Pryse-Phillips, Meta & Wee Yong, 2011; Carlye, 1997; Mehta, 2010; Koch-Henrikson & Sorensen, 2010).

The onset of MS generally occurs during young adulthood (Weinshenker, 1993) and is usually characterized by an initial relapsing and remitting course followed by a progressive course (Wienshenker, 1998; Vukusic & Confavreux, 2007). As a result of impairment of the CNS bowel dysfunction is one of many symptoms experienced by persons with MS that consists of constipation and fecal incontinence. Constipation, defined as two or fewer bowel movements per week, the need to manipulate the rectum digitally to facilitate defecation all or most of the time, and/or use of laxatives, enemas, or suppositories more than once a week, has a prevalence rate between 43% and 73% in the MS population (Hinds, Eidelman & Wald, 1990; Nordenbo, Andersen, & Andersen, 1996). Fecal incontinence, defined as uncontrolled or involuntary emissions of flatus and/or stools, has a prevalence of between 51% and 53% in the MS population (Hinds et al. 1990; Nordenbo et al. 1996).

### **3. Bowel functions and neural control**

Principal functions of the colon include 1) absorption of water and electrolytes from the chime, ingested food that is mixed with stomach secretions that pass into the small intestine and on to the large intestine, and 2) storage of fecal matter until it can be expelled (Guyton & Hall, 2006). Mixing movements known as haustrations promote absorption of fluid and dissolved substances causing the chime to become a semisolid slush. Haustral contractions propel the material in the colon toward the rectum. Beginning of the transverse colon and continuing to the sigmoid, mass movements mainly take over the propulsive role which occur only one to three times each day and most frequently for 15 minutes during the first hour after eating breakfast. Mass movements are facilitated by the gastrocolic and duodenocolic reflexes that result from distention of the stomach and duodenum via extrinsic nerves of the autonomic nervous system. When a mass movement forces feces into the rectum, the desire for defecation is normally initiated, including reflex contraction of the rectum and relaxation of the anal sphincters. Loss of fecal matter through the anus is prevented by tonic contraction of the internal and external anal sphincters. The external sphincter is controlled by nerve fibers in the pudendal nerve which is under voluntary conscious control. Defecation is initiated by defecation reflexes and is fortified by the parasympathetic defecation reflex that involves the sacral segments of the spinal cord. Conscious relaxation of the internal sphincter and forward movement of feces toward the anus normally initiate contraction of the external sphincter which prevents defecation and if kept contracted defecation reflexes die out after a few minutes and remain quiescent for several hours or until additional amounts of feces enter the rectum (Guyton & Hall, 2006).

The autonomic nervous system, consisting of sympathetic and parasympathetic nerve fibers, controls the visceral functions pertaining to gastrointestinal mobility and secretion and is activated mainly by centers located in the spinal cord, brain stem and hypothalamus (Guyton & Hall, 2006). Sympathetic nerves originate in the spinal cord between segments T-1 and L-2 and pass from here into the sympathetic chain and then to the tissue and organs that are stimulated by the sympathetic nerves. Sympathetic fibers from cord segments T-7 through T-11 pass into the abdomen. Sympathetic nerve endings secrete norepinephrine and have two major types of adrenergic receptors: alpha and beta. Alpha receptors cause intestinal relaxation, intestinal sphincter contraction, and bladder sphincter contraction. Beta receptors cause intestinal and uterus relaxation and bladder wall relaxation. Autonomic reflexes that inhibit gastrointestinal activity that severely block movement of food through the intestines are initiated by sensory signals that pass to the prevertebral sympathetic ganglia or to the spinal cord and then are transmitted through the sympathetic nervous system back to the gut (Guyton & Hall, 2006).

Parasympathetic fibers leave the CNS through cranial nerves III, VII, IX, and X; and the second and third sacral spinal nerves; and the first and fourth sacral nerves (Guyton & Hall, 2006). The vagus, cranial nerve X, supplies parasympathetic nerves to the proximal half of the colon. The sacral parasympathetic fibers congregate in the pelvic nerves which leave the sacral plexus at S-2 and S-3 levels and distribute their peripheral fibers to the descending colon, rectum, and external genitalia. Parasympathetic nerve endings secrete acetylcholine which increases the overall activity of the gastrointestinal tract by promoting peristalsis and relaxing the sphincters to allow rapid propulsion of contents along the tract and is associated with increases in rates of secretion by many of the gastrointestinal glands. However, strong sympathetic stimulation inhibits peristalsis and increases the tone of the sphincters resulting in greatly slowed propulsion of food through the tract and sometimes decreases secretion as well (Guyton & Hall, 2006). Figure 1 illustrates bowel anatomy and neural components associated with bowel function.

Hypothalamic centers can control gastrointestinal activity. Thus, autonomic centers in the brain stem act as relay stations for control of activities initiated at higher levels of the brain. Higher areas of the brain can alter all or portions of the autonomic system to cause constipation.

### **4. Constipation**

118 Constipation – Causes, Diagnosis and Treatment

Principal functions of the colon include 1) absorption of water and electrolytes from the chime, ingested food that is mixed with stomach secretions that pass into the small intestine and on to the large intestine, and 2) storage of fecal matter until it can be expelled (Guyton & Hall, 2006). Mixing movements known as haustrations promote absorption of fluid and dissolved substances causing the chime to become a semisolid slush. Haustral contractions propel the material in the colon toward the rectum. Beginning of the transverse colon and continuing to the sigmoid, mass movements mainly take over the propulsive role which occur only one to three times each day and most frequently for 15 minutes during the first hour after eating breakfast. Mass movements are facilitated by the gastrocolic and duodenocolic reflexes that result from distention of the stomach and duodenum via extrinsic nerves of the autonomic nervous system. When a mass movement forces feces into the rectum, the desire for defecation is normally initiated, including reflex contraction of the rectum and relaxation of the anal sphincters. Loss of fecal matter through the anus is prevented by tonic contraction of the internal and external anal sphincters. The external sphincter is controlled by nerve fibers in the pudendal nerve which is under voluntary conscious control. Defecation is initiated by defecation reflexes and is fortified by the parasympathetic defecation reflex that involves the sacral segments of the spinal cord. Conscious relaxation of the internal sphincter and forward movement of feces toward the anus normally initiate contraction of the external sphincter which prevents defecation and if kept contracted defecation reflexes die out after a few minutes and remain quiescent for several hours or until additional amounts of feces enter the rectum (Guyton & Hall, 2006). The autonomic nervous system, consisting of sympathetic and parasympathetic nerve fibers, controls the visceral functions pertaining to gastrointestinal mobility and secretion and is activated mainly by centers located in the spinal cord, brain stem and hypothalamus (Guyton & Hall, 2006). Sympathetic nerves originate in the spinal cord between segments T-1 and L-2 and pass from here into the sympathetic chain and then to the tissue and organs that are stimulated by the sympathetic nerves. Sympathetic fibers from cord segments T-7 through T-11 pass into the abdomen. Sympathetic nerve endings secrete norepinephrine and have two major types of adrenergic receptors: alpha and beta. Alpha receptors cause intestinal relaxation, intestinal sphincter contraction, and bladder sphincter contraction. Beta receptors cause intestinal and uterus relaxation and bladder wall relaxation. Autonomic reflexes that inhibit gastrointestinal activity that severely block movement of food through the intestines are initiated by sensory signals that pass to the prevertebral sympathetic ganglia or to the spinal cord and then are transmitted through the sympathetic nervous

Parasympathetic fibers leave the CNS through cranial nerves III, VII, IX, and X; and the second and third sacral spinal nerves; and the first and fourth sacral nerves (Guyton & Hall, 2006). The vagus, cranial nerve X, supplies parasympathetic nerves to the proximal half of the colon. The sacral parasympathetic fibers congregate in the pelvic nerves which leave the sacral plexus at S-2 and S-3 levels and distribute their peripheral fibers to the descending colon, rectum, and external genitalia. Parasympathetic nerve endings secrete acetylcholine which increases the overall activity of the gastrointestinal tract by promoting peristalsis and relaxing the sphincters to allow rapid propulsion of contents along the tract and is associated with increases in rates of secretion by many of the gastrointestinal glands.

**3. Bowel functions and neural control** 

system back to the gut (Guyton & Hall, 2006).

Constipation can be primary or secondary (Candelli, Nista, Zocco, & Gasbarrini, 2001). Primary constipation, also known as idiopathic or functional constipation, is considered when no definite cause is found and specific diseases cannot be demonstrated. Constipation is considered secondary when specific causes are recognized such as poor fiber diet, intestinal neoplasm, drugs, or specific diseases such as multiple sclerosis. Constipation in MS patients can be caused either by slow colonic transit, abnormal rectal function, or abnormal pelvic floor function (Chia, Fowler, Kamm, Henry, Lemieux & Swash, 1995; DasGupta & Fowler, 2003; Weber, Grise, Roquebert, Hellot, Mihout, Samson, Beuret-Blanquart, Pasquis &Denis, 1987).

Slow transit constipation is characterized by prolonged delay in the transit of stool through the colon due to a primary dysfunction of the colonic smooth muscle or its nerve innervations (Rao, 2007). Symptoms may include straining during defecations, lumpy or hard stools, sensation of incomplete evacuation of stool, sensation of anorectal obstruction of stool, and manual maneuvers to facilitate defecation. Pathologic conditions include phasic colonic motor activity; diminished gastrocolonic response following a meal; the high amplitude, prolonged duration, propagated contractions are decreased; and the velocity of propagation is slower, waves have a greater tendency to abort prematurely, and their amplitude is also decreased (Rao, 2007). Weber et al. (1987) in a study of 16 MS patients reported that transit times of radiopaque markers led to an objective confirmation of constipation in 13 of the 15 patients. Interruption of sympathetic innervations from the dorsolumbar spinal cord via the superior mesenteric ganglion and vagal parasympathetic innervations to the right colon together with sympathetic innervations from the dorsolumbar spinal cord via the inferior mesenteric ganglion and parasympathetic innervations from the sacral spinal cord via the erigentes nerves to the left colon were proposed to explain the decreased transit observed in MS patients (Weber et al. 1987). Wald (1986) reported that prolonged transit time throughout the entire colon among MS patients responded poorly to treatment compared to those characterized by slow transit restricted to the left colon or delay only through the anorectal structures.

Abnormal rectal function, also known as dyssynergic defecation, obstructive defecation, anismus, pelvic floor dyssynergia, or outlet obstruction, is characterized by difficulty to expel stool from the anorectum (Rao, 2007). Symptoms include the need to strain excessively, feeling of incomplete evacuation, abdominal fullness or bloating, and need to use fingers to facilitate defecation (Rao, Tuteja, Vellema, Kempf & Stessman, 2004). Dyssynergic defecation may be caused by paradoxical anal contraction or involuntary anal spasm during defecation

Fig. 1. Bowel anatomy and neural components associated with bowel function

(Rao, 2007). Munteis, Andreu, Martinez-Rodriquez, Ois, Bory & Roquer, (2008) reported that 32 MS patients with constipation compared to 22 patients without neurological or gastroenterologic abnormalities had significantly lower squeeze maximal sphincter pressure and higher anal inhibitory reflex, conditions that impede defecation. Women with pelvic organ prolapse and who reported chronic straining to defecate reportedly have a high risk for constipation (Arya, Novi, Shaunik, Morgan & Bradley, 2005). The authors theorized that chronic straining may produce weakness of the pelvic floor resulting in pudendal nerve injury with loss of tonicity of pelvic floor muscles and subsequent development of prolapse.

### **5. Fecal incontinence**

120 Constipation – Causes, Diagnosis and Treatment

**C-1**

Fig. 1. Bowel anatomy and neural components associated with bowel function

(Rao, 2007). Munteis, Andreu, Martinez-Rodriquez, Ois, Bory & Roquer, (2008) reported that 32 MS patients with constipation compared to 22 patients without neurological or gastroenterologic abnormalities had significantly lower squeeze maximal sphincter pressure and higher anal inhibitory reflex, conditions that impede defecation. Women with pelvic organ prolapse and who reported chronic straining to defecate reportedly have a high risk Fecal incontinence is characterized by an urgent need to defecate and loss of stool. Major factors causing fecal incontinence among MS patients include the lack of voluntary control of the external anal sphincter, rectal hyperreactivity, reduced rectal tone and contractility causing fecal impaction and rectal distension, and reduced or lost anal sensibility (Chia, et al. 1995; Hennessey, Robertson, Swingler & Compston, 1999; Krogh & Christensen, 2009). Studies among persons with MS have shown that fecal incontinence is associated with reduced rectal sensation, a markedly reduced external sphincter function, weakness of pelvic floor musculature and an inability to close the anorectal angle (Nordenbo, et al. 1995; Waldron et al. 1993). Causes of fecal incontinence unrelated to MS include diarrheal infections due to viral, bacterial, and protozoal agents (Walker, 2006); food allergy (Walker, 2006); or pudendal nerve damage associated with childbirth (Swash, Snooks & Chalmers, 1987).

### **6. Assessment of bowel dysfunction**

Bowel problems particularly fecal incontinence is often withheld from sharing the problem with health care providers due to feelings of embarrassment or shame (Khan, Pallant, Shea & Whishaw, 2009; Powell & Rigby, 2000; Wald, 2007). Therefore, since bowel dysfunction is relatively common among persons with MS it is important for health care providers to ask their MS patients in a careful supportive manner about their bowel function as accurate assessment of the presenting bowel problem is key to the successful treatment and management of bowel dysfunction (Irwin, 2003). Important bowel assessment information needed by the health care provider can be obtained through periodically patientadministered surveys and/or through patient interviews. A description of several patientadministered survey questionnaires are described below.

### **6.1 Instruments used to assess bowel function/dysfunction**

Patient-administered questionnaires regarding their bowel function or dysfunction can provide health care providers with information that can assist them in determining appropriate treatment, counseling, or needed referrals. Periodic assessments are important to determine if the current treatment is effective or in need of change. Periodic assessments are also needed because of possible change in the patient's disability status that may increase bowel problems (Wiesel, Norton, Glickman, & Kamm, 2001). Several patientadministered questionnaires are described below.

### **6.1.1 The Bowel Function Questionnaire for Persons with Multiple Sclerosis (BFQ-MS)**

The BFQ-MS, developed for persons with MS, is a patient-administered scale that consists of 15 items pertaining to constipation, 13 items pertaining to fecal incontinence and 20 items pertaining to both constipation and fecal incontinence (Gulick, 2010). The questionnaire items inquire about one's medical/surgical background that may be related to bowel dysfunction; medications with constipating or diarrheal effects; symptoms (frequency, consistency, time spent on the toilet, amount of time once the urge is felt before defecation occurs, skin breakdown around anus or perineum, pain/discomfort on defecation, flatulence, strain to defecate, feel bowel is not empty after defecation); nondrug interventions; drug interventions; and improvement or worsening over time. The items are rated on a Likert scale that ranges between 0 and 5 with higher scores indicating a worsening of bowel problems. Cronbach alpha reliability coefficients for the Constipation, Fecal Incontinence, and both Constipation and Fecal Incontinence subscales were 0.70, 0.68, and 0.69, respectively. The three subscales demonstrate satisfactory validity as they were able to differentiate symptom and treatment differences between the three types of bowel dysfunction.

### **6.1.2 The Quality of Life Scoring Tool Relating to Bowel Management (QOL-BM)**

The QOL-BM, originally developed for use with spinal cord injured patients (Slater, 2003), was tested for reliability and validity with a sample of 502 persons with MS (Gulick, 2011). Principal component analysis and Varimax rotation factor analysis of the 11-item scale used with MS patients resulted in two factors: Management and Relationships. The 6-item Management subscale consists of items related to severity of bowel difficulty, convenience/inconvenience of bowel care, and satisfaction with bowel care. The 5-item Relationships subscale consists of items related to worry about bowel accidents, personal relationships and social activity. Internal consistency reliability for the total scale was 0.90 and was 0.86 for the Management subscale and 0.83 for the Relationships subscale suggesting satisfactory reliability. Discriminant validity was shown for the total and subscales based on the MS patient's disability level (p < .05).

### **6.1.3 Constipation Symptom Assessment Instrument (PAC-SYM)**

The PAC-SYM is a constipation symptom assessment scale consisting of 12 items that measure stool symptoms, rectal symptoms and abdominal symptoms (Frank, Kleinman, Farup, Taylor & Miner, 1999). Items are rated on a 5-point Likert scale from absence of symptoms (0) to very severe (4). Internal consistency (Cronbach's alpha = 0.89) and testretest reliability (intraclass correlation = 0.75) were high. Within subject change over a 6 week period demonstrated significantly improved scores. The PAC-SYM scale has been used with opium-induced constipation patients (Slappendel, Simpson, Dubois & Keininger, 2006) and with women with pelvic organ prolapse and constipation (Arya et al. 2005).

### **6.1.4 The Brief Fecal Incontinence Score**

The Brief Fecal Incontinence Score is a 7-item scale that measures frequency of stool, stool consistency, flatulence, altered lifestyle, drug and nondrug interventions, and inability to defer defecation for 15 minutes (Vaizey, Carapeti, Cahill & Kamm, 1999). A five-point Likert rating scale from Never (0) to Daily (5) is used. The scale correlated closely with clinical assessment (r=0.79), showed high test-retest reliability (r=0.87), and showed sensitivity to change from pre-surgery to 6-weeks post-surgery (p<0.004) suggesting good reliability and validity. The scale has not reportedly been used with MS patients.

items inquire about one's medical/surgical background that may be related to bowel dysfunction; medications with constipating or diarrheal effects; symptoms (frequency, consistency, time spent on the toilet, amount of time once the urge is felt before defecation occurs, skin breakdown around anus or perineum, pain/discomfort on defecation, flatulence, strain to defecate, feel bowel is not empty after defecation); nondrug interventions; drug interventions; and improvement or worsening over time. The items are rated on a Likert scale that ranges between 0 and 5 with higher scores indicating a worsening of bowel problems. Cronbach alpha reliability coefficients for the Constipation, Fecal Incontinence, and both Constipation and Fecal Incontinence subscales were 0.70, 0.68, and 0.69, respectively. The three subscales demonstrate satisfactory validity as they were able to differentiate symptom and treatment differences between the three types of bowel

**6.1.2 The Quality of Life Scoring Tool Relating to Bowel Management (QOL-BM)** 

subscales based on the MS patient's disability level (p < .05).

**6.1.4 The Brief Fecal Incontinence Score** 

**6.1.3 Constipation Symptom Assessment Instrument (PAC-SYM)** 

validity. The scale has not reportedly been used with MS patients.

The QOL-BM, originally developed for use with spinal cord injured patients (Slater, 2003), was tested for reliability and validity with a sample of 502 persons with MS (Gulick, 2011). Principal component analysis and Varimax rotation factor analysis of the 11-item scale used with MS patients resulted in two factors: Management and Relationships. The 6-item Management subscale consists of items related to severity of bowel difficulty, convenience/inconvenience of bowel care, and satisfaction with bowel care. The 5-item Relationships subscale consists of items related to worry about bowel accidents, personal relationships and social activity. Internal consistency reliability for the total scale was 0.90 and was 0.86 for the Management subscale and 0.83 for the Relationships subscale suggesting satisfactory reliability. Discriminant validity was shown for the total and

The PAC-SYM is a constipation symptom assessment scale consisting of 12 items that measure stool symptoms, rectal symptoms and abdominal symptoms (Frank, Kleinman, Farup, Taylor & Miner, 1999). Items are rated on a 5-point Likert scale from absence of symptoms (0) to very severe (4). Internal consistency (Cronbach's alpha = 0.89) and testretest reliability (intraclass correlation = 0.75) were high. Within subject change over a 6 week period demonstrated significantly improved scores. The PAC-SYM scale has been used with opium-induced constipation patients (Slappendel, Simpson, Dubois & Keininger, 2006) and with women with pelvic organ prolapse and constipation (Arya et al. 2005).

The Brief Fecal Incontinence Score is a 7-item scale that measures frequency of stool, stool consistency, flatulence, altered lifestyle, drug and nondrug interventions, and inability to defer defecation for 15 minutes (Vaizey, Carapeti, Cahill & Kamm, 1999). A five-point Likert rating scale from Never (0) to Daily (5) is used. The scale correlated closely with clinical assessment (r=0.79), showed high test-retest reliability (r=0.87), and showed sensitivity to change from pre-surgery to 6-weeks post-surgery (p<0.004) suggesting good reliability and

dysfunction.

### **6.2 Patient interview regarding bowel function/dysfunction**

One or more of the survey questionnaires could be used prior to conducting an interview with the patient. Suggested questions to be asked during the patient interview are described in Table 1. General questions are presented and depending on the individual's response more detailed questions can be explored.

A follow-up to the interview questions includes a physical assessment, described below, to determine if abnormalities of the anorectum and perineum can be detected.

### **6.3 Physical assessment and laboratory tests pertaining to bowel dysfunction**

The following examinations are recommended to assist in identifying underlying causes of bowel dysfunction (Hinds & Wald, 1989; Irwin, 2002; Namey & Halper, 2000).


Information obtained from the interview, physical assessment and blood work should guide the development of an individualized bowel program.

### **7. Interventions to control bowel function/dysfunction**

### **7.1 Basic bowel program: Constipation**

Development of the bowel program should be comprehensive and individualized to include the physical abilities of the patient, availability of care, the chosen lifestyle and preferences of the patient and education of the patient and caregiver (Coggrave, Wiesel & Norton, 2006). The approach to treating bowel problems in MS should be guided by an evaluation of likely pathophysiology of the bowel symptoms (Hay-Smith, Siegert, Weatherall & Abernethy, 2007). Simple and conservative approaches of a bowel program include appropriate diet and fluid intake, awareness of medications that may have a constipating or diarrheal effect, active or passive exercise, and toileting regime.

### **7.1.1 Diet and fluid intake**

Good nutrition is vital for one's overall health and for a 1800 calorie diet the recommendations include a daily intake of 1 ½ cups of fruit, 2 ½ cups of dark green/orange/red vegetables, 6 ounces of grains, 5 ½ ounces of meat and beans, 3 cups of milk, 24 grams of oils, and 20-30 grams of fiber (Dietary Guidelines for Americans-2010). A


Table 1. Interview Regarding Bowel Functions/Dysfunctions

common cause of constipation is a diet low in fiber. Fiber may be soluble that dissolves easily in water and takes on a gel-like texture in the intestine or insoluble fiber that passes through the intestine almost unchanged. Together, the bulk and soft texture of fiber helps

1. Do you strain to pass your stool? If yes, what is the frequency?

 or need to go again quickly? If yes, what is the frequency?

 you move your bowels? Tell me about them.

Tell me about them.

2. Do you feel your bowel is not empty

3. What things have you done to help

4. Do you use laxatives, suppositories, or enemas to help with bowel care?

3. Are your bowel movements usually liquid, loose, soft, hard, lumpy or does the

**Additional background questions to ask pertaining to possible causes of bowel** 

3. Tell me about the foods you usually eat and the type and amount of beverage

7. How much does your bowel problem bother you and interfere with every

8. Are there conditions that may be related to your current bowel problem?

10. Is there anything else you'd like to tell me about your bowel problem?

common cause of constipation is a diet low in fiber. Fiber may be soluble that dissolves easily in water and takes on a gel-like texture in the intestine or insoluble fiber that passes through the intestine almost unchanged. Together, the bulk and soft texture of fiber helps

2. What medications are you currently taking other than laxatives or anti-

 4. Do you experience pain or discomfort when moving your bowels? 5. Do you need assistance from other persons to help you with bowel care?

4. Now ask questions shown below according to reported stool consistency. **Stools usually Liquid or Loose Stools Usually Hard or Lumpy** 

1. Tell me about your bowel movements during the past week. 2. How frequently do you move your bowels during the week? Is this your typical pattern? Are you satisfied with this pattern?

stool consistency vary?

them.

1. Do you lose some or all of the stool before making it to the toilet? If yes, when and where does this occur?

2. What things have you done to help control loss of stool. Tell me about

3. Do you use medications to help you control loss of stool or bowel leakage? Tell me about them.

4. Do you have any food allergies? If yes, tell me about them.

**dysfunction and toileting facilities** 

Difficult childbirth (woman)

diarrheal agents?

each day.

day activities?

Sexual abuse

1. How long have you experienced your bowel problem?

6. Are toilet facilities readily available and comfortable?

 Medical conditions such as colitis, Crohns disease Failure to heed the urge to move your bowels

Medications with constipating or diarrheal effects

Table 1. Interview Regarding Bowel Functions/Dysfunctions

9. Is there a family history of bowel problems?

Surgical procedures: abdomen, rectal, anal, or perineum

prevent hard, dry stools (Rigby & Powel, 2005). However, based on a meta-analysis of studies of the effect of fiber treatment on bowel function, Muller-Lissner (1988) concluded that there is no justification for claiming rye bran, a form of insoluble fiber, given to patients with constipation can return stool output and transit time to normal since there may be a motility disorder of the colon which is primary or secondary to an underlying disease or an altered lifestyle that is responsible for constipation.

The addition of high fiber foods to one's diet has mixed results. A study of 41 women with pelvic floor disorder given slow increases of high-fiber cereal until 28 grams were reached over a 42 day period resulted in withdrawal of 11 patients largely due to inability to tolerate the fiber diet (Shariati, Maceda & Hale, 2008). The 30 patients who completed the study reported significant decreases in adominal pain and bloating, painful bowel movements, rectal bleeding, incomplete bowel movements, consistency of stool, straining or squeezing, laxative use, vaginal and/or perineal splinting. Increasing fiber to one's diet should be introduced slowly in order to control for symptoms of bloating and gas. The addition of yoghurt containing Lactobacillus GG along with a fiber rich diet can decrease gastrointestinal symptoms associated with a fiber rich diet (Hongisto, Paajanen, Saxelin & Korpela, 2006). A list of fiber foods together with the standard serving size and grams of fiber identified by the USDA and USDHHS (2010) are presented in Table 2.

### **7.1.2 Medications that can adversely affect bowel dysfunction**

Control of various MS-related symptoms or other non-MS conditions such as hypertension may require medications that have constipating affects. A list of these medications is shown in Table 3. Patients need to be queried about the medications that they currently are taking to determine if any of them have constipating and/or diarrheal effects.

### **7.1.3 Physical activity to promote bowel function**

Body movement through exercise helps promote peristalisis of the colon, that may reduce the likelihood of constipation (Petajan , Gappmaier, White, Spencer, Mino & Hicks, (1996). Exercise may be passive or active depending on the disability status of the person with MS. Physical activity may be increased according to functional level by performing activities of daily living, pursuing more active recreation and eventually developing a structured exercise program (Petajan & White, 1999). Several studies with persons with MS given aerobic training and fitness (Petajan et al. 1996) or extended outpatient rehabilitation program (Di Fabio, Soderberg, Choi, Hansen & Schapiro,1998) demonstrated improvement in the study participants' bowel functioning. A study by Gulick and Goodman (2006) evaluated the effect of everyday activities performed in and around the home among 123 persons with MS ranging between mild to severe disability. After controlling for disability level, bowel and bladder symptoms increased with increased levels of physical activity.

### **7.1.4 Toileting regime to assist in bowel evacuation**

A number of activities related to toileting can aid defecation. Planning the toileting routine during the first hour following breakfast takes advantage of increased peristalsis of the colon which moves the chime/feces into the sigmoid colon and rectum (Guyton & Hall, 2006). Patients who are able to sit safely and tolerate sitting on a commode or toilet for short


Table 2. Selected Food Sources Ranked by Standard Food Portion and Amounts of Dietary Fiber

1/3 cup (about 1 ounce) 5.6-8.1

1/3-3/4 cup (about 1 ounce) 2.6-5

½ cup (about 1 ounce) 2.7-3.8

½ cup 2.5-3.5

½ cup 6.2-9.6

½ cup 5.6-8.1

Standard Portion (g)

Food Standard Portion Size Dietary Fiber in

Plain rye wafer crackers 2 wafers 5.0

 Whole wheat English muffin 1 muffin 4.4 Soybeans, green, cooked ½ cup 3.8

 Whole wheat spaghetti, cooked ½ cup 3.1 Oat bran muffin 1 small 3.0 Pearled barley, cooked ½ cup 3.0

 Artichoke, cooked ¼ cup hearts 7.2 Green peas, cooked 1/2 cup 3.5-4.4 Mixed vegetables, cooked ½ cup 4.0 Sweet potato, baked in skin 1 medium 3.8

 Sauerkraut, canned ½ cup 3.4 Potato, baked, with skin 1 small 3.0 Broccoli, cooked ½ cup 2.6-2.8

 Asian pear 1 small 4.4 Raspberries ½ cup 4.0 Blackberries ½ cup 3.8 Prunes, stewed ½ cup 3.8 Figs, dried ¼ cup 3.7 Apple, with skin 1 small 3.6 Banana 1 medium 3.1 Orange 1 medium 3.1 Strawberries 1 cup 3.0 Guava 1 fruit 3.0 Dates ¼ cup 2.9

 Soybeans, mature, cooked ½ cup 5.2 Almonds 1 ounce 3.5

Table 2. Selected Food Sources Ranked by Standard Food Portion and Amounts of Dietary

**Grains**

(100%)

(various)

cereal

**Vegetables**

**Fruit**

**Lentils and Nuts**

or cowpeas, cooked

Fiber

 Beans (navy, pinto, black, kidney, white, great northern, lima), cooked

Split peas, lentils, chickpeas,

Bran ready-to-eat cereal

Bran ready-to-eat cereals

Shredded wheat ready-to-eat

 Greens (spinach, collards, turnip greens), cooked


Table 3. Medications Containing Constipating or Diarrheal Effects

periods and lean forward to bring pressure onto the colon may promote defecation (Lewicky-Gaupp et al. 2008; Pierce et al. 2001). Toilet facilities must be readily accessible and comfortable. The need for toilet assistance from caretakers as well as their attitude towards bowel care needs to be assessed (Irwin, 2003).

### **7.2 Other components of a bowel program: Constipation**

Some persons with MS may benefit from other forms of bowel control depending on their disability level and comfort of the particular procedure. These include abdominal massage, biofeedback, anal stimulation, digital removal of feces, and rectal or trans-anal irrigation. Various laxatives may be used and/or enemas. Gastroenterology referrals may be indicated for some persons with MS.

### **7.2.1 Abdominal massage**

Abdominal massage reportedly aids peristalsis of the colon to enhance the mass movement of the gut and increases the strength of the contractions and propulsion force through sensory stimulation of the parasympathetic division (McClurg, Hagen, Hawkins & Lowe-Strong, 2010). This stimulation increases the mobility of the muscles to the gut, increases digestive secretions and relaxes the sphincters in the rectoano region. McClurg, using abdominal massage instruction over a four week period given to 15 MS patients compared to 15 MS patient controls with an EDSS disability score between 2.5-6.0 (mean = 3.5) resulted in improved frequency of defecation from 2 to 4.5 defecations per week, decreased time spent defecating from 10 minutes to 6 minutes for the experimental group compared to 12 to 10 minutes per day for the control group. Consistency of stools for both the experimental and control groups was softer at the end of the four week period compared to baseline.

### **7.2.2 Biofeedback for constipation**

Biofeedback represents a number of behavioral modification techniques, which, when applied to treatment of constipation and fecal incontinence, may include sphincter exercises, bowel habit retraining, counseling, health education and use of medications (Wiesel, Norton, Roy, Storrie, Bowers & Kamm, 2000). In a study of 18 persons with MS given biofeedback instruction for anorectal dysfunction, improvement was shown in 8 (44.4%) of the MS patients given biofeedback who had milder manometric abnormalities (squeeze maximal sphincter pressure, anal inhibitory reflex, and paradoxical contraction of the puborectal musculature) and limited disability (Munteis et al. 2008).

### **7.2.3 Anal stimulation**

The defecation reflex can be stimulated by dilating the anus with a lubricated gloved finger. This procedure stimulates the anal sigmoid reflex which causes the colon to contract, the anus relaxes, and fecal contents can be pushed out and is most effective if performed when the patient is in a sitting position (Pierce, et al. 2001).

### **7.2.4 Digital removal of feces**

Digital removal of feces may be performed by patients themselves or by nurses who have received specialized training in the performance of digital removal of feces (Kyle, et al. 2005). However, this procedure should only be used as the last resort and after all other methods of bowel evacuation have failed (Powell & Rigby, 2000). Because of the invasive nature of the procedure patient consent is needed for health care providers to perform the procedure.

### **7.2.5 Rectal or trans-anal irrigation**

This procedure involves a process of facilitating evacuation of feces from the bowel by passing water or other liquids in to the bowel via the anus in a quantity sufficient to reach beyond the rectum (Coggrave, 2008). The infused water distends the rectal wall and stimulates the stretch receptors to stimulate defecation (Pellatt, 2007).

### **7.2.6 Laxatives, suppositories and enemas**

Persons with MS use a range of interventions to help manage the symptoms of constipation, fecal incontinence and/or both constipation and fecal incontinence, with varying degrees of success. A list of medications used for constipation together with their action and either precautions or contraindications (Curry Jr. & Butler, 2006) are presented in Table 4. Close monitoring of the frequency and duration of laxative use can be beneficial in determining whether normal bowel habits are reestablished between bouts of constipation or if a more severe condition exists (Curry & Butler, 2006).

### **7.2.7 Gastroenterology referrals**

128 Constipation – Causes, Diagnosis and Treatment

spent defecating from 10 minutes to 6 minutes for the experimental group compared to 12 to 10 minutes per day for the control group. Consistency of stools for both the experimental and control groups was softer at the end of the four week period compared to baseline.

Biofeedback represents a number of behavioral modification techniques, which, when applied to treatment of constipation and fecal incontinence, may include sphincter exercises, bowel habit retraining, counseling, health education and use of medications (Wiesel, Norton, Roy, Storrie, Bowers & Kamm, 2000). In a study of 18 persons with MS given biofeedback instruction for anorectal dysfunction, improvement was shown in 8 (44.4%) of the MS patients given biofeedback who had milder manometric abnormalities (squeeze maximal sphincter pressure, anal inhibitory reflex, and paradoxical contraction of the

The defecation reflex can be stimulated by dilating the anus with a lubricated gloved finger. This procedure stimulates the anal sigmoid reflex which causes the colon to contract, the anus relaxes, and fecal contents can be pushed out and is most effective if performed when

Digital removal of feces may be performed by patients themselves or by nurses who have received specialized training in the performance of digital removal of feces (Kyle, et al. 2005). However, this procedure should only be used as the last resort and after all other methods of bowel evacuation have failed (Powell & Rigby, 2000). Because of the invasive nature of the procedure patient consent is needed for health care providers to perform the

This procedure involves a process of facilitating evacuation of feces from the bowel by passing water or other liquids in to the bowel via the anus in a quantity sufficient to reach beyond the rectum (Coggrave, 2008). The infused water distends the rectal wall and

Persons with MS use a range of interventions to help manage the symptoms of constipation, fecal incontinence and/or both constipation and fecal incontinence, with varying degrees of success. A list of medications used for constipation together with their action and either precautions or contraindications (Curry Jr. & Butler, 2006) are presented in Table 4. Close monitoring of the frequency and duration of laxative use can be beneficial in determining whether normal bowel habits are reestablished between bouts of constipation or if a more

stimulates the stretch receptors to stimulate defecation (Pellatt, 2007).

puborectal musculature) and limited disability (Munteis et al. 2008).

the patient is in a sitting position (Pierce, et al. 2001).

**7.2.2 Biofeedback for constipation** 

**7.2.3 Anal stimulation** 

**7.2.4 Digital removal of feces** 

**7.2.5 Rectal or trans-anal irrigation** 

**7.2.6 Laxatives, suppositories and enemas** 

severe condition exists (Curry & Butler, 2006).

procedure.

Although most patients with chronic constipation can usually be treated successfully in the primary care setting, some patients may require referral to a gastroenterologist. Reasons for referral include suspicion of defecatory disorders such as pelvic floor dyssynergia, lack of sufficient response to empiric treatment, and worsening of symptoms despite treatment (Bleser, 2006). Objective testing for bowel dysfunction include Anorectal Manometry, the Balloon Expulsion Test, Defecography and Colonic Transit Studies.

Anorectal Manometry is used to assess basal pressure in the rectum and anal canal, squeeze maximal sphincter pressure, rectal sensation, simulated defecation, inhibitory reflex, and presence of paradoxical contraction of the puborectal musculature (Munteis et al. 2008). The Balloon Expulsion Test is used to quantify the ability of a patient to evacuate a water-filled (usually 50 ml) balloon. It can serve as a functional marker in biofeedback programs for pelvic floor retraining (Gill, Chia, Henry & Shorvon, 1994; Locke III, Pemberton & Phillips, 2000). Defecography includes the scintigraphic method used to evaluate anorectal angulation and pelvic floor descent during evacuation. Barium defecography is performed in conjunction with a standard enema. These tests can determine failure of the anorectal angle to open and degree of pelvic floor descent during defecation (Locke, Pemberton & Phillips, 2000). Colonic Transit Studies are used to determine the rate at which fecal residue moves through the colon using radiopaque markers (Locke, Pemberton & Phillips, 2000). The test provides quantitative information about colonic transit, enables the identification and characterization of transit abnormality, and allows assessment of the severity of the problem (Ringel, 2003).




### **7.3 Components of a bowel program: Fecal incontinence**

As was noted for the Bowel Program described for constipation, the development of the bowel program for fecal incontinence should be comprehensive and individualized to include the physical abilities of the patient, availability of care, the chosen lifestyle and preferences of the patient and education of the patient and caregiver (Coggrave, et al. 2006). Except for fecal incontinence caused by viral, bacterial or protozoal infections, treatment for fecal incontinence commonly experienced by MS patients should entail a conservative approach. These include dietary considerations, medications that have diarrheal effects, toileting routine, incontinent pads, biofeedback, antidiarrheal medications and possibly anal plugs or sacral nerve stimulation.

### **7.3.1 Dietary considerations**

130 Constipation – Causes, Diagnosis and Treatment

**Medication Action Precautions or** 

Produce both secretory and motor reactions that draw water into the intestine, to increase intraluminal pressure which in turn increases intestinal motility.

Increase the propulsive peristaltic activity of the intestine by local irritation of the mucosa or by a more selective action on the intramural nerve plexus of intestinal smooth muscle, thus increasing motility. Stimulate secretion of water and electrolytes in either the small or large intestine

A hyperosmotic laxative that irritates the lining of the intestine. Draws water into the rectum to stimulate a bowel movement. Has a direct stimulating effect on the network of nerves in the large intestine. Provides lubrication to promote elimination of stool.

Lubricates the colon and allows for added cleansing. Pulls water from the body into the bowel which helps to soften the stool and cause a bowel movement.

or both.

**Saline Laxatives (Osmotics)**

Citroma®

 MiraLAX® Lactulose

**Stimulants** Senna, Senokot® Bisacodyl Castor oil

**Suppositories** Glycerin

Dulcolax

**Enemas** Mineral Oil

Fleet Enema

Table 4. Medications used to Manage Constipation

Magnesium citrate,

Magnesium hydroxide, Milk of Magnesium® Magnesium sulfate, Epson Salts® Polyethylene Glycol,

**Contraindications** 

Indicated for acute evacuation of the bowel. Take on an empty stomach as food will delay its action. May cause abdominal cramping, diuresis, nausea, vomiting, and dehydration. Acts within 30 minutes to 3

hours.

Used for simple

from excessive hypermotility and

24 hours.

vomiting.

minutes

constipation, but not to be used for more than 1 week unless ordered by a physician. May cause severe cramping, electrolyte and fluid deficiencies, enteric loss of protein, malabsorption resulting

catharsis, and hypokalemia. Usually acts within 6 to 12 hours or may require up to

Do not use if abdominal pain, feel sick, or have

Take plenty of fluids while taking the medication. Usually acts within 30

Enema solutions can cause fluid and electrolyte disturbances in the blood if used on a chronic basis. May cause anal irritation, diarrhea, gas, nausea, stomach, cramps. Acts within 5 to 15 minutes.

Persons with MS could benefit from monitoring their food intake through use of a food diary to determine if certain foods may be related to fecal incontinence. A food diary should list what and how much one eats and when one has an incontinent episode to determine if a pattern between certain foods and incontinence occur. Known foods that have been associated with fecal incontinence include milk, egg, peanut, tree nuts, fish, shellfish, soy seeds, wheat, fruits and vegetables (Sicherer, 2011). Avoidance of fatty foods, foods rich in simple sugars, spicy foods, and caffeine may be helpful in controlling fecal incontinence (Walker, 2006). Hinds and Wald (1989) suggest reducing fiber intake if incontinence of solid stool occurs.

### **7.3.2 Medications associated with fecal incontinence**

Medications given to control various MS-related symptoms and/or conditions unrelated to MS may contain diarrheal properties. Table 3 lists several of these medications.

### **7.3.3 Toileting regime to control fecal incontinence**

Although patients are strongly encouraged to establish a daily time for defecation (DasGupta & Fowler, 2003) fewer than five percent of MS patients with fecal incontinence reported using a daily time for defecation (Gulick, 2010). Hinds and Wald (1989) suggest establishing a routine schedule of enemas or suppositories (e.g., once a week) to keep the rectum empty.

### **7.3.4 Use of incontinent pads**

Incontinence pads have been shown to be used by approximately one third of MS patients who experience fecal incontinence (Gulick, 2010). Use of these pads can conceal the incontinence problem from others particularly if the quantity of lost stool is small. When soiling of the pad occurs, it needs to be changed in order to prevent skin breakdown of the perineum and/or buttocks that can result in incontinence dermatitis and/or pressure ulcers (Whitely, 2007).

### **7.3.5 Biofeedback for fecal incontinence**

This intervention may be helpful by improving the strength of pelvic floor muscles and rectal sensory perception to improve anorectal coordination (Nordenbo, et al. 1996). Biofeedback retraining is more successful in persons with MS with limited disability and a non-progressive disease course (Wiesel, et al. 2000).

### **7.3.6 Antidiarrheal medications**

These medications remain the main treatment for fecal incontinence. In taking antidiarrheal medications patients need to be cautioned about the potential adverse effects of dehydration. Antidiarrheal medications have been shown to be used by approximately one third of MS patients who experience fecal incontinence (Gulick, 2010). Commonly used antidiarrheal medications (Walker, 2006) are shown in Table 5.



### **7.3.7 Anal plug**

132 Constipation – Causes, Diagnosis and Treatment

Biofeedback retraining is more successful in persons with MS with limited disability and a

These medications remain the main treatment for fecal incontinence. In taking antidiarrheal medications patients need to be cautioned about the potential adverse effects of dehydration. Antidiarrheal medications have been shown to be used by approximately one third of MS patients who experience fecal incontinence (Gulick, 2010). Commonly used

**Medication Action Precautions and/or** 

**Contraindications** 

Occasional dizziness and constipation may occur. Infrequent occurrence of abdominal pain, abdominal distention, nausea, vomiting, dry

mouth, fatigue, and hypersensitivity reactions.

quinolone antibiotics.

Discontinue drug if one experiences extreme thirst, decreased urination, muscle cramps, or weakness.

Shown to promptly and significantly reduce total stool output in 48 to 72 hours after initiation of treatment. Is well tolerated in adults and children.

Mild tinnitus is a dose-related side effect that may be associated with moderate to severe salicylate toxicity. Discontinue drug if tinnitus occurs. The drug may interact with other medications, such as aspirin, tetracycline and

non-progressive disease course (Wiesel, et al. 2000).

antidiarrheal medications (Walker, 2006) are shown in Table 5.

secretion.

Slows intestinal motility, allowing absorption of electrolytes and water through the intestine and decreased gastro-intestinal

Reduces the frequency of unformed stools, increases stool consistency, relieves symptoms of abdominal cramping, and decreases nausea and vomiting.

Slows intestinal contractions and peristalisis allowing the body to consolidate intestinal contents and prolong transit time, thus allowing the intestines to draw moisture out of the intestinal material to stop the formation of loose

Acts as a peripherally acting enkephalinase inhibitor that has an antisecretory effect by reducing secretion of water and electrolytes into the

or liquid stools.

intestine

Table 5. Medications used to Manage Fecal Incontinence

**7.3.6 Antidiarrheal medications** 

Loperamide, Imodium®

Bismuth Subsalicylate, Kaopectate®

Diphenoxylate/ Atropine, Lomotil®

Racecadotril Acetorphan Hidrasec®

The anal plug has been developed to prevent loss of stool and is a disposable device for patients with anorectal incontinence. In a study of 10 patients with incontinence to gas and both liquid and solid stool the use of variable anal plugs for three consecutive weeks resulted in one patient withdrawing from the study due to discomfort of the anal plug, and for the remaining subjects there were no episodes of incontinence during 82% of time in which anal plugs were used with a median time of 7 to 12 hours depending on type of plug (Mortensen & Humphreys, 1991). Norton and Kamm (1999) evaluated two sizes of anal plugs each of which was tested for a two week period in a sample of 20 ambulatory and selfcaring patients with intractable fecal incontinence for solid or liquid stool. Results indicated that the majority 14 (70%) could not tolerate a plug due to discomfort but for those that could tolerate the plug, it was highly successful at controlling fecal incontinence. Patients with neurogenic bowel dysfunction and have attenuated anorectal sensation may tolerate the presence of the anal plug (Emmanuel, 2010). Research is needed to determine if the use of anal plugs are helpful in controlling fecal incontinence in persons with MS.

### **7.3.8 Sacral Nerve Stimulation**

Sacral nerve stimulation (SNS) for patients with severe fecal incontinence undergo implantation with a quadripolar electrode and pulse generator placed subcutaneously in the gluteal area (Tjandra, Chan, Yeh & Murray-Green, 2008). Compared to a control group who received medical therapy that comprised bulking agents, pelvic floor exercises, and dietary management, fecal incontinence was greatly improved with chronic SNS immediately after implantation and was sustained during the 12 month follow-up period in a randomized study of non-MS patients with severe fecal incontinence (Tjandra et al. 2008). Adverse events with SNS included pain at implant site which resolved after percutaneous aspiration and excessive tingling in the vaginal region. Research is needed to determine if the use of SNS is helpful in controlling fecal incontinence in persons with MS.

### **8. Outcome of various management strategies for bowel dysfunction in persons with MS**

Possibly due to the multiplicity of causes of bowel dysfunction in persons with MS the outcome from the various treatment/intervention approaches have not yielded very satisfactory results. In a study of bowel dysfunction among persons with MS, Gulick (2010) noted that 54.1% (99/183) reported their constipation had worsened over time; 38.6% (22/57) reported their fecal incontinence worsened over time; and 71.8% (117/163) who experienced both constipation and fecal incontinence reported their constipation problem had worsened over time. Additionally, a survey of MS respondents who reportedly used a wide range of strategies to manage their bowel problems indicated that few of them were rated as very helpful (Norton & Chelvanayagam, 2010).

Many conditions and treatments that accompany MS over its long term illness trajectory may as a single entity or in combination lead to bowel dysfunction. These conditions frequently include ambulation difficulty, spasticity, fatigue, depression, urinary incontinence and various medications. In addition to MS related causes of bowel dysfunction there may be other health problems unrelated to MS that can cause bowel dysfunction.

Studies clearly acknowledge the adverse impact that bowel dysfunction has on the quality of life of persons with MS as the various bowel problems greatly interfere with the person's physical and social activities, family relationships, which also lead to the development of considerable emotional distress (Gulick, 1997; Norton & Chelvanayagam, 2010; Nortvedt, Riise, Frugard, Mohn, Bakke, Skar, Nyland, Glad & Myhr, 2007; Wollin, Bennie, Leech, Windsor, & Spencer, 2005). With regard to bowel dysfunction, persons with MS report that fecal incontinence has a significantly greater negative impact on their quality of life than constipation (Gulick, 2011; Norton & Chelvanayagam, 2010). Of the various MS related symptoms, respondents in the study by Norton and Chelyanayagam reported that bowel dysfunction and bowel management had the greatest negative impact on their quality of life.

### **9. Conclusion**

Bowel dysfunction consisting of constipation and/or fecal incontinence is common in persons with MS. Causes of bowel dysfunction may be due to neurological lesions in the CNS or by non-neurological causes. The relapsing-remitting or progressive MS course may result in acute or chronic symptoms of constipation and/or fecal incontinence. Subjective and objective assessments of bowel symptoms using a team of specialists to determine the causes, appropriate treatment/intervention with ongoing monitoring of the condition is essential. Further studies with persons with MS are needed to determine the effectiveness of treatments/interventions given to improve bowel functions among those with bowel problems while controlling for confounding issues. Further study is also needed to determine the effectiveness of using objective laboratory procedures to identify or rule out specific causes of bowel problems.

### **10. References**


Studies clearly acknowledge the adverse impact that bowel dysfunction has on the quality of life of persons with MS as the various bowel problems greatly interfere with the person's physical and social activities, family relationships, which also lead to the development of considerable emotional distress (Gulick, 1997; Norton & Chelvanayagam, 2010; Nortvedt, Riise, Frugard, Mohn, Bakke, Skar, Nyland, Glad & Myhr, 2007; Wollin, Bennie, Leech, Windsor, & Spencer, 2005). With regard to bowel dysfunction, persons with MS report that fecal incontinence has a significantly greater negative impact on their quality of life than constipation (Gulick, 2011; Norton & Chelvanayagam, 2010). Of the various MS related symptoms, respondents in the study by Norton and Chelyanayagam reported that bowel dysfunction and bowel management had the greatest negative impact on their quality of

Bowel dysfunction consisting of constipation and/or fecal incontinence is common in persons with MS. Causes of bowel dysfunction may be due to neurological lesions in the CNS or by non-neurological causes. The relapsing-remitting or progressive MS course may result in acute or chronic symptoms of constipation and/or fecal incontinence. Subjective and objective assessments of bowel symptoms using a team of specialists to determine the causes, appropriate treatment/intervention with ongoing monitoring of the condition is essential. Further studies with persons with MS are needed to determine the effectiveness of treatments/interventions given to improve bowel functions among those with bowel problems while controlling for confounding issues. Further study is also needed to determine the effectiveness of using objective laboratory procedures to identify or rule out

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### **Multimodal Treatment of Constipation: Surgery, Rehabilitation or Both?**

Luigi Brusciano et al.\*

*XI Division of General and Obesity Surgery, Master in Coloproctology, Second University of Naples Italy* 

### **1. Introduction**

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*self-care,* R.R. Berardi, L.A. Kroon, J.H. McDermott, G.D. Newton, M.A. Oszko, N.G. Popovich, T.L. Remington, C.J. Rollins, L.A. Shimp, & K. J. Tietze, (Eds.), 327--350,

F., Pasquis, P. & Denis, P. (1987). Radiopague markers transit and anorectal manometry in 16 patients with multiple sclerosis and urinary bladder dysfunction. Constipation accounts for 20% in western world population. In absence of any organic aetiology, this disorder may be related to bad alimentary habits based on inadequate introduction of the three components of stool (fibres, probiotics and water) that are essential for the physiologic activity of colon. Chronic constipation may be also associated with either colic or rectal anatomo-functional alterations. Colonic constipation (slow transit constipation) is usually related to a motility disorder (inertia coli) associated with a reduction of propagating contraction waves and decreased Cajal' cells; on the other hand, rectal outlet dysfunction type constipation may be related to anatomical alterations (e.g. internal mucosal prolapse, rectocele) causing difficult rectal outlet and functional pelviperineal dyssynergia. The physiologic defaecatory act involves not only synchronism between rectum and anus, but even correct thoraco-abdominoperineal dynamics and vertebral position. This has to be carefully assessed by considering patient's ability to accomplish adequate thoraco-abdominoperineal muscle movements needed for both adequate defaecatory dynamics and urine and stool retention. Therefore, the ideal treatment should not only address anatomical alterations such as mucosal prolapse, rectocele, rectorectal intussusception and sphincter defects, usually requiring a surgical approach, but even functional disorders, often insidious and difficult to detect. Surgery is mandatory to treat pathological findings, that physically represent an obstacle to fecal transit in the rectum. Many surgical techniques have been developed for the treatment of outlet obstruction with conflicting results. STARR (stapled transanal rectal resection) is a new surgical procedure that was launched by Longo in 2001. It is a minimally invasive transanal operation for rectocele and mucosal/rectal prolapse using a double circular stapler. This procedure is indicated when rectal mucosal prolapse is thought to be the cause of difficult defecation, and appears to be a rational treatment. This treatment aims to normalize the anatomical relationship of the anal mucosa with hemorrhoidal piles and anal sphincters by restoring the prolapse and improving venous perfusion. The procedure pulls the anal

<sup>\*</sup> Crescenzo Di Stazio, Paolo Limongelli, Gian Mattia Del Genio, Salvatore Tolone, Saverio Sansone, Francesco Lucido, Ignazio Verde, Antonio D'Alessandro, Roberto Ruggiero, Simona Gili, Assia Topatino, Vincenzo Amoroso, Pina Casalino, Giovanni Docimo and Ludovico Docimo

*XI Division of General and Obesity Surgery. Master in Coloproctology. Second University of Naples, Italy* 

mucosa and perianal tissues upwards and decreases the friction and impact on the tissue surface, which is a cause of difficult defecation. In the mechanism of defecation, the movement associated with the anal sphincters is triggered by the sensory perception on the anal mucosa and anal skin. If the physiological functions of all the involved organs are under optimal conditions, then the mucosa and sphincters can maintain the normal anatomical relationshiep. In January 2006, the European STARR registry was initiated. According to the results published in 2009 on 2838 patients, the improvement in rectal function and quality of life was statistically significant. A multicenter study conducted in Spain between 2001 and 2006 concluded that this procedure is associated with low morbidity and short hospital stay and is an effective treatment option for obstructed defecation syndrome. According to a Milan study reported in 2008, STARR is safe and effective in the treatment of solitary rectal ulcer associated with internal rectal prolapse and has minimal complications and no recurrence after 2 years (Boccasanta et al., 2008). After operation functional outcome shows an improvement in defecation with reduction of the mean Constipation Score. Less pain during evacuation was reported by patients, also as a consequence of reduced pushing to defecate and reduced use of digital assistance. The frequency of complete defecation was increased, so the patient's satisfaction was favorable. Anorectal manometry reveals decrease in the maximum resting and squeezing pressure of the anal canal and in rectal compliance until one month after the operation, compared with the preoperative levels, but they recovered to preoperative levels at 6 months after the operation. This effect is probably the consequence of the anal stretching during operation. Patients show increase in basal sphincter pressure and maximal squeeze pressure, probably for the absence of inhibition that was acted by redundant rectal mucosa on the transitional zone. Recently, a new device the CCS-30 Contour Transtarr was developed by the same Professor Longo. A multicenter prospective study from Naples confirms that the device is effective and safe and has functional results similar to those of the conventional STARR (Renzi et al., 2008). This procedure (with both techniques), according to most authors, is effective; the postoperative pain is mild, and the procedure is very much accepted among colorectal surgeons for the treatment of rectocele as well as for internal rectal prolapse in patients with obstructed defecation. Yet, it should be emphasized that STARR is associated with complications such as postoperative bleeding, chronic proctalgia, rectovaginal fistula, stricture, and fecal incontinence (Gagliardi et al., 2008). Some of these are "learning curve" complications and can be avoided instead many authors stress that if this procedure is performed in selected cases by skilled specialists, most complications can be avoided. The use of an anastomotic stapler has been reported to result in a higher rate of anastomotic stricture formation. However, staples applied to the lower mucosal layer with few connecting tissues are eliminated during a short time, and do not form granuloma that might induce stenosis. In patients with enterocele and puborectalis dyssynergia, this procedure is contraindicated (unless the enterocele is repaired simultaneously on laparoscopy). In view of conflicting reports on the safety and efficacy of the STARR procedure, a European group of experts was founded in October 2006; and in June 2008, following a consensus conference with evidencebased conclusions, they published guidelines on inclusion and exclusion criteria as well as a diagnostic and therapeutic algorithm for the STARR procedure in ODS. These recommendations were based on the experience of 11 specialists in coloproctology and pelvic floor disease, pioneers in the STARR procedure, and it was concluded after a 100% consensus within the group. It was also concluded that this procedure can be performed with either of the devices, depending on the size of the prolapsed or rectocele and on the personal experience

mucosa and perianal tissues upwards and decreases the friction and impact on the tissue surface, which is a cause of difficult defecation. In the mechanism of defecation, the movement associated with the anal sphincters is triggered by the sensory perception on the anal mucosa and anal skin. If the physiological functions of all the involved organs are under optimal conditions, then the mucosa and sphincters can maintain the normal anatomical relationshiep. In January 2006, the European STARR registry was initiated. According to the results published in 2009 on 2838 patients, the improvement in rectal function and quality of life was statistically significant. A multicenter study conducted in Spain between 2001 and 2006 concluded that this procedure is associated with low morbidity and short hospital stay and is an effective treatment option for obstructed defecation syndrome. According to a Milan study reported in 2008, STARR is safe and effective in the treatment of solitary rectal ulcer associated with internal rectal prolapse and has minimal complications and no recurrence after 2 years (Boccasanta et al., 2008). After operation functional outcome shows an improvement in defecation with reduction of the mean Constipation Score. Less pain during evacuation was reported by patients, also as a consequence of reduced pushing to defecate and reduced use of digital assistance. The frequency of complete defecation was increased, so the patient's satisfaction was favorable. Anorectal manometry reveals decrease in the maximum resting and squeezing pressure of the anal canal and in rectal compliance until one month after the operation, compared with the preoperative levels, but they recovered to preoperative levels at 6 months after the operation. This effect is probably the consequence of the anal stretching during operation. Patients show increase in basal sphincter pressure and maximal squeeze pressure, probably for the absence of inhibition that was acted by redundant rectal mucosa on the transitional zone. Recently, a new device the CCS-30 Contour Transtarr was developed by the same Professor Longo. A multicenter prospective study from Naples confirms that the device is effective and safe and has functional results similar to those of the conventional STARR (Renzi et al., 2008). This procedure (with both techniques), according to most authors, is effective; the postoperative pain is mild, and the procedure is very much accepted among colorectal surgeons for the treatment of rectocele as well as for internal rectal prolapse in patients with obstructed defecation. Yet, it should be emphasized that STARR is associated with complications such as postoperative bleeding, chronic proctalgia, rectovaginal fistula, stricture, and fecal incontinence (Gagliardi et al., 2008). Some of these are "learning curve" complications and can be avoided instead many authors stress that if this procedure is performed in selected cases by skilled specialists, most complications can be avoided. The use of an anastomotic stapler has been reported to result in a higher rate of anastomotic stricture formation. However, staples applied to the lower mucosal layer with few connecting tissues are eliminated during a short time, and do not form granuloma that might induce stenosis. In patients with enterocele and puborectalis dyssynergia, this procedure is contraindicated (unless the enterocele is repaired simultaneously on laparoscopy). In view of conflicting reports on the safety and efficacy of the STARR procedure, a European group of experts was founded in October 2006; and in June 2008, following a consensus conference with evidencebased conclusions, they published guidelines on inclusion and exclusion criteria as well as a diagnostic and therapeutic algorithm for the STARR procedure in ODS. These recommendations were based on the experience of 11 specialists in coloproctology and pelvic floor disease, pioneers in the STARR procedure, and it was concluded after a 100% consensus within the group. It was also concluded that this procedure can be performed with either of the devices, depending on the size of the prolapsed or rectocele and on the personal experience of the surgeon. Patient selection is crucial, as is the use of the standardized diagnostic and therapeutic approach. A considerable example of this is given by the study of Zehler that compared functional and clinical short and long-term outcome after stapled transanal rectal resection and found results after 1 year comparable with the functional outcome even after 5 years. The median clinical score improved significantly already after 1 year in these patients and remained stable at 5-year follow-up. In contrast, those patients who failed treatment showing no improvement in the short term, remained symptomatic without improvement in OOS and SSS scores. Eighty per cent of the patients were still satisfied. The author concludes that short-term improvement after STARR predicts long-term outcome in obstructed defecation syndrome caused by a rectocele. The reason of such findings is probably the unaccomplished diagnosis of the disease with an omission of the functional aspect of the trouble. In those patients showing poor outcome, or unstable with time, the functional disturbance was probably prevalent compared to anatomical; diagnosis missed this aspect and consequently treatment was inadequate. Pelviperineal dyssynergia is a functional alteration, characterized by absence of puborectalis muscle relaxation, and inability to relax pelvic floor during attempted defecation. This can cause a delay of rectal stool transit, so that the rectum itself reabsorbs water and stools become harder, drier and difficult to evacuate. Clinically, this can result in painful effort, bleeding after defecation, long periods spent in bathroom, digitation, and sense of incomplete evacuation. In the long term patient may develop reduction of rectal sensitivity with larger volumes of faeces required to feel the need to evacuate (Brusciano et al., 2009). The frequent presence of concurrent alterations (anatomical and functional) causing the symptoms is the explanation of worse results than expected after treatment. This is particularly frequent in those with a thoraco-abdomino-perineal dyssynergia not adequately recognized and simultaneously treated. Supporting this theory Rao showed that systematically assessing anorectal physiology in patients with defecation disorders revealed new information in 88% of patients that led to a change in the management in 76% of cases. Pelviperineal rehabilitation, that teaches patients how to relax pelvic floor muscles, has showed good results by treating the functional aspect of pelvic floor disorders. Nowadays treatment comprises a series of rehabilitation techniques as physiokinesitherapy, biofeedback, electrostimulation and volumetric rehabilitation. Previously published studies reporting on the use of rehabilitation techniques such as biofeedback, muscular training and electrostimulation, have showed a success rate ranging between 47% and 100%. There is lack of agreement on a standard test to select patients who may benefit from such treatment. Particularly, although a clinical and instrumental work-up is commonly carried out by proctologists to characterize these patients, physiatric assessment is not thoroughly accomplished. To correctly approach the problem each aspect of pathology must be detected and specifically treated, with surgery (when anatomical), rehabilitation (when functional) or both (when associated). While the anatomical aspect of the problem is commonly detected by standard clinical and instrumental work-up associated functional disorders are often neglected. A diagnostic protocol, including the evaluation of either physiatric or instrumental findings, has been previously reported by our group to identify patients amenable for pelviperineal rehabilitation treatment (Brusciano et al., 2007). The protocol is based on proctologic examination, clinico-physiatric assessment (puborectalis contraction, pubococcygeal test, perineal defence reflex, muscular synergies, postural examination) and instrumental evaluation (anorectal manometry, anal US and dynamic defaecography).

### **2. Diagnostic protocol**

*Clinical and functional evaluation* was based on the analysis of the following parameters:

Puborectalis relaxation (relaxation pattern), searching for a paradox muscle's contraction and absence or incomplete relaxation, by rectal examination.

Pubococcygeal (PC) test (puborectalis contraction pattern) evaluating either the phasic contraction, subjectively classified as good, moderate or fair, or the tonic contraction by asking patient to contract the anus, for the longest period of time (classified as good when >9 sec; moderate when ranging between 2 and 9 sec; or fair when < 2sec). The muscular fatigue is also assessed by asking patient to contract the anus as many times as possible for at least 5 seconds, and to rest for 10 sec (classifying it as good when more then 9 times; moderate when ranging between 2 and 9 times; fair when <less than 2 times).

Perineal defence reflex consisted in the assessment of pelvic floor and abdominal muscles' action, following an intra-abdominal pressure's increase. Patient is asked to cough, so that the physician can notice the perineal muscles' contraction, resulting either in a physiological rising (reflex present) or a pathological descending (reflex absent) that, if marked, can be associated with emission of urine and flatulence.

Muscular synergyes, i.e. the activity of both agonist (glutei and abductors) and antagonist muscles (abdominals, diaphragm), were evaluated in Sims' position by asking the patient to contract the anus, after placing a hand over the abdominal wall while observing gluteus and abductor contraction.

Muscle synergy was defined as agonist, by the simultaneous contraction of anus and either glutei or abductors, whereas antagonist by the simultaneous contraction of anus and abdominal muscle.

Postural examination was based on the evaluation of lumbar lordosis by using a "plumb line". This is a straight line formed by a string attached to a hanging weight. It establishes a vertical line which is straight up and down the spine. The distance between the "plumb line" and the spinous process of L3 is measured by a ruler considering a range between 25 and 35 mm as normal*.*

### **2.1 Instrumental assessment**

Anorectal manometry evaluated a series of distinct parameters:

anal resting pressure (ARP) (normal value between 55 and 75 mmHg; hypertonic if > 75 mmHg; hypotonic if < 50 mmHg);

maximal voluntary contraction (MCV) (amplitude normal value if > 120 mmHg; duration normal value if > 22 sec);

rectal sensory included conscious rectal sensory threshold (CRST) (normal value 25-45 ml), and maximum tolerated volume (MCV) (normal value 80-160 ml) , defining either hyposensitivity (MTV > 160 or CRST > 40) or hypersensitivity (CRST < 40);

rectoanal inhibitory reflex (RAIR) by considering both the percentage of relaxation ( normal values 85%) and the balloon expulsion test (the balloon was filled up with air until the

Puborectalis relaxation (relaxation pattern), searching for a paradox muscle's contraction

Pubococcygeal (PC) test (puborectalis contraction pattern) evaluating either the phasic contraction, subjectively classified as good, moderate or fair, or the tonic contraction by asking patient to contract the anus, for the longest period of time (classified as good when >9 sec; moderate when ranging between 2 and 9 sec; or fair when < 2sec). The muscular fatigue is also assessed by asking patient to contract the anus as many times as possible for at least 5 seconds, and to rest for 10 sec (classifying it as good when more then 9 times;

Perineal defence reflex consisted in the assessment of pelvic floor and abdominal muscles' action, following an intra-abdominal pressure's increase. Patient is asked to cough, so that the physician can notice the perineal muscles' contraction, resulting either in a physiological rising (reflex present) or a pathological descending (reflex absent) that, if marked, can be

Muscular synergyes, i.e. the activity of both agonist (glutei and abductors) and antagonist muscles (abdominals, diaphragm), were evaluated in Sims' position by asking the patient to contract the anus, after placing a hand over the abdominal wall while observing gluteus and

Muscle synergy was defined as agonist, by the simultaneous contraction of anus and either glutei or abductors, whereas antagonist by the simultaneous contraction of anus and

Postural examination was based on the evaluation of lumbar lordosis by using a "plumb line". This is a straight line formed by a string attached to a hanging weight. It establishes a vertical line which is straight up and down the spine. The distance between the "plumb line" and the spinous process of L3 is measured by a ruler considering a range between 25

anal resting pressure (ARP) (normal value between 55 and 75 mmHg; hypertonic if > 75

maximal voluntary contraction (MCV) (amplitude normal value if > 120 mmHg; duration

rectal sensory included conscious rectal sensory threshold (CRST) (normal value 25-45 ml), and maximum tolerated volume (MCV) (normal value 80-160 ml) , defining either

rectoanal inhibitory reflex (RAIR) by considering both the percentage of relaxation ( normal values 85%) and the balloon expulsion test (the balloon was filled up with air until the

hyposensitivity (MTV > 160 or CRST > 40) or hypersensitivity (CRST < 40);

*Clinical and functional evaluation* was based on the analysis of the following parameters:

moderate when ranging between 2 and 9 times; fair when <less than 2 times).

and absence or incomplete relaxation, by rectal examination.

associated with emission of urine and flatulence.

**2. Diagnostic protocol** 

abductor contraction.

abdominal muscle.

and 35 mm as normal*.*

**2.1 Instrumental assessment** 

mmHg; hypotonic if < 50 mmHg);

normal value if > 22 sec);

Anorectal manometry evaluated a series of distinct parameters:

subject reported desire to defecate: the ballon was considered not expelled if the time required by the patient overcame 1 minute).

Defaecography evaluated the pelvic floor descent. This was defined as the vertical distance between the pubococcygeal line and the ano-rectal junction in straining (expressed in millimetres) A distance greater than 4 cm was considered as pathologic perineal descent.

Anal ultrasonography assessed the puborectalis relaxation. The absence of relaxation of the puborectalis muscle was defined when no increase of the distance between the inner edge of the muscle posteriorly and the probe measured at rest and on straining was detectable. In female patients the puborectalis relaxation was also evaluated by vaginal US that leaves the puborectalis sling relatively undisturbed and therefore more free to relax.

To assess potential implications of these parameters, considered responsible of constipation, in the functional aspects of these disorders we compared them in a large number of patients with constipation and incontinence as well as in healthy controls.

Several altered parameters were identified in patients with constipation or incontinence compared to HC demonstrating strong correlations between physiatric disorders and the symptoms.

We, moreover, recently performed further studies that show how successful specific treatment of the physiatric disorders, in patients with altered physiatric parameters, improves proctologic symptoms.

These results allow to suppose a causal relationship between physiatric parameters, functional alteration and clinical symptoms.

A rehabilitation scheme based on different techniques (biofeedback, electrostimulation, physiokinesitherapy, and volumetric rehabilitation) should seek to correct those functional alterations. For instance, the finding of lumbar lordosis needs to be treated by postural physiokinesitherapy, whereas the absence of perineal defense reflex needs physiokinesitherapy to synchronize the muscular function of the thoracic, abdominal, and pelviperineal muscle district. On the other hand, an absence of puborectalis muscle relaxation and a decrease in the maximum voluntary contraction of external anal sphincter should be managed by biofeedback and electrostimulation therapy.

Another example, in the case of a constipated patient with a rectocele, and with concurrent abnormal rectal sensation or non-relaxing puborectalis muscle on straining and alteration of recto anal inhibitory reflex (RAIR), although surgical correction will improve rectal emptying, therapy could not be considered appropriate without addressing the functional component of the syndrome.

Similarly, the mere treatment of the functional disorders without correcting anatomical alteration is a sketchy therapy. Concerning this, we also assessed the outcome of rehabilitation treatment, using the rehabilitation diagnostic protocol, in patients with or without previous surgery for rectal outlet obstruction.

All patients selected for rehabilitation treatment were divided into two groups:

group A consisted of patients with rectal outlet obstruction never submitted to previous surgical treatment;

group B consisted of patients operated of STARR procedure for rectal outlet obtruction (with a rectocele > 4 cm, rectal internal mucosal prolapse, and recto-rectal and recto-anal intussusceptions).

We observed in both groups significant improvement of physiatric parameters while operated patients showed better clinical outcome at six months follow-up. These results support the theory of a multifactorial pathogenesis of such disorders and show that specific treatment of different components causing the same symptoms is the best approach with the best outcome.

### **3. Pelvi-perineal rehabilitation programme**

Patients were offered one session of treatment, lasting an average of 45 minutes, every 5 days for a minimum of 10-12 overall sessions. The rehabilitation treatment aims to correct the thoraco-abdomino-perineal dyssinergia by using different means as physiokinesytherapy (by operator's hands), biofeedback and electrostimulation (by specific probes) and volumetric rehabilitation (by enema). Although the sequential use of these different tools may differ among patients, all techniques are indispensable for a thorough rehabilitation treatment as following described. Firstly, patients were informed on the anatomical and physiological principles of pelvic floor district, stressing on the importance of the re-educational aspect of rehabilitation. Thus, patients should be knowledged in terms of anatomical and physiological notions on which body area is to be treated, in order to best interact during rehabilitation. By performing anal and/or vaginal digital exploration, physician highlights puborectalis anatomical position, inviting patients either to pushing out or squeezing to respectively simulate evacuation or stool retention. Moreover, patients were informed about the role of thoraco-abdominal and perineal muscles districts, whose synergy is determinant for an adequate defaecation act; one way to let patient learn this harmony between thoracoabdominal-perineal districts is to show the distinction between thoracic and abdominal breathing. Rehabilitation treatment was based on four different techniques:

1. Physiokinesitherapy, obtained throughout thoraco-abdomino-perineal muscles coordination training, as previously described. According to Bourdiol-Bortolin technique, patients were taught to direct propulsive force into the pelvis by taking a deep breath, contracting the upper abdominal and diaphragmatic muscles (diaphragmatic breathing exercises), and simultaneously relaxing and protruding the lower abdomen. A visible protrusion of the latter, indicated a correct performance. Unlike other rehabilitation techniques specifically focused on pelvic floor dyssinergia, physiokinesotherapy aims to treat postural defects and limitation of hips motion as well as improve respiratory dynamics required for the stability of thoraco-abdominal and perineal muscles districts. The need for such a treatment have to be highlighted with a general evaluation (while often attention is focused on pelvic district) to identify postural defects, articular blocks (specially lumbosacral) or anomaly in respiratory dynamics.

2. external electrical stimulation was used to help patients to be conscious of the perineal district and then improve its muscles performance. It was performed using an anal probe with pulse generator (Pelveen Care, Coloplast, Bologna Italia). Indeed, an adequate electrical stimulation method, along with standard values of different parameters, have not yet been determined in patients with defaecatory disorders. Prior to therapy the electrical stimulation level fit for each patient, was evaluated by fixing it just below the point where patient started to feel either discomfort or pain. Stimulation therapy was performed once a day, for 20 min over 10–12 sessions either at outpatient clinic or home.

3. Biofeedback (BFT) was performed using the electromyographic (EMG) biofeedback system (Pelveen Care, Coloplast, Bologna Italy). The visual feedback was provided by observing changes in pressure activity on a monitor screen. The patients were taught to practice mainly contraction and relaxation manoeuvres of the anal canal, meanwhile evaluating the activity of abdominal muscles or glutei/abductors muscles, by using the surface electromyography. Each session lasted 30–50 min over 10–14 sessions.

4. The principles of volumetric rehabilitation (VR) are based on the mechanical distension of the rectum (enema)

The aim of this technique is to restore the impaired rectal sensation. The technique involves the administration, twice daily, of a tepid water enema. The initial volume equals the manometric maximum tolerated volume (MTV) or conscious rectal sensitivity threshold (CRST) on the basis of the underlined defaecatory disorders. The subject is asked to hold the liquid after perceiving it in the rectum, by strongly contracting the anus for no more than 30 seconds. The last step is to expel the water through a relaxation of the pelvic floor and an effective abdominal straining. The goal of this rehabilitation technique is to let patient understand the three basic phases of the defaecatory act (perception; retaining; passing), in order to become aware of the pelviperineal muscolar activity. Thus, patients may improve their own rectal sensibility. Patients are instructed to self-administer the enemas at home.

### **4. Results**

144 Constipation – Causes, Diagnosis and Treatment

group B consisted of patients operated of STARR procedure for rectal outlet obtruction (with a rectocele > 4 cm, rectal internal mucosal prolapse, and recto-rectal and recto-anal

We observed in both groups significant improvement of physiatric parameters while operated patients showed better clinical outcome at six months follow-up. These results support the theory of a multifactorial pathogenesis of such disorders and show that specific treatment of different components causing the same symptoms is the best approach with the best outcome.

Patients were offered one session of treatment, lasting an average of 45 minutes, every 5 days for a minimum of 10-12 overall sessions. The rehabilitation treatment aims to correct the thoraco-abdomino-perineal dyssinergia by using different means as physiokinesytherapy (by operator's hands), biofeedback and electrostimulation (by specific probes) and volumetric rehabilitation (by enema). Although the sequential use of these different tools may differ among patients, all techniques are indispensable for a thorough rehabilitation treatment as following described. Firstly, patients were informed on the anatomical and physiological principles of pelvic floor district, stressing on the importance of the re-educational aspect of rehabilitation. Thus, patients should be knowledged in terms of anatomical and physiological notions on which body area is to be treated, in order to best interact during rehabilitation. By performing anal and/or vaginal digital exploration, physician highlights puborectalis anatomical position, inviting patients either to pushing out or squeezing to respectively simulate evacuation or stool retention. Moreover, patients were informed about the role of thoraco-abdominal and perineal muscles districts, whose synergy is determinant for an adequate defaecation act; one way to let patient learn this harmony between thoracoabdominal-perineal districts is to show the distinction between thoracic and abdominal

1. Physiokinesitherapy, obtained throughout thoraco-abdomino-perineal muscles coordination training, as previously described. According to Bourdiol-Bortolin technique, patients were taught to direct propulsive force into the pelvis by taking a deep breath, contracting the upper abdominal and diaphragmatic muscles (diaphragmatic breathing exercises), and simultaneously relaxing and protruding the lower abdomen. A visible protrusion of the latter, indicated a correct performance. Unlike other rehabilitation techniques specifically focused on pelvic floor dyssinergia, physiokinesotherapy aims to treat postural defects and limitation of hips motion as well as improve respiratory dynamics required for the stability of thoraco-abdominal and perineal muscles districts. The need for such a treatment have to be highlighted with a general evaluation (while often attention is focused on pelvic district) to identify postural defects, articular blocks (specially lumbo-

2. external electrical stimulation was used to help patients to be conscious of the perineal district and then improve its muscles performance. It was performed using an anal probe with pulse generator (Pelveen Care, Coloplast, Bologna Italia). Indeed, an adequate electrical stimulation method, along with standard values of different parameters, have not yet been determined in patients with defaecatory disorders. Prior to therapy the electrical stimulation level fit for each patient, was evaluated by fixing it just below the point where

breathing. Rehabilitation treatment was based on four different techniques:

intussusceptions).

**3. Pelvi-perineal rehabilitation programme** 

sacral) or anomaly in respiratory dynamics.

In our study the diagnostic protocol revealed abnormal values in symptomatic patients compared to Healthy Controls. Particularly they showed significantly higher values of lumbar lordosis values as well as lower rate in the presence of both perineal defence reflex and puborectalis relaxation. Furthermore patients performed a worse PC tests and showed a higher rate of muscle synergies presence (either agonist or antagonist) as compared to controls. Instrumental diagnostic examination also evidenced important differences between groups for all analyzed parameters; both manometric and defecographic patterns resulted pathologically skewed in terms of values or percentage comparing patients with Healthy Controls. Rehabilitation treatment acted positively on symptoms and exerted a tangible action on all evaluated clinical-instrumental parameters. Along with the Wexner score, all clinico-physiatric parameters (lumbar lordosis, perineal defence reflex, pubo-rectalis relaxation, PC test and agonist and antagonist muscular synergies) significantly improved after treatment. Some parameters received a particularly positive influence by rehabilitation: correction of lumbar lordosis was rapidly achieved with restoration of physiologic posture by means of physiatric exercises and this allows to reach a correct extension of pubo-rectalis muscle and, consequently, a better function with an improved grade of relaxation. Also Pubococcygeal (PC) test (puborectalis contraction pattern) recorded a great improvement after treatment, both about the entity than about the duration of contraction and the muscular fatigue. This effect is clearly consequence of muscular exercise, as for any other skeletal muscle, and is associated to hypertrophy. For the same reason this effect is strictly dependent by exercise and in the long term, with a reduction of interest by patient, it tends to decrease. To the contrary improvement of agonist antagonist muscular synergies tends to be stable with time; rehabilitation produced a strong impact on this parameter by teaching patients to correctly recruit muscles involved in one action and to selectively relax those opponents. This learned pattern of muscular contraction and relaxation involves many different anatomical structure, and his target is the instauration of an harmonic interaction between thoracic abdominal and pelvic districts. Clinical improvements reflexes on instrumental findings; particularly manometrics parameters showing positive modification were anal resting pressure, rectal sensation, recto-anal inhibitory reflex and duration of MCV, and balloon expulsion test. Those are expression of muscular reinforcement and coordination but also of sensitive improvement and consciousness. Finally both groups showed improvement in PAC-QOL after rehabilitation treatment. Scanty reports have been published in literature regarding the assessment of patients affected by rectal outlet obstruction and amenable for pelviperineal rehabilitation treatment. Our results seem to justify the need for conducting in patients with defaecatory disorders, an extensive diagnostic protocol based on the evaluation of 14 different parameters aiming to identify muscle dyssynergia. In our opinion, it would not seem fair to select patients on the basis of a single modified parameter (e.g. absence of puborectalis muscle relaxation) as usually reported by the majority of proctologists, whereas a thorough pre-treatment study protocol may help to better understand the physiopathologic mechanisms underlying each patient's clinical picture and to predict the impact of rehabilitation on outcome. The frequent finding of anatomical alterations in patients with constipation is probably the reason of the great rate of unrecognized functional disorders. Those anatomical abnormality are commonly considered the only responsible of symptoms and often the therapy is focused selectively on their correction with a complete omission of functional aspects also composing the clinical picture. Consequently surgical therapy of such a patient will be only a partial correction of the problem, with incomplete resolution of symptoms and predisposing to recurrence. A systematic evaluation of those patients, with particular attention to functional patterns, should be considered as a routine diagnostic protocol to clearly understand each aspect of the pathology and to allow a tailored surgical, rehabilitative or combined treatment.

#### **5. References**


### **Core Aspects of Clinical Development and Trials in Chronic Idiopathic Constipation**

M. Scott Harris and Oranee T. Daniels

*Georgetown University School of Medicine and Theravance, Inc. USA* 

### **1. Introduction**

146 Constipation – Causes, Diagnosis and Treatment

patients to correctly recruit muscles involved in one action and to selectively relax those opponents. This learned pattern of muscular contraction and relaxation involves many different anatomical structure, and his target is the instauration of an harmonic interaction between thoracic abdominal and pelvic districts. Clinical improvements reflexes on instrumental findings; particularly manometrics parameters showing positive modification were anal resting pressure, rectal sensation, recto-anal inhibitory reflex and duration of MCV, and balloon expulsion test. Those are expression of muscular reinforcement and coordination but also of sensitive improvement and consciousness. Finally both groups showed improvement in PAC-QOL after rehabilitation treatment. Scanty reports have been published in literature regarding the assessment of patients affected by rectal outlet obstruction and amenable for pelviperineal rehabilitation treatment. Our results seem to justify the need for conducting in patients with defaecatory disorders, an extensive diagnostic protocol based on the evaluation of 14 different parameters aiming to identify muscle dyssynergia. In our opinion, it would not seem fair to select patients on the basis of a single modified parameter (e.g. absence of puborectalis muscle relaxation) as usually reported by the majority of proctologists, whereas a thorough pre-treatment study protocol may help to better understand the physiopathologic mechanisms underlying each patient's clinical picture and to predict the impact of rehabilitation on outcome. The frequent finding of anatomical alterations in patients with constipation is probably the reason of the great rate of unrecognized functional disorders. Those anatomical abnormality are commonly considered the only responsible of symptoms and often the therapy is focused selectively on their correction with a complete omission of functional aspects also composing the clinical picture. Consequently surgical therapy of such a patient will be only a partial correction of the problem, with incomplete resolution of symptoms and predisposing to recurrence. A systematic evaluation of those patients, with particular attention to functional patterns, should be considered as a routine diagnostic protocol to clearly understand each aspect of

the pathology and to allow a tailored surgical, rehabilitative or combined treatment.

*aspects of these disorders.* Int J Colorectal Dis 2009; 24: 961-967.

Boccasanta P, Venturi M, Calabro G, Maccioco M, Roviaro GC. *Stapled transanal rectal* 

Brusciano L, Limongelli P, Del Genio G, Rossetti G, Sansone S, Healey A, Maffettone V,

Brusciano L, Limongelli P, del Genio G, Sansone S, Rossetti G, Maffettone V, Napolitano V,

Gagliardi G, Pescatori M, Altomare DF, et al. *Results, outcome, predictors and complications after stapled transanal resection for obstructed defecation. Dis Colon Rectum* 2008; 51: 186-95. Renzi A, Talento P, Giardiello C et al. *Stapled transanal rectal resection by a new dedicated device* 

*resection in solitary rectal ulcer associated with prolaps of the rectum: a prospective study.* 

Napolitano V, Pizza F, Tolone S, Del Genio A*. Clinical and instrumental parameters in patients with constipation and incontinence: their potential implications in the functional* 

Sagnelli C, Pizza F, del Genio A. *Useful parameters helping proctologists to identify patients with defaecatory disorders that may be treated with pelvic floor rehabilitation*. Tech

*for the surgical treatment of obstructed defecation syndrome caused by rectal intussusaption and rectocele: early results of a multicenter prospective study. Int J* 

**5. References** 

*Dis Colon Rectum* 2008; 51: 348-54.

Coloproctol. 2007 11:45–50

*Colorectal Dis* 2008; 23: 999-1005

Chronic constipation is one of the most common conditions, with prevalence by various estimates ranging from 1.9% to 27.2% in the American population (Bharucha et al., 2000; Higgins & Johanson, 2004; Shah et al., 2008). Treatment options range from older over-thecounter laxatives to recently approved prescription drug therapies (Longstreth et al., 2006; Motola et al., 2002; Ramkumar & Rao, 2005; Tack & Müller-Lissner, 2009; Tack et al., 2011; Tramonte et al., 1997). It has been estimated that 6 million to 8.5 million patients seek medical care for constipation each year. Over 70% of these individuals express dissatisfaction with prior medications, pointing to the need for new therapies (Johanson & Kralstein, 2007).

Drugs that have been recently approved or which are in late-stage trials for treatment of constipation are listed in Table 1. These include prokinetic agents (5-HT4 receptor agonists),


Table 1. Drugs recently approved or in late-stage clinical trials for chronic idiopathic constipation

secretagogues (guanylate cyclase C receptor agonists, bile acid transport inhibitors, Cl channel activators), and Na-H exchange inhibitors. Prokinetic agents promote colonic motor activity and propulsion, while secretagogues and Na-H exchange inhibitors either induce secretion of water and electrolytes or inhibit their absorption, resulting in more water in luminal contents. All of these agents appear to accelerate colonic transit time and accentuate stool output. There is little known at this point regarding comparative efficacy and safety between individual drugs or drug classes. Although speculative, it is likely that different drugs and drug classes will be used concomitantly in patients who fail to achieve the desired therapeutic response.

Serotonin (5-hydroxytryptamine, 5-HT) is a critical regulator of gastrointestinal motility, sensitivity, and secretion (Gershon, 2004). 5-HT triggers and coordinates intestinal peristalsis through 5-HT4 receptors expressed mainly on enteric neurons (Gershon & Tack, 2007). The safety of the 5-HT4 subclass has been brought into scrutiny because of the withdrawal of two previously marketed drugs, as will be discussed below. The highly selective 5-HT4 agonists currently under development are expected to exhibit more favorable safety profiles with low potential for cardiovascular side effects (DeMaeyer et al., 2008).

This review will provide an oversight of drugs that have been recently approved or are currently in late-stage clinical development for chronic idiopathic constipation (CIC). We will focus on methodologies (endpoints, study populations, biomarkers) that have been employed in proof-of-concept (Phase 2) and late-stage confirmatory clinical trials (Phase 3). We will discuss specific drug properties (dosing, drug-drug interactions, and specificity) that are the expected outcome of these trials. The goal of the clinical development program in CIC is to thoroughly document a drug profile with an acceptable balance between efficacy and safety.

The use of opioids and the side effects of opioid use have reached near epidemic proportions in the United States. The prevalence of constipation in this population is estimated to range between 20% and 70% (Bell et al., 2009; Brown et al., 2006; Kalso et al., 2004). While there have been considerable efforts directed towards the development of drugs for treating opioid-induced constipation, our review will focus on constipation from other causes.

### **2. Drug properties impacting clinical development**

### **2.1 Pharmacokinetic and pharmacodynamic profiles**

Compounds currently in clinical development are intended to be used as chronic oral therapies rather than periodically as rescue treatment. Therefore, pharmacokinetics of each compound after repeated dosing will play an important role in differentiating ease of use (i.e., once daily), potential accumulation, drug-drug interaction, etc. Drugs that promote more frequent and complete defecation may act locally on the GI mucosa or exert their effects systemically. The degree in which systemic exposure drives clinical efficacy varies by drug class, expected site of action in GI tract, and pharmacokinetics of each compound. High molecular weight (e.g., peptides) ordinarily renders a drug non-absorbable. Some constipation drugs have been postulated to exert their effects by local and systemic mechanisms simultaneously (Hoffman et al., 2010). 5-HT4 agonists currently under development are small molecules that are absorbed and systemically available, while the

secretagogues (guanylate cyclase C receptor agonists, bile acid transport inhibitors, Cl channel activators), and Na-H exchange inhibitors. Prokinetic agents promote colonic motor activity and propulsion, while secretagogues and Na-H exchange inhibitors either induce secretion of water and electrolytes or inhibit their absorption, resulting in more water in luminal contents. All of these agents appear to accelerate colonic transit time and accentuate stool output. There is little known at this point regarding comparative efficacy and safety between individual drugs or drug classes. Although speculative, it is likely that different drugs and drug classes will be used concomitantly in patients who fail to achieve the

Serotonin (5-hydroxytryptamine, 5-HT) is a critical regulator of gastrointestinal motility, sensitivity, and secretion (Gershon, 2004). 5-HT triggers and coordinates intestinal peristalsis through 5-HT4 receptors expressed mainly on enteric neurons (Gershon & Tack, 2007). The safety of the 5-HT4 subclass has been brought into scrutiny because of the withdrawal of two previously marketed drugs, as will be discussed below. The highly selective 5-HT4 agonists currently under development are expected to exhibit more favorable safety profiles with low

This review will provide an oversight of drugs that have been recently approved or are currently in late-stage clinical development for chronic idiopathic constipation (CIC). We will focus on methodologies (endpoints, study populations, biomarkers) that have been employed in proof-of-concept (Phase 2) and late-stage confirmatory clinical trials (Phase 3). We will discuss specific drug properties (dosing, drug-drug interactions, and specificity) that are the expected outcome of these trials. The goal of the clinical development program in CIC is to thoroughly document a drug profile with an acceptable balance between

The use of opioids and the side effects of opioid use have reached near epidemic proportions in the United States. The prevalence of constipation in this population is estimated to range between 20% and 70% (Bell et al., 2009; Brown et al., 2006; Kalso et al., 2004). While there have been considerable efforts directed towards the development of drugs for treating opioid-induced constipation, our review will focus on constipation from

Compounds currently in clinical development are intended to be used as chronic oral therapies rather than periodically as rescue treatment. Therefore, pharmacokinetics of each compound after repeated dosing will play an important role in differentiating ease of use (i.e., once daily), potential accumulation, drug-drug interaction, etc. Drugs that promote more frequent and complete defecation may act locally on the GI mucosa or exert their effects systemically. The degree in which systemic exposure drives clinical efficacy varies by drug class, expected site of action in GI tract, and pharmacokinetics of each compound. High molecular weight (e.g., peptides) ordinarily renders a drug non-absorbable. Some constipation drugs have been postulated to exert their effects by local and systemic mechanisms simultaneously (Hoffman et al., 2010). 5-HT4 agonists currently under development are small molecules that are absorbed and systemically available, while the

potential for cardiovascular side effects (DeMaeyer et al., 2008).

**2. Drug properties impacting clinical development 2.1 Pharmacokinetic and pharmacodynamic profiles** 

desired therapeutic response.

efficacy and safety.

other causes.

newer secretagogues, such as linaclotide and plecanatide, are peptides that are unabsorbed and systemically inert (Harris & Cromwell, 2007; Shailubhai et al., 2010). The maximal tolerated dose (MTD) of a systemically available drug depends on many factors, including end-organ toxicities and drug interactions, while the therapeutic limit of non- or minimally absorbed drugs mainly reflects GI tolerance. Irrespective of these considerations, all compounds for the treatment of constipation possess the inherent potential to produce diarrhea when administered at sufficient doses, due presumably to their exaggerated pharmacology rather than some off-target activity. Diarrhea led to study discontinuation in almost 5% of subjects in recent Phase 3 trials of linaclotide (Lembo et al., 2010a).

Absence of systemic exposure minimizes but does not eliminate the possibility drug-drug interactions or drug toxicity. Drug interactions, for example, could still occur with efflux proteins (e.g., p-glycoprotein) at the enterocyte brush border (Huang & Woodcock, 2009). A3309, a non-absorbed inhibitor of bile acid transport (IBAT) that blocks bile acid reabsorption by the terminal ileum (Chey et al., 2011a) could theoretically impair long-term fat-soluble vitamin absorption (Vitamin A, E, D) or lead to other nutritional deficiencies. The choleretic compound class has also been associated with higher rates of abdominal cramping and diarrhea in clinical trials (Odynsi-Shiyanbade et al., 2010).

There have been few examples of non-GI adverse events using the newer 5-HT4 agonists. As will be discussed below, the infrequency of these events probably relates to higher specificity for the 5-HT4 receptor than earlier agents. Certain 5-HT4 agonists (prucalopride and velusetrag) have been associated with a low but increased incidence of headaches and nausea compared with placebo. Although these side effects were reported in smaller percentages of patients in clinical trials of naronapride, the relationship between these adverse events and degree of CNS penetration is unclear (Palme et al., 2010). These side effects have been shown to resolve after the first day of treatment (Camilleri et al., 2008; Goldberg et al., 2010).

Linaclotide is a GCCR agonist and synthetic analog of E. coli STa toxin that stimulates intracellular c-GMP activity and active Cl secretion. Linaclotide is released and degraded rapidly in the duodenum (Kessler et al., 2008). This being the case, the stool hydrating effect of linaclotide must rely on a rapid burst of secretion in the upper intestine. Colonic motor dysfunction could potentially blunt or eliminate the subsequent therapeutic responses to linaclotide, reflecting the prodigious organ specific capacity for water reabsorption by the colon, coupled with prolonged transit (Debongnie & Phillips, 1978). Titration of distal stool volume might be difficult to control by a proximally active mechanism, resulting in wider swings in fecal output and higher rates of diarrhea-associated adverse events. Consistent targeting of specific sites along the length of the GI tract could be difficult with a luminally active agent. A 10-fold to 100-fold inter-individual variability in GCC mRNA expression has been observed in the human intestine (Bharucha et al., 2010), adding to the challenge of proper dosing in individual patients.

Plecanatide is a synthetic analogue of naturally occurring uroguanylin that mediates basal secretion and cell volume in humans (Shailubhai et al., 2010). In contrast to linaclotide, which is stabilized by three disulfide bonds that maintain the peptide in a tight configuration (Harris & Cromwell, 2007), the molecular structure of plecanatide contains only two disulfide bonds (Shailubhai et al., 2010), potentially rendering it less stable at its intestinal site of action. Furthermore, its binding to GCC receptors is pH-dependent. Perhaps as a result of these properties, plecanatide manifests three-fold to five-fold lower potency compared with linaclotide in human studies on a concentration basis (Lembo et al., 2010a; Shailubhai et al., 2010). Plecanatide was associated with a lower incidence of diarrhea in a preliminary trial of constipated patients, but this could potentially be representative of lower rates of intestinal secretion induced by the compound (Shailubhai et al., 2010).

### **2.2 Receptor specificity and off-target effects**

5-HT in the GI tract is primarily stored in gut enterochromaffin cells, with a much smaller portion in enteric neurons. High selectivity is an important feature of newer 5-HT4 agonists like prucalopride, velusetrag, and naronapride. Early 5-HT4 agonists were associated with non-specific receptor binding and off-target cardiac findings. Metoclopramide, a mixed 5- HT4 agonist and D2 antagonist, has been associated with tardive dyskinesia as a result of antagonism of striatal dopamine receptors, leading the FDA to issue a black box warning restricting recommended use (Metozolv Prescribing Information, 2009). Up to 30% of patients using metoclopramide discontinue treatment due to various other CNS side effects (Lee and Kuo, 2010).

Cisapride, a benzamide, was a 5-HT4 agonist that facilitated release of acetylcholine throughout the gut. It was used widely for treatment of gastro-esophageal reflux disease, gastroparesis and functional dyspepsia (Wiseman & Faulds, 1994). While the efficacy of cisapride in upper gastrointestinal tract motility was widely recognized, its effects on constipation and lower GI motility have been questioned (Abourmarzouk 2011). The loss of effect in the lower GI tract was attributed to concomitant antagonism of the 5-HT3 and potentially 5-HT2 receptor, leading to opposing effects on colonic transit and secretion (Masaoka & Tack, 2009).

In 2000, cisapride was withdrawn from the market due to fatal arrhythmias and dosedependent QT interval prolongation (Masaoka & Tack, 2009). These events occurred notably in patients taking other medications that are known to inhibit the CYP450 3A4 isozyme, e.g., erythromycin, fluconazole and amiodarone. Although the basis of cisapride's arrhythmogenic effect was not fully understood, it has been attributed to blockade of hERG (human ether-a-go-go) potassium channels, and a resulting delay in cardiac action potential repolarization in ventricular muscle and Purkinje fibers, and unrelated to its 5-HT4 agonist properties (Tonini et al., 1999).

Tegaserod, a 5-HT4 receptor partial agonist of aminoguanidine indole class, was approved in the United States for the treatment of chronic constipation and irritable bowel syndrome with constipation (Al-Judaibi et al., 2010). Although several studies (Prather et al., 2000; Foxx-Orenstein et al., 2005) demonstrated prokinetic action of tegaserod in both upper and lower GI tract, data regarding improvement of gastric emptying in humans are inconsistent (Talley et al., 2006; Degen et al., 2001, 2005). Tegaserod was withdrawn from the market in 2007 because of a reported numerical imbalance in the number of patients with cardiovascular ischemic adverse events in trials for patients who received tegaserod compared with those on placebo (Pasricha, 2007). Subsequent epidemiologic studies (Anderson et al., 2009; Loughlin et al., 2010) failed to confirm a reported large event differential for tegaserod that was noted incidentally in this clinical trial database. Tegaserod is now recognized to have significant affinity for non-5-HT4 receptors, including the 5-HT1B, 5-HT1D and 5-HT2B subtypes (Borman et al., 2002; DeMaeyer et al., 2008). The effects of tegaserod on 5-HT1 receptors present on blood vessels and platelet aggregation have been implicated as a mechanism accountable for ischemic changes (Chan et al., 2009; DeMaeyer et al., 2008; Serebruany et al., 2010). Moreover, the potent 5-HT2B antagonism of tegaserod has been postulated to counteract its 5-HT4 prokinetic effect (Borman et al., 2002). Low oral bioavailability (10%) may also have reduced the efficacy of the compound (Johanson et al., 2004; Kamm et al., 2005).

### **3. First-in-human trials**

150 Constipation – Causes, Diagnosis and Treatment

intestinal site of action. Furthermore, its binding to GCC receptors is pH-dependent. Perhaps as a result of these properties, plecanatide manifests three-fold to five-fold lower potency compared with linaclotide in human studies on a concentration basis (Lembo et al., 2010a; Shailubhai et al., 2010). Plecanatide was associated with a lower incidence of diarrhea in a preliminary trial of constipated patients, but this could potentially be representative of

5-HT in the GI tract is primarily stored in gut enterochromaffin cells, with a much smaller portion in enteric neurons. High selectivity is an important feature of newer 5-HT4 agonists like prucalopride, velusetrag, and naronapride. Early 5-HT4 agonists were associated with non-specific receptor binding and off-target cardiac findings. Metoclopramide, a mixed 5- HT4 agonist and D2 antagonist, has been associated with tardive dyskinesia as a result of antagonism of striatal dopamine receptors, leading the FDA to issue a black box warning restricting recommended use (Metozolv Prescribing Information, 2009). Up to 30% of patients using metoclopramide discontinue treatment due to various other CNS side effects

Cisapride, a benzamide, was a 5-HT4 agonist that facilitated release of acetylcholine throughout the gut. It was used widely for treatment of gastro-esophageal reflux disease, gastroparesis and functional dyspepsia (Wiseman & Faulds, 1994). While the efficacy of cisapride in upper gastrointestinal tract motility was widely recognized, its effects on constipation and lower GI motility have been questioned (Abourmarzouk 2011). The loss of effect in the lower GI tract was attributed to concomitant antagonism of the 5-HT3 and potentially 5-HT2 receptor, leading to opposing effects on colonic transit and secretion

In 2000, cisapride was withdrawn from the market due to fatal arrhythmias and dosedependent QT interval prolongation (Masaoka & Tack, 2009). These events occurred notably in patients taking other medications that are known to inhibit the CYP450 3A4 isozyme, e.g., erythromycin, fluconazole and amiodarone. Although the basis of cisapride's arrhythmogenic effect was not fully understood, it has been attributed to blockade of hERG (human ether-a-go-go) potassium channels, and a resulting delay in cardiac action potential repolarization in ventricular muscle and Purkinje fibers, and unrelated to its 5-HT4 agonist

Tegaserod, a 5-HT4 receptor partial agonist of aminoguanidine indole class, was approved in the United States for the treatment of chronic constipation and irritable bowel syndrome with constipation (Al-Judaibi et al., 2010). Although several studies (Prather et al., 2000; Foxx-Orenstein et al., 2005) demonstrated prokinetic action of tegaserod in both upper and lower GI tract, data regarding improvement of gastric emptying in humans are inconsistent (Talley et al., 2006; Degen et al., 2001, 2005). Tegaserod was withdrawn from the market in 2007 because of a reported numerical imbalance in the number of patients with cardiovascular ischemic adverse events in trials for patients who received tegaserod compared with those on placebo (Pasricha, 2007). Subsequent epidemiologic studies (Anderson et al., 2009; Loughlin et al., 2010) failed to confirm a reported large event differential for tegaserod that was noted incidentally in this clinical trial database.

lower rates of intestinal secretion induced by the compound (Shailubhai et al., 2010).

**2.2 Receptor specificity and off-target effects** 

(Lee and Kuo, 2010).

(Masaoka & Tack, 2009).

properties (Tonini et al., 1999).

### **3.1 Exposure-response relationship and dose-selection**

Single and repeat dose studies are routinely conducted first in healthy volunteers with normal bowel function. The benefit of this approach is the ability to establish preliminary pharmacokinetics and safety profiles in subjects without significant pre-existing conditions. These compounds induce defecatory changes in healthy volunteers, such as increasing bowel movement frequency. However, the doses responsible for these changes in healthy volunteers appear to be higher than the therapeutic dose in chronic constipation patients. GI pharmacodynamic effects in healthy volunteers are dose-dependent and the GI adverse events (i.e., diarrhea) tend to subside after the first dose. In general, there is very limited information on the pharmacokinetic-pharmacodynamic relationship for drugs for this indication. These first-in-man studies are typically followed by pilot dose-ranging safety and efficacy trials in the affected population. Study phases were compressed in the plecanatide program (Shailubhai et al., 2010), which chose to progress to initial repeat-dose studies directly in constipated patients rather than after single-dose studies in normal volunteers. This accelerated approach would seem justified due to the absence of systemic bioavailability and dose accumulation.

In addition to the typical Phase 1 safety studies, gut transit time measurements have been employed to test the prokinetic effects of these compounds in the upper and lower GI tract. These studies have utilized scintigraphic techniques in patients and healthy volunteers (Degen et al., 2001, 2005; Camilleri et al., 2007; Manini et al., 2010; Talley et al., 2006). Endpoints have included colonic transit time (GC24), ascending colon emptying (ACE) T1/2, gastric emptying (GE) time and colonic filling at 6 hours (CF6). These endpoints have served as biomarkers for drug effect in the upper and lower GI tract and have guided subsequent indications. Pharmacodynamic endpoints such as scintigraphic transit time are easier to achieve and require fewer subjects than those than those employed in registration trials. This approach minimizes study timeline and cost. It is worth noting that subsequent therapeutic doses for chronic constipation also tend to be lower than the doses needed to demonstrate pharmacodynamic effect in transit studies (Goldberg et al., 2010; Manini et al., 2010).

Dose proportional effects on stool frequency, stool consistency, and other symptoms associated with constipation are ordinarily observed with compounds in both the 5-HT4 and secretagogue drug classes. With the possible exception of plecanatide, the incidence of diarrhea rises with use of these agents at higher doses. Drugs such as prucalopride, velusetrag, linaclotide, plecanotide, A3309, and RDX-5791 exhibit prolonged pharmacokinetic exposures and/or pharmacodynamic effects and offer the advantage of once daily dosing.

### **4. Late-stage clinical trials**

### **4.1 Study population**

Despite treatment dissatisfaction with OTC medications (Johanson & Kralstein, 2007), there have been no prospective definitions of treatment failure with prior treatment in clinical trials. To date, treatment failure has not been an entry requirement into any late-stage constipation trial. In one of the three pivotal trials that formed the basis of the approval of prucalopride for CIC in Europe in 2009, 87% of subjects with constipation reported dissatisfaction with prior laxative regimens (Tack et al., 2009). Other than this one trial, the concept of treatment refractoriness has not been adequately addressed in registrational trials, which regulatory authorities use to develop label claims. It will be important to make this distinction prospectively if the role of newer medications in the constipation treatment paradigm is to be fully understood. Other study population considerations are outlined in Table 2.

Rome III Criteria (Modified)

	- Straining during bowel movements
	- Lumpy or hard stools
	- Sensation of incomplete evacuation

Treatment dissatisfaction or failure

Gender Elderly population (over 65 years of age) Pelvic floor dyssynergia Renal or hepatic impairment

*Exploratory*:

Transit time measurements

Table 2. Key Inclusion/Exclusion Criteria and Considerations in Constipation Trials

It is important to demonstrate safety and efficacy in most patients who are most often affected. In general, CIC is more common in women (Chuong et al., 2007), and not surprisingly, the majority of subjects who have participated in clinical trials have been women. The label claim of prucalopride was restricted to women because the enrollment of low number of male subjects in clinical trials precluded proof of efficacy in men. Although the data are very limited, the effective dose in males may also be higher than females (European Medicines Agency, 2009).

Constipation affects up to 50% of elderly individuals and is especially prevalent in nursing home residents (Camilleri et al., 2009; Chuong et al., 2007; Müller-Lissner et al., 2010). However, pharmacokinetics, the safety and tolerability profile and clinical efficacy in elderly patients may be different than in the younger population. The elderly population is routinely restricted in earlier pharmaceutical development due to safety considerations. The efficacy of prucalopride in the elderly population was demonstrated in a late-stage, multicenter trial of 300 elderly patients (Müller-Lissner et al., 2010). A subsequent safety trial was conducted in frail elderly patients residing in a nursing facility (Camilleri et al., 2009). Dosing should take diminishing renal function into the consideration if the drug is eliminated through the kidney. The effect of age on the pharmacokinetics of prucalopride was studied in an open, parallel-group trial in 12 healthy elderly (age range 65 to 81 years) and 12 young subjects (European Medicines Agency, 2009). Peak plasma concentrations and AUC of prucalopride were 26% to 28% higher in elderly subjects compared with young adults, due to diminishing renal function with age.

Patients participating in late-stage constipation trials should meet established definitions for chronic idiopathic constipation. The Rome II criteria for CIC were published in 1999 (Thompson et al., 1999), and followed by the Rome III criteria in 2006 (Longstreth et al., 2006). Modifications of these criteria have become working standards for inclusion and exclusion in constipation trials. The Rome criteria provide for a history of ≤ 3 SBMs per week and having one or more of the following symptoms for at least 12 weeks during the 12 months preceding the study: (1) straining during ≥ 25% of BMs; (2) lumpy or hard stools during ≥ 25% of BMs; or (3) sensation of incomplete evacuation during ≥ 25% of BMs.

The unmodified Rome III criteria for CIC include the sensation of anorectal obstruction or need for manual maneuvers to facilitate defecation (e.g., digital evacuation, support of the pelvic floor). Approximately 10% of subjects with CIC have functional outlet obstruction associated with pelvic floor dysfunction (Lembo & Camilleri, 2003). Formal radiographic or manometric testing is required to establish the diagnosis. These patients may be less responsive to pharmaceutical approaches than other patients, and are more appropriately treated with biofeedback or surgical methods (Lembo & Camilleri, 2003; Locke et al., 2000). Study protocols have typically tried to exclude patients with a history of dyssynergic defecation or in whom the history and physical examination was felt to indicate the presence of this type of constipation (Johanson et al., 2004; Lembo et al., 2010b).

To confirm the diagnosis of CIC, patients typically undergo a two-week baseline screening period during which time they must report an average of ≤ 3 CSBMs and ≤ 6 SBMs per week for inclusion. The patient responses are generally captured via an electronic diary or interactive voice response system. Use of a laxative, enema, and/or suppository usage for two or more days, or the report of any watery stools (Type 7) or > 1 loose (mushy) stools (Type 6) on the Bristol Stool Form Scale [BSFS] (Lewis & Heaton, 1997) would exclude a patient from participation.

Although constipation is associated with slower colonic transit, only a small portion of patients with CIC have abnormally slow transit times on formal testing (Lembo & Camilleri, 2003). Although transit time measurements may be a useful gauge for the effectiveness of an investigational agent, particularly in the early stages of clinical development, there would appear to be insufficient rationale to qualify patients for late-stage trials based on these transit time measurements.

### **4.2 Endpoints**

152 Constipation – Causes, Diagnosis and Treatment

Despite treatment dissatisfaction with OTC medications (Johanson & Kralstein, 2007), there have been no prospective definitions of treatment failure with prior treatment in clinical trials. To date, treatment failure has not been an entry requirement into any late-stage constipation trial. In one of the three pivotal trials that formed the basis of the approval of prucalopride for CIC in Europe in 2009, 87% of subjects with constipation reported dissatisfaction with prior laxative regimens (Tack et al., 2009). Other than this one trial, the concept of treatment refractoriness has not been adequately addressed in registrational trials, which regulatory authorities use to develop label claims. It will be important to make this distinction prospectively if the role of newer medications in the constipation treatment paradigm is to be fully understood. Other study population considerations are outlined in


Table 2. Key Inclusion/Exclusion Criteria and Considerations in Constipation Trials

It is important to demonstrate safety and efficacy in most patients who are most often affected. In general, CIC is more common in women (Chuong et al., 2007), and not surprisingly, the majority of subjects who have participated in clinical trials have been women. The label claim of prucalopride was restricted to women because the enrollment of low number of male subjects in clinical trials precluded proof of efficacy in men. Although the data are very limited, the effective dose in males may also be higher than females

Constipation affects up to 50% of elderly individuals and is especially prevalent in nursing home residents (Camilleri et al., 2009; Chuong et al., 2007; Müller-Lissner et al., 2010). However, pharmacokinetics, the safety and tolerability profile and clinical efficacy in elderly patients may be different than in the younger population. The elderly population is routinely restricted in earlier pharmaceutical development due to safety considerations. The efficacy of prucalopride in the elderly population was demonstrated in a late-stage, multicenter trial of 300 elderly patients (Müller-Lissner et al., 2010). A subsequent safety

**4. Late-stage clinical trials** 

Rome III Criteria (Modified) - ≤ 3 SBM per week

Lumpy or hard stools

Treatment dissatisfaction or failure

Pelvic floor dyssynergia Renal or hepatic impairment

Transit time measurements

(European Medicines Agency, 2009).

Elderly population (over 65 years of age)

weeks during the preceding 12 months Straining during bowel movements

Sensation of incomplete evacuation

**4.1 Study population** 

Table 2.

Gender

*Exploratory*:

Efficacy in constipation trials should signify improvement in constipation-associated symptoms. Endpoints in constipation trials are therefore patient-reported. Regulatory standards for tools to measure symptom-based endpoints in the United States is built on the FDA Guidance for Patient Reported Outcomes, issued in draft form in February 2006 and finalized in December 2009 (US Food and Drug Administration, 2009). Primary efficacy endpoints in late-stage constipation trials typically embody increases in the number of bowel movements (BM) per day, either improvement in spontaneous bowel movements (SBM) or complete spontaneous bowel movements (CSBM) (Table 3). A BM is deemed an SBM if no laxative, enema, or suppository was taken in the preceding 24 hours, and a CSBM if the patient indicated that the SBM is associated with a sensation of complete bowel emptying. Until there is a well-validated patient reported outcome tool the FDA accepts, PRO development will need to be considered in parallel with the clinical development program. In addition, translation and validation of these tools in different languages will also be essential for clinical development plans that expand beyond English speaking populations.


Table 3. Endpoints in Clinical Trials in Constipation. Abbreviations: *BSFS*, Bristol Stool Form Scale; *TT*, transit time; *MID*, minimally important difference; *CSBM*, complete spontaneous bowel movement; *SBM*, spontaneous bowel movement

The conceptual framework of constipation treatment response embodies symptoms considered important to the patient. These typically include stool consistency, straining,

finalized in December 2009 (US Food and Drug Administration, 2009). Primary efficacy endpoints in late-stage constipation trials typically embody increases in the number of bowel movements (BM) per day, either improvement in spontaneous bowel movements (SBM) or complete spontaneous bowel movements (CSBM) (Table 3). A BM is deemed an SBM if no laxative, enema, or suppository was taken in the preceding 24 hours, and a CSBM if the patient indicated that the SBM is associated with a sensation of complete bowel emptying. Until there is a well-validated patient reported outcome tool the FDA accepts, PRO development will need to be considered in parallel with the clinical development program. In addition, translation and validation of these tools in different languages will also be essential for clinical development plans that expand beyond English speaking

**Phase of Development Instrument Measurement**

Scintigraphy Whole gut or colon TT Geometric center Stool consistency BSFS 7-point ordinal scale

SBM Daily diary Average change from baseline CSBM Daily diary Average change from baseline

Responder definition CSBM Daily diary Categorical variables based

− Abdominal pain or discomfort Severity score 11-point ordinal severity scale − Straining Severity score 5-point ordinal severity scale − Bloating Severity score 5-point ordinal severity scale

 Constipation severity Severity score 5-point ordinal severity scale Global relief of constipation Numerical rating scale 7-point balanced scale Treatment satisfaction Numerical rating scale 5-point ordinal scale Adequate relief Binary question Binary (yes/no)

− Stool consistency BSFS 7-point ordinal scale

− Use of rescue medications Change in mean − PAC-SYM Composite instrument Total /domain scores − PAC-QoL Composite instrument Total /domain scores

Table 3. Endpoints in Clinical Trials in Constipation. Abbreviations: *BSFS*, Bristol Stool Form Scale; *TT*, transit time; *MID*, minimally important difference; *CSBM*, complete

The conceptual framework of constipation treatment response embodies symptoms considered important to the patient. These typically include stool consistency, straining,

spontaneous bowel movement; *SBM*, spontaneous bowel movement

− Achieving of ≥ 3 CSBM/week on MID

populations.

*First-in-man* 

*Late-phase* 

*Early phase (pilot studies)* 

Primary endpoint:

− Increase of ≥ 1 CSBM/week

Secondary or exploratory endpoints

− Global endpoints

(either co-primary or key secondary endpoint)

abdominal pain, bloating, and feeling of bowel emptying. Stool consistency is typically measured on the Bristol Stool Form Scale (BSFS). The constipation symptom roster is usually elicited in focus groups of individuals suffering from constipation. Patient responses are then structured into questionnaires using psychometric methods described in the guidance. These symptoms comprise primary and secondary endpoints that form the basis of label claims in the United States.

Earlier stage trials in constipation typically utilize continuous variables, such as mean change in SBM and/or CSBM from baseline across patients groups, for primary efficacy endpoints. These endpoints are easier to power and therefore engender lower sample sizes. Lubiprostone was approved in the US on the basis of trials that employed changes in SBM (Barisch et al., 2010; Johanson et al., 2008). However, the recent guidance makes clear the need for responder definitions in late-stage clinical trials (US Food and Drug Administration, 2009).

Responder definitions should be predicated on subjects achieving minimally important differences (MID) (US Food and Drug Administration, 2009). These differences are derived from factor analyses of clinical data in Phase 2 trials. MIDs are typically determined by comparing symptomatic improvement to global improvement questions. The primary efficacy endpoint in the prucalopride Phase 3 programs utilized the responder definition of ≥ 3 CSBM per week (Camilleri et al., 2008; Quigley et al., 2009; Tack et al., 2009), with the key secondary efficacy endpoint being the proportion of subjects achieving an increase of ≥ 1 CSBM per week. Three CSBM per week, i.e., approximately one BM every other day, represents normalization of bowel function in many individuals (Drossman et al., 1982), and therefore has clinical meaningfulness. The linaclotide Phase 3 program provided for coprimary endpoints that included achieving both ≥ 3 CSBM and improvement of ≥ 1 CSBM/week (Lembo et al., 2010a). The achievement of ≥ 3 CSBM per week is a more stringent and clinically more relevant endpoint than improvement of ≥ 1 CSBM, and efficacy responses on this co-primary endpoint predominantly reflect the subject's response on the first co-primary. It should also be pointed out that CSBM is a more stringent outcome than SBM, and that while endpoints predicated on CSBM may have lower response rates than SBM, the drudging of placebo performance typically results in improved study power, lower sample sizes, and higher chances of trial success.

Drugs have typically achieved responses in the 18% to 29% range on these CSBM-based responder definitions compared with 5% to 15% placebo response in Phase 3 CIC trials. This compares to treatment responses of 30% to 40% using SBM-based definitions, but with higher placebo responses and overall lower levels of statistical significance (Camilleri et al, 2008; Lembo et al, 2010a; Quigley et al, 2009; Tack et al, 2009). The observation that only a quarter of patients normalize bowel function with monotherapy-based trials suggests that the majority of patients will require combination therapy with these agents in the clinic.

Additional efficacy parameters in constipation trials have included the PAC-SYM (Frank et al., 1999), a composite index of constipation-associated symptoms, and PAC-QOL (Marquis et al., 2005), a health-related quality of life instrument, neither of which are recognized by the FDA as acceptable endpoints for clinical trials in the United States. Use of rescue medications and time to first bowel movement have also served as secondary or exploratory endpoints in selected trials. Sponsors have typically included global endpoints such as constipation severity and adequate relief as secondary or exploratory endpoints (Lembo et al., 2010a), and the FDA supports use of these outcomes other than for primary efficacy endpoints (US Food and Drug Administration, 2009).

### **4.3 Drug safety**

Safety concerns are tantamount in drug development for constipation, which is viewed by both clinicians and regulators a non-lifethreatening condition rather than a disease. The tolerance for safety concerns in the treatment of constipation is understandably low. Safety exposure databases should be expected at a minimum to follow ICH Guidelines for chronic disease and include 300-600 six-month exposures and 100 twelve-month exposures (US Food and Drug Administration, 1995). Higher standards may be set by regulatory agencies in the future, and the requirement for risk management programs could be imposed on drugs seeking approval in the US (US Food and Drug Administration, 2005). Pharmacovigilence post-approval has become standard industry practice. When safety is a concern, it is important that drug development identify a minimal effective dose and provide guidance to clinicians on how dosing should be escalated from that point forward. The burden of safety is likely to be reduced for drugs that are locally active compared with those that are systemically available, meaning lower requirements for pre-approval exposures and lower post-approval safety commitments. The GI tract is ideally suited for local or topical exposure by oral or rectal routes of administration.

Potential for QT interval prolongation and drug-drug interactions that potentiate this effect must be identified early in the development program. QT interval prolongation led to the market withdrawal of cisapride in 2000 (Masaoka & Tack, 2009). Tegaserod was associated with a higher incidence of cardiac ischemic events and withdrawn from the market in 2007 (Pasricha, 2007). This concern has shadowed development with all subsequent 5-HT4 agonists, although current data suggest that QT prolongation and cardiac ischemia may have been due to off-target effects on other receptors or 5-HT receptor subclasses (Chan et al., 2009; DeMaeyer et al., 2008; Serebruany et al., 2010; Tonini et al., 1999). To date, no such events have been observed with prucalopride or any of the current 5-HT4 development programs.

### **4.4 Biomarkers**

A biomarker is a measureable physical, functional, or biochemical surrogate for a physiological or disease process that has diagnostic and/or prognostic utility (US Food and Drug Administration, 2010a). For many diseases, there is no good way to document the course of a disease or the response to treatment. A biomarker may represent the features of a biologic processes or a response to a therapeutic intervention and reduce the expense and duration of clinical trials. Changes in biomarkers following treatment may reduce uncertainty in drug development by predicting drug performance, identifying safety problems, or revealing pharmacological activity or other benefit from treatment. The European Medicines Agency has also issued guidance for biomarker development in the European Union (European Medicines Agency, 2008).

Radio-opaque markers have been used to assess colonic transit, but recent studies have demonstrated scintigraphic imaging to be a more precise tool for drug development in constipation (Camilleri, 2010; Rao S.S. et al., 2011). Scintigraphic transit time fulfills all regulatory criteria for a disease biomarker: known performance characteristics, reproducible and accurate data over a range of conditions, and evidence of linkage to biological processes and clinical endpoints. Changes in colonic transit by scintigraphic technique have generally predicted the responses to treatment across a variety of compounds (Camilleri, 2010). This may prove to be a biomarker in new drug applications in colonic motility disorders. As noted previously, these transit time measurements define transit time abnormalities in only a minority of patients and are therefore of no specific utility towards defining subjects who enter late-stage clinical trials (Lembo & Camilleri, 2003). Stool frequency correlates poorly with colonic transit, but there appears to be good correlation between gut transit and stool consistency (O'Donnell, Virgie & Heaton, 1990). These markers are generally well accepted and are useful for predicting dose range in subsequent efficacy studies.

### **5. Clinical trials of approved drugs or drugs in development**

### **5.1 5-HT4 receptor agonists**

### **5.1.1 Prucalopride**

156 Constipation – Causes, Diagnosis and Treatment

constipation severity and adequate relief as secondary or exploratory endpoints (Lembo et al., 2010a), and the FDA supports use of these outcomes other than for primary efficacy

Safety concerns are tantamount in drug development for constipation, which is viewed by both clinicians and regulators a non-lifethreatening condition rather than a disease. The tolerance for safety concerns in the treatment of constipation is understandably low. Safety exposure databases should be expected at a minimum to follow ICH Guidelines for chronic disease and include 300-600 six-month exposures and 100 twelve-month exposures (US Food and Drug Administration, 1995). Higher standards may be set by regulatory agencies in the future, and the requirement for risk management programs could be imposed on drugs seeking approval in the US (US Food and Drug Administration, 2005). Pharmacovigilence post-approval has become standard industry practice. When safety is a concern, it is important that drug development identify a minimal effective dose and provide guidance to clinicians on how dosing should be escalated from that point forward. The burden of safety is likely to be reduced for drugs that are locally active compared with those that are systemically available, meaning lower requirements for pre-approval exposures and lower post-approval safety commitments. The GI tract is ideally suited for

Potential for QT interval prolongation and drug-drug interactions that potentiate this effect must be identified early in the development program. QT interval prolongation led to the market withdrawal of cisapride in 2000 (Masaoka & Tack, 2009). Tegaserod was associated with a higher incidence of cardiac ischemic events and withdrawn from the market in 2007 (Pasricha, 2007). This concern has shadowed development with all subsequent 5-HT4 agonists, although current data suggest that QT prolongation and cardiac ischemia may have been due to off-target effects on other receptors or 5-HT receptor subclasses (Chan et al., 2009; DeMaeyer et al., 2008; Serebruany et al., 2010; Tonini et al., 1999). To date, no such events have been observed with prucalopride or any of the current 5-HT4 development

A biomarker is a measureable physical, functional, or biochemical surrogate for a physiological or disease process that has diagnostic and/or prognostic utility (US Food and Drug Administration, 2010a). For many diseases, there is no good way to document the course of a disease or the response to treatment. A biomarker may represent the features of a biologic processes or a response to a therapeutic intervention and reduce the expense and duration of clinical trials. Changes in biomarkers following treatment may reduce uncertainty in drug development by predicting drug performance, identifying safety problems, or revealing pharmacological activity or other benefit from treatment. The European Medicines Agency has also issued guidance for biomarker development in the

Radio-opaque markers have been used to assess colonic transit, but recent studies have demonstrated scintigraphic imaging to be a more precise tool for drug development in

endpoints (US Food and Drug Administration, 2009).

local or topical exposure by oral or rectal routes of administration.

European Union (European Medicines Agency, 2008).

**4.3 Drug safety** 

programs.

**4.4 Biomarkers** 

Prucalopride (Resolor®) is a benzofuran carboxamide that is structurally distinct from cisapride and tegaserod. Prucalopride exhibits a more than 2-log scale greater selectivity for 5-HT4 compared with other receptors (DeMaeyer et al., 2008). This selectivity offers promise for greater efficacy and safety. The 2 mg once daily dose was approved in Europe in 2009 for the treatment of chronic constipation in women who fail to respond to laxatives. Due to the pharmacokinetic considerations described above, it is recommended that the drug be initiated at 1 mg in elderly patients and increased to 2 mg as needed (European Medicines Agency, 2009).

In pharmacodynamic studies, prucalopride dose-dependently enhanced colonic transit both in healthy controls and in patients with chronic constipation. In patients with chronic constipation, prucalopride 2 mg and 4 mg were significantly more effective than placebo in decreasing GI and colonic transit time. This was also reflected in increased stool frequency and looser stool consistency (Bouras et al., 1999, 2001; Sloots et al., 2002). Response in patients with constipation was dose-dependent and effective dosage was generally achieved with 2 mg once daily, although some studies reported significant beneficial effects on 1 mg (Emmanuel et al., 2002; Sloots et al., 2002).

A total of 2717 patients with chronic constipation were treated in placebo-controlled, double-blind, Phase 2 and Phase 3 trials (Miner et al., 1999; Emmanuel et al., 2002; Coremans et al., 2003; Camilleri et al., 2008; Quigley et al., 2009; Tack et al., 2009; Müeller-Lissner et al., 2009). Doses of prucalopride ranged from 0.5 to 4 mg per day. Two of these trials recruited patients who were either resistant to, or dissatisfied with laxatives (Coremans et al., 2003, Tack et al., 2009), one of these being pivotal (Tack et al., 2009), and one trial involved patients aged over 65 years (Müeller-Lissner et al., 2009).

In the Phase 3 program that served as the basis of approval of prucalopride in Europe, three identically designed, multicenter, pivotal trials were conducted (Camilleri et al., 2008; Quigley et al., 2009; Tack et al., 2009). More than 85% of the subjects in these trials were women. Patients were included based on the criteria of two or fewer SBMs per week in the previous 6 months and very hard or hard stools and/or a sensation of incomplete evacuation and/or straining during defecation for at least a quarter of the stools. The primary parameter was the proportion (%) of patients with an average of 3 or more spontaneous, complete bowel movements per week (responders, ≥ 3 CSBM/week). The main secondary endpoint was the proportion of patients with an average increase of ≥ 1 CSBM per week from run-in. The key time-point was assessed at Week 12. Treatment with prucalopride 2 mg and 4 mg once daily resulted in an average of three spontaneous, complete bowel movements (CSBM) per week in 19.5% to 28.5% of subjects treated with prucalopride vs. 9.6% to 13.6% receiving placebo. Significant changes were also seen in the main secondary endpoint.

Clinically relevant improvement in constipation-associated symptoms and quality of life were observed using the PAC-SYM and PAC-QOL questionnaires in these pivotal trials. Nearly 2600 patients were treated with prucalopride in open, long-term studies. 1490 of these subjects received treatment for at least 6 months and 869 received at least 1 year of treatment. The effects of the 2 mg and 4 mg doses of prucalopride were similar, and both were determined to be safe and well tolerated.

Only one cardiovascular event was reported, an episode of supraventricular tachycardia, and extensive cardiovascular safety assessments demonstrated no signals of arrhythmogenic potential (Camilleri et al., 2009). The incidence of serious adverse events was similar to placebo. Headache, nausea, and diarrhea were reported more often in subjects receiving prucalopride, but these adverse events were mainly driven by the occurrence on Day 1 of treatment. It was postulated that this represented a transient effect of 5-HT4 agonists that penetrate the CNS. However, the relationship between these adverse events and the degree of CNS penetration is inconsistent across this class of compounds.

Data from a series of thorough QT studies appear to show that the influence, if any, of prucalopride on QT interval and other ECG variables is negligible. The number of cardiovascular ischemic-related events was low and comparable between prucalopride groups and placebo (0.1%). Clinical trials with prucalopride were temporarily suspended in 1999 following positive carcinogenicity studies in rodents; however, these findings were deemed to be rodent-specific and were not thought on regulatory review to apply to humans (European Medicines Agency, 2009).

### **5.1.2 Velusetrag**

Velusetrag (TD-5108) is a high-affinity and selective 5-HT4 receptor agonist with high intrinsic activity at the human 5-HT4 receptor. Unlike tegaserod, velusetrag has no appreciable affinity for 5-HT1D, 5-HT2A, or 5-HT2B receptors (Beattie et al., 2004; Smith et al., 2007). In contrast to cisapride, velusetrag has no significant affinity for the human ether-ago-go-related gene potassium channel (Smith et al., 2008). In animal models, velusetrag demonstrated gastrointestinal activity in the digestive tract. To date, no significant effects of velusetrag on blood pressure, heart rate or electrocardiogram have been noted in animals or humans at clinically relevant doses, nor does velusetrag have any contractile activity in porcine- or canine-isolated coronary arteries (Beattie et al. 2007).

A dose-response transit study showed that velusetrag administration was associated with acceleration of colonic and orocecal transit after single dose administration to healthy subjects with substantive and significant effects on gastric and colonic transit were observed with multiple dosing (Manini et al., 2010). In an evaluation of patients with chronic constipation and matched healthy control subjects, velusetrag pharmacokinetics and effects on laxation and bowel function were similar in chronic constipation and health. Bioavailability of velusetrag from a single, orally administrated dose was good, and the elimination half-life in both populations was consistent with once daily administration (Goldberg, Wong, & Ganju 2007; Wong S.L. et al., 2007).

A Phase 2, double-blind, placebo-controlled, randomized, parallel-group, multicenter trial included 401 subjects with chronic idiopathic constipation (< 3 SBM per week) randomized to velusetrag 15 mg, 30 mg, 50 mg or placebo po QD for 4 weeks (Goldberg et al, 2010). The study population was 92% female. Patients receiving velusetrag achieved statistically significant and clinically meaningful increases in SBM and CSBM relative to placebo at all doses. There were no differences in changes in SBM and CSBM rates between doses. Median times with first SBM were 21, 25 and 18 hours, respectively, compared to 47 hours for placebo (p < 0.0001 for all treatments). Use of velusetrag was significantly associated with a relief of straining and bloating, a reduced need for a rescue laxative, and normalization of stool consistency.

The most common adverse events in patients were those frequently associated with 5-HT4 agents such as prucalopride and included diarrhea, headache, and nausea. These adverse events were dose-related, occurred during the initial days of dosing, and were of mild to moderate intensity. A total of 19 patients discontinued because of adverse events, with the majority occurring in the 50 mg velusetrag group. No clinically relevant changes in hematology, biochemistry, urinalysis, vital signs and ECG parameters were observed in any group.

### **5.1.3 Naronapride**

158 Constipation – Causes, Diagnosis and Treatment

previous 6 months and very hard or hard stools and/or a sensation of incomplete evacuation and/or straining during defecation for at least a quarter of the stools. The primary parameter was the proportion (%) of patients with an average of 3 or more spontaneous, complete bowel movements per week (responders, ≥ 3 CSBM/week). The main secondary endpoint was the proportion of patients with an average increase of ≥ 1 CSBM per week from run-in. The key time-point was assessed at Week 12. Treatment with prucalopride 2 mg and 4 mg once daily resulted in an average of three spontaneous, complete bowel movements (CSBM) per week in 19.5% to 28.5% of subjects treated with prucalopride vs. 9.6% to 13.6% receiving placebo.

Clinically relevant improvement in constipation-associated symptoms and quality of life were observed using the PAC-SYM and PAC-QOL questionnaires in these pivotal trials. Nearly 2600 patients were treated with prucalopride in open, long-term studies. 1490 of these subjects received treatment for at least 6 months and 869 received at least 1 year of treatment. The effects of the 2 mg and 4 mg doses of prucalopride were similar, and both

Only one cardiovascular event was reported, an episode of supraventricular tachycardia, and extensive cardiovascular safety assessments demonstrated no signals of arrhythmogenic potential (Camilleri et al., 2009). The incidence of serious adverse events was similar to placebo. Headache, nausea, and diarrhea were reported more often in subjects receiving prucalopride, but these adverse events were mainly driven by the occurrence on Day 1 of treatment. It was postulated that this represented a transient effect of 5-HT4 agonists that penetrate the CNS. However, the relationship between these adverse events and the degree

Data from a series of thorough QT studies appear to show that the influence, if any, of prucalopride on QT interval and other ECG variables is negligible. The number of cardiovascular ischemic-related events was low and comparable between prucalopride groups and placebo (0.1%). Clinical trials with prucalopride were temporarily suspended in 1999 following positive carcinogenicity studies in rodents; however, these findings were deemed to be rodent-specific and were not thought on regulatory review to apply to

Velusetrag (TD-5108) is a high-affinity and selective 5-HT4 receptor agonist with high intrinsic activity at the human 5-HT4 receptor. Unlike tegaserod, velusetrag has no appreciable affinity for 5-HT1D, 5-HT2A, or 5-HT2B receptors (Beattie et al., 2004; Smith et al., 2007). In contrast to cisapride, velusetrag has no significant affinity for the human ether-ago-go-related gene potassium channel (Smith et al., 2008). In animal models, velusetrag demonstrated gastrointestinal activity in the digestive tract. To date, no significant effects of velusetrag on blood pressure, heart rate or electrocardiogram have been noted in animals or humans at clinically relevant doses, nor does velusetrag have any contractile activity in

A dose-response transit study showed that velusetrag administration was associated with acceleration of colonic and orocecal transit after single dose administration to healthy subjects with substantive and significant effects on gastric and colonic transit were observed

Significant changes were also seen in the main secondary endpoint.

of CNS penetration is inconsistent across this class of compounds.

porcine- or canine-isolated coronary arteries (Beattie et al. 2007).

were determined to be safe and well tolerated.

humans (European Medicines Agency, 2009).

**5.1.2 Velusetrag** 

Naronapride (ATI-7505) is a 5-HT4 receptor agonist belonging to the benzamide series of similar compounds (Camilleri et al, 2007). The design of naronapride was based on the prototypical benzamide agent, cisapride. Unlike cisapride, naronapride was designed to be devoid of other 5-HT receptor activities and to have negligible inhibitory activity at the hERG channel, with an affinity ratio between IKr and 5-HT4 receptors of at least 1000- fold. In addition, the compound was to have low potential for drug–drug interactions. Unlike prucalopride and velusetrag, naronapride does not exhibit CNS penetration, which may lead to a lower incidence of side effects (Aryx Corporation, 2008). However, other 5-HT4 agonist with limited CNS penetration (i.e., tegaserod) did show comparable rate of adverse events to prucalopride and velusetrag.

A randomized, parallel-group, double-blind, placebo-controlled study evaluated effects of 9-day treatment with naronapride (3, 10 or 20 mg TID) on scintigraphic GI and colonic transit in healthy volunteers (12 per group) (Camilleri et al., 2007). Primary endpoints were gastric-emptying (GE) T1/2, colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T1/2. Naronapride increased colonic transit with greatest effect vs. placebo observed at 10 mg TID. The effect on transit was associated with looser stool consistency.

A randomized, multinational, multicenter, double-blind, placebo-controlled, dose-ranging trial was performed in patients with CIC (Palme et al., 2010). Patients were randomized to naronapride 20 mg, 40 mg, 80 mg or 120 mg or placebo BID orally for four weeks. Although 400 subjects were planned in the original study design, the study was terminated early due to business reasons, and only 214 patients were randomized. The primary outcome was total number of SBMs during Week 1 compared with placebo. Treatment response, a secondary endpoint, was defined as the proportion of subjects achieving ≥ 3 CSBM/wk or ≥ 3 SBMs/wk on each of the four weeks in the absence of rescue medications. Despite the reduction from the intended original sample size, all doses of naronapride still met the primary endpoint, and median time to first SBM was reduced in all active treatment groups. SBM response was achieved by 51.2% of subjects treated with naronapride 80 mg vs. 24.4% receiving placebo, while CSBM response was achieved by 26.8% of these subjects vs. 4.9% receiving placebo. Adverse event frequency, including headache, diarrhea, nausea and vomiting, was similar to placebo in all ATI-7505 dose groups except the 120 mg BID group, where abdominal pain and headache were more frequently reported.

### **5.2 Colonic secretagogues**

### **5.2.1 Lubiprostone**

Lubiprostone is a poorly absorbed lipophylic prostanoid component that is thought to stimulate colonic water and electrolyte secretion through the activation of type-2 chloride channels on enterocytes from the luminal side (Lacy & Levy, 2007). There is also evidence that the Cl secretion induced by lubiprostone may be mediated by CFTR channels (Bijvelds et al., 2009). Lubiprostone dose-dependently enhances colonic transit, and this was hypothesized to be an indirect consequence of increased colonic water content (Camilleri et al., 2006).

In two Phase 3 studies of 4 weeks duration, lubiprostone 24 mg BID significantly enhanced SBM frequency (5.69 and 5.89 spontaneous bowel movements per week with lubiprostone vs. 3.46 and 3.99 with placebo, p < 0.0001) and relieved other constipation-related symptoms compared with placebo (Barish et al., 2010; Johanson et al., 2008). The incidence of nausea in patients receiving the approved dose of lubiprostone for chronic idiopathic constipation was approximately 29% in clinical trials, and resulted in 9% of patients discontinuing in these studies (Lacy & Chey, 2009; Sucampo Pharmaceuticals, 2009). The prevalence of nausea is increased with higher dose and could be mediated by an adverse prostaglandin-like effect on gastric motility (Lacy & Levy, 2007). Although the systemic availability of lubiprostone is reportedly low (Lacy & Levy, 2007), this side effect could potentially reflect systemic absorption post oral administration.

Lubiprostone was approved by the US FDA in 2006 for the treatment of chronic idiopathic constipation (24 mg BID) and for the treatment of female IBS patients with constipation (8 mg BID) (Drossman et al, 2009) in 2008 but, apart from Switzerland, has not been approved in Europe at this time.

### **5.2.2 Linaclotide**

Linaclotide is a 14-amino acid peptide analog of E. coli STa enterotoxin that acts as an agonist at guanylate cyclase-C (GCC) receptor to induce cyclic GMP production and intestinal chloride and fluid secretion (Bharucha, Scott & Waldman, 2010). The drug is nonabsorbed and exerts local effects on the enterocyte at the level of the gut lumen. In a mechanistic study, linaclotide enhanced colonic transit in IBS with constipation (Andresen et al., 2007). It dose-dependently increased SBM and CSBM frequency, loosened stool consistency, and improved other symptoms of constipation over four weeks (Lembo et al., 2010b).

Favorable outcomes were recently achieved in two large Phase 3 studies, each involving more than 600 subjects, and 12 weeks of treatment. Trial design considered the Food and Drug Administration's recent recommendations to transition from global (e.g., overall relief) to symptom-based primary endpoints (US Food and Drug Administration, 2010b). Subjects were randomized to placebo and 133 or 266 mg of linaclotide (Lembo et al, 2010a). The primary endpoint was based on a responder analysis of subjects achieving both ≥ 3 CSBM and an increase of ≥1 CSBM per week. In both trials, significantly higher percentages of patients met the primary endpoint with linaclotide 133 mg (respectively 16% and 21.2%) and 266 mg (respectively 21.4% and 19.3%) compared with placebo (respectively 6% and 3.3%, all p-values < 0.001). The onset of efficacy occurred in the first week and was maintained for 12 weeks. Symptoms of abdominal discomfort, bloating and straining were also significantly improved. There was also improvement in health-related quality of life, and constipation severity. Linaclotide is also under evaluation for IBS with constipation (Johnston et al, 2010), and an application for marketing approval of linaclotide in the US and Europe for both indications is expected in the near future.

### **5.2.3 Plecanatide**

160 Constipation – Causes, Diagnosis and Treatment

400 subjects were planned in the original study design, the study was terminated early due to business reasons, and only 214 patients were randomized. The primary outcome was total number of SBMs during Week 1 compared with placebo. Treatment response, a secondary endpoint, was defined as the proportion of subjects achieving ≥ 3 CSBM/wk or ≥ 3 SBMs/wk on each of the four weeks in the absence of rescue medications. Despite the reduction from the intended original sample size, all doses of naronapride still met the primary endpoint, and median time to first SBM was reduced in all active treatment groups. SBM response was achieved by 51.2% of subjects treated with naronapride 80 mg vs. 24.4% receiving placebo, while CSBM response was achieved by 26.8% of these subjects vs. 4.9% receiving placebo. Adverse event frequency, including headache, diarrhea, nausea and vomiting, was similar to placebo in all ATI-7505 dose groups except the 120 mg BID group,

Lubiprostone is a poorly absorbed lipophylic prostanoid component that is thought to stimulate colonic water and electrolyte secretion through the activation of type-2 chloride channels on enterocytes from the luminal side (Lacy & Levy, 2007). There is also evidence that the Cl secretion induced by lubiprostone may be mediated by CFTR channels (Bijvelds et al., 2009). Lubiprostone dose-dependently enhances colonic transit, and this was hypothesized to be an indirect consequence of increased colonic water content (Camilleri et

In two Phase 3 studies of 4 weeks duration, lubiprostone 24 mg BID significantly enhanced SBM frequency (5.69 and 5.89 spontaneous bowel movements per week with lubiprostone vs. 3.46 and 3.99 with placebo, p < 0.0001) and relieved other constipation-related symptoms compared with placebo (Barish et al., 2010; Johanson et al., 2008). The incidence of nausea in patients receiving the approved dose of lubiprostone for chronic idiopathic constipation was approximately 29% in clinical trials, and resulted in 9% of patients discontinuing in these studies (Lacy & Chey, 2009; Sucampo Pharmaceuticals, 2009). The prevalence of nausea is increased with higher dose and could be mediated by an adverse prostaglandin-like effect on gastric motility (Lacy & Levy, 2007). Although the systemic availability of lubiprostone is reportedly low (Lacy & Levy, 2007), this side effect could potentially reflect systemic

Lubiprostone was approved by the US FDA in 2006 for the treatment of chronic idiopathic constipation (24 mg BID) and for the treatment of female IBS patients with constipation (8 mg BID) (Drossman et al, 2009) in 2008 but, apart from Switzerland, has not been approved

Linaclotide is a 14-amino acid peptide analog of E. coli STa enterotoxin that acts as an agonist at guanylate cyclase-C (GCC) receptor to induce cyclic GMP production and intestinal chloride and fluid secretion (Bharucha, Scott & Waldman, 2010). The drug is nonabsorbed and exerts local effects on the enterocyte at the level of the gut lumen. In a mechanistic study, linaclotide enhanced colonic transit in IBS with constipation (Andresen

where abdominal pain and headache were more frequently reported.

**5.2 Colonic secretagogues** 

absorption post oral administration.

in Europe at this time.

**5.2.2 Linaclotide** 

**5.2.1 Lubiprostone** 

al., 2006).

Plecanatide (SP-304) is an oral peptide analogue of uroguanylin, a natriuretic hormone that regulates ion and fluid transport in the GI tract. T84 cell assays have demonstrated that plecanatide has an 8-fold higher binding affinity to GC-C receptors than uroguanylin. In a double-blind, placebo-controlled, randomized, single ascending dose study conducted in healthy volunteers, plecanatide appeared to demonstrate an increase in post-dose stool consistency score versus placebo (Shailubhai et al., 2008). The drug was well-tolerated at all doses with no systemic exposure. A subsequent Phase 2a trial in constipated subjects studied doses between 0.3 and 9 mg once daily for 14 days (Shailubhai et al., 2010). Dose proportionate reduction in time to first BM, SBM, CSBM, and stool consistency, and improvement of straining were observed up to 1.0 mg, subsequent to which no additional effects were noted. There was no detectable absorption of plecanatide at any dose, and minimal adverse events were observed. There were no reports of diarrhea in any dose groups, although the effects of plecanatide on SBM frequency and stool consistency were less pronounced than in earlier linaclotide trials.

### **5.2.4 A3309**

A3309 is a potent and selective inhibitor of the ileal bile acid transporter (IBAT) with minimal systemic exposure. It dose-dependently inhibits the reabsorption of bile acids (BA). This results in an increased concentration of bile acids in the colon, which, in turn, increase fluid secretion and colonic motility.

In a randomized, double-blind, dose-escalating study, 30 patients were administered A3309 (0.1, 0.3, 1, 3 or 10 mg once daily) or placebo for 14 days (Simrén et al., 2011). Colonic transit was measured using radio-opaque markers and fluoroscopy at baseline and at Day 14. Bowel movements (BMs), stool consistency (Bristol Stool Form Scale) and GI symptoms were recorded daily. Hepatic BA synthesis was estimated by measurement of 7α-hydroxy-4 cholesten-3-one (C4) in peripheral blood. Dose-dependent inhibition of bile acid desorption and acceleration of colonic transit time and SBMs were noted.

In a follow-up trial, 36 female patients were randomized to placebo, 15 mg A3309, or 20 mg A3309 administered orally once daily for 14 consecutive days (Wong B.S. et al., 2011). Whole gastrointestinal and colonic transit, stool consistency, constipation symptoms, serum 7αC4, and fasting serum total and LDL cholesterol (surrogates of inhibition of BA absorption) were measured. Colonic transit at 48h was significantly accelerated with both A3309 dosages. Significantly looser stool consistency, lower constipation severity and straining, and improved ease of stool passage were noted with both A3309 dosages. A3309 treatment significantly and reversibly increased fasting 7αC4. The most common side effect was lower abdominal pain or cramping.

Positive results from a larger, proof-of-concept trial have recently been published (Chey et al., 2011a). 190 patients with severe constipation were treated with 5 mg, 10 mg, or 15 mg A3309 or placebo for 8 weeks. Subjects were mainly female (90%) and averaged 0.4 CSBMs per week at baseline. The primary efficacy endpoint, change from baseline in spontaneous bowel movements (SBMs), showed a dose-dependent increase and highly significant results were obtained for the two highest dose levels. In addition, the secondary endpoints of effects on SBM and CSBM frequencies were also dose dependent and statistically significant. Bloating and straining, important constipation symptoms, also decreased significantly during A3309 treatment. The effect of A3309 was rapid and a significantly higher proportion of the A3309-treated patients had a CSBM within 24 hours of the first administration. The beneficial effects were maintained over the eight-week trial period.

Abdominal pain and diarrhea once again appeared to be the most common side effects with A3309 treatment. These events were observed in 10%, 11%, and 25% and 8%, 11%, and 17%, respectively, in the A3309 5 mg, 10 mg, and 15 mg dose groups, compared with only 0% and 4% in placebo-treated subjects. A similar adverse event profile was recently noted with use of chenodeoxycholic acid in healthy volunteers and female subjects with constipationpredominant IBS (Odynsi-Shiyanbade et al., 2010; Rao A.S. et al., 2010). These observations leave the tolerability of choleretic agent an open-ended question at this time. Increased C4 and reduced LDL cholesterol suggested increased BA synthesis due to inhibition of ileal BA transport. As previously discussed, the long-term effects of this therapeutic approach on fatsoluble vitamin absorption remains to be established.

### **5.3 Na-H exchange inhibitors**

### **5.3.1 RDX-5791**

RDX5791 is a unique, minimally systemic, small molecule NHE3 inhibitor in clinical development for the treatment of CIC. Unlike secretagogues that induce active Cl secretion, RDX5791 inhibits the intestinal Na-H antiport protein (NHE3) that plays a key role in the uptake of sodium and thus water from the intestinal lumen. The most attractive feature of the drug's mechanism is the fact the NHE3 transporter accounts for the principal mechanism of Na and water absorption in humans from duodenum to left colon. Unlike linaclotide, the actions of which may be restricted to the duodenum, RDX5791 may exert its effects along the GI tract. This would theoretically allow for more gradual hydration of stool, and less of a tendency for diarrhea as the dose is increased. The effects of RDX5791 on stool consistency and transit time have been demonstrated in animal models (Spencer et al., 2011). RDX5791 has been demonstrated to be anti-nocioceptive in an animal model of visceral hypersensitivity (Eutamene et al., 2011). Pharmacokinetic trials have been completed, and proof-of-concept studies are currently underway in patients with IBS-c.

### **6. Related indications**

162 Constipation – Causes, Diagnosis and Treatment

were recorded daily. Hepatic BA synthesis was estimated by measurement of 7α-hydroxy-4 cholesten-3-one (C4) in peripheral blood. Dose-dependent inhibition of bile acid desorption

In a follow-up trial, 36 female patients were randomized to placebo, 15 mg A3309, or 20 mg A3309 administered orally once daily for 14 consecutive days (Wong B.S. et al., 2011). Whole gastrointestinal and colonic transit, stool consistency, constipation symptoms, serum 7αC4, and fasting serum total and LDL cholesterol (surrogates of inhibition of BA absorption) were measured. Colonic transit at 48h was significantly accelerated with both A3309 dosages. Significantly looser stool consistency, lower constipation severity and straining, and improved ease of stool passage were noted with both A3309 dosages. A3309 treatment significantly and reversibly increased fasting 7αC4. The most common side effect was lower

Positive results from a larger, proof-of-concept trial have recently been published (Chey et al., 2011a). 190 patients with severe constipation were treated with 5 mg, 10 mg, or 15 mg A3309 or placebo for 8 weeks. Subjects were mainly female (90%) and averaged 0.4 CSBMs per week at baseline. The primary efficacy endpoint, change from baseline in spontaneous bowel movements (SBMs), showed a dose-dependent increase and highly significant results were obtained for the two highest dose levels. In addition, the secondary endpoints of effects on SBM and CSBM frequencies were also dose dependent and statistically significant. Bloating and straining, important constipation symptoms, also decreased significantly during A3309 treatment. The effect of A3309 was rapid and a significantly higher proportion of the A3309-treated patients had a CSBM within 24 hours of the first administration. The

Abdominal pain and diarrhea once again appeared to be the most common side effects with A3309 treatment. These events were observed in 10%, 11%, and 25% and 8%, 11%, and 17%, respectively, in the A3309 5 mg, 10 mg, and 15 mg dose groups, compared with only 0% and 4% in placebo-treated subjects. A similar adverse event profile was recently noted with use of chenodeoxycholic acid in healthy volunteers and female subjects with constipationpredominant IBS (Odynsi-Shiyanbade et al., 2010; Rao A.S. et al., 2010). These observations leave the tolerability of choleretic agent an open-ended question at this time. Increased C4 and reduced LDL cholesterol suggested increased BA synthesis due to inhibition of ileal BA transport. As previously discussed, the long-term effects of this therapeutic approach on fat-

RDX5791 is a unique, minimally systemic, small molecule NHE3 inhibitor in clinical development for the treatment of CIC. Unlike secretagogues that induce active Cl secretion, RDX5791 inhibits the intestinal Na-H antiport protein (NHE3) that plays a key role in the uptake of sodium and thus water from the intestinal lumen. The most attractive feature of the drug's mechanism is the fact the NHE3 transporter accounts for the principal mechanism of Na and water absorption in humans from duodenum to left colon. Unlike linaclotide, the actions of which may be restricted to the duodenum, RDX5791 may exert its effects along the GI tract. This would theoretically allow for more gradual hydration of

and acceleration of colonic transit time and SBMs were noted.

beneficial effects were maintained over the eight-week trial period.

soluble vitamin absorption remains to be established.

**5.3 Na-H exchange inhibitors** 

**5.3.1 RDX-5791** 

abdominal pain or cramping.

### **6.1 Constipation-predominant irritable bowel syndrome**

Drugs that are effective in CIC also appear to be effective in patients with irritable bowel syndrome with constipation (IBS-c). The dual effect on CIC and IBS-c appears to apply to most prokinetic agents and secretagogues. The distinction between CIC and IBS-c patients may be difficult in practice, and it is likely many patients are cross-included in their respective clinical trials. Patients typically qualify for IBS-c trials by fulfilling Rome Criteria for IBS-c and demonstrating of minimal level of abdominal pain on pre-randomization screening diaries, at least 3 out of a possible 10 on a numerical rating scale (Chey et al., 2011b). This practice was recently codified in the FDA IBS draft guidance (U.S. Food and Drug Administration, 2010b). However, while there have been minimum pain requirements to enter IBS-c trials, there have been no maximums that would exclude patients from CIC trials. In fact, it is recognized that a number of patients enter CIC trials reporting baseline pain that exceeds the IBS-c minimum (Lembo et al., 2010b). A retrospective analysis of Phase 3 CIC data demonstrated that CIC patients with a pain score ≥ 3 (on a scale of 10) were as likely to respond to linaclotide as the overall study population (Lembo et al, 2011). Interestingly, patients entering a recent multicenter IBS-c trial with linaclotide demonstrated more severe constipation than those entering CIC trials with the same compound (Johnston et al., 2010).

The mechanism of pain relief in IBS-c most likely relates to decompression of colonic distention, although reduction of visceral hypersensitivity has been suggested using animal models (Eutamene et al., 2009). The mechanism of this anti-nocioceptive effect is uncertain, since the phenomenon also appears to apply broadly across a variety of promotility agents that could have utility in CIC and IBS-c (Eutamene et al., 2011, Greenwood-van Meerveld et al., 2006). It has been suggested that stimulation of intracellular c-GMP is responsible for the pain reductions with linaclotide use (Eutamene et al., 2009). However, the mechanism of this effect remains uncertain, since linaclotide is non-absorbed and appears to be released and degraded principally in the duodenum (Kessler et al., 2008), while has been presumed that IBS pain originates in the lower GI tract.

### **6.2 Opioid-induced constipation**

A number of peripherally acting -opiate antagonists are currently being investigated for the treatment of opioid-induced constipation (OIC). These drugs are designed not to penetrate or cross the blood brain barrier or adversely impact the efficacy of concomitant analgesic therapy. Methylnaltrexone bromide (Relistor®) has been approved for the treatment of opiate-induced constipation in patients with advanced illness (Thomas et al., 2008). The drug is administered subcutaneously and appears to have onset of effect within four hours. Oral bioavailability has been a challenge, although a new formulation has recently entered Phase 3 trials.

Alvimopan is an orally administered peripherally-acting -opioid antagonist approved for the treatment of postoperative ileus (Delaney et al., 2008). In one controlled study in 522 patients on opioids for chronic non-cancer pain, alvimopan in doses of 0.5 mg BID to 2 mg BID was superior to placebo in inducing spontaneous bowel movements and reducing constipation-associated symptoms without antagonism of opioid analgesia (Jansen J.P. et al., 2011; Paulson et al., 2005; Webster et al., 2008), although one of the two pivotal trial failed to meet statistical significance (Irving et al., 2011). This could have resulted from loss of statistical power due to use of SBM rather than CSBM as a primary endpoint, and a placebo response exceeding 50%. Development of alvimopan for OIC was discontinued in 2008 because of a numeric imbalance in myocardial infarction, neoplasm, and bone fracture adverse events that appeared in a long-term safety study.

Several other peripherally-acting -opioid antagonists are currently in development for OIC, including TD-1211, NKTR-118, and ALKS-37. One of the challenges will be the development of combination drugs that permit co-administration of opioid with opioid antagonists as a means to prevent constipation from occurring. It is worth noting that opioid antagonists are not expected to cause an increase in the frequency of bowel movements in healthy volunteers or patients with constipation associated with other causes rather than opioid. In contrast, prokinetic agents are likely to improve constipation associated with opioid usage. Lubiprostone and prucalopride are also being studies for the treatment of opioid-induced constipation.

### **7. Conclusions**

Prokinetic agents and secretagogues in development will most likely assume a position on formularies with other constipation therapies, including prucalopride and lubiprostone, and OTC agents. Based on current data, it is unlikely that one agent or class of compounds will suffice for most patients. The challenge will be to integrate different mechanisms into treatment algorithms that optimize safety, cost-effectiveness and therapeutic response. This information will be established in future therapeutic trials.

### **8. References**


Alvimopan is an orally administered peripherally-acting -opioid antagonist approved for the treatment of postoperative ileus (Delaney et al., 2008). In one controlled study in 522 patients on opioids for chronic non-cancer pain, alvimopan in doses of 0.5 mg BID to 2 mg BID was superior to placebo in inducing spontaneous bowel movements and reducing constipation-associated symptoms without antagonism of opioid analgesia (Jansen J.P. et al., 2011; Paulson et al., 2005; Webster et al., 2008), although one of the two pivotal trial failed to meet statistical significance (Irving et al., 2011). This could have resulted from loss of statistical power due to use of SBM rather than CSBM as a primary endpoint, and a placebo response exceeding 50%. Development of alvimopan for OIC was discontinued in 2008 because of a numeric imbalance in myocardial infarction, neoplasm, and bone fracture

Several other peripherally-acting -opioid antagonists are currently in development for OIC, including TD-1211, NKTR-118, and ALKS-37. One of the challenges will be the development of combination drugs that permit co-administration of opioid with opioid antagonists as a means to prevent constipation from occurring. It is worth noting that opioid antagonists are not expected to cause an increase in the frequency of bowel movements in healthy volunteers or patients with constipation associated with other causes rather than opioid. In contrast, prokinetic agents are likely to improve constipation associated with opioid usage. Lubiprostone and prucalopride are also being studies for the treatment of opioid-induced

Prokinetic agents and secretagogues in development will most likely assume a position on formularies with other constipation therapies, including prucalopride and lubiprostone, and OTC agents. Based on current data, it is unlikely that one agent or class of compounds will suffice for most patients. The challenge will be to integrate different mechanisms into treatment algorithms that optimize safety, cost-effectiveness and therapeutic response. This

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### *Edited by Anthony G. Catto-Smith*

Constipation is common in both adults and children. Estimates would suggest a median prevalence of around 12-16% in the general population. While regarded as a minor nuisance in some cases, its consequences can be severe, with a substantial impact on quality of life. Secondary faecal soiling has a profound psychological effect at all ages. This book provides contributions from authors with a range of backgrounds which clarify the pathogenesis, diagnosis, and therapy of constipation for the general population and also for certain high risk groups.

Constipation - Causes, Diagnosis and Treatment

Constipation

Causes, Diagnosis and Treatment

*Edited by Anthony G. Catto-Smith*

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