**1. Introduction**

Opioid analgesics are commonly and in most cases effectively used to manage chronic pain of moderate to severe intensity. Apart from analgesia, opioids exert numerous adverse ef‐ fects, several of which impact the gastrointestinal (GI) tract. The chronic use of opioid anal‐ gesics in fact is commonly associated with adverse effects on the gastrointestinal tract. [1] Opioid–induced bowel dysfunction (OIBD) comprises gastrointestinal symptoms such as dry mouth, anorexia, gastroesophageal reflux (GERD), delayed digestion, abdominal pain, flatulence, bloating, nausea, vomiting, and constipation with hard stool and incomplete evacuation. Further, side effects from long–term opioid therapy may result in more serious intestinal complications such as faecal impaction with overflow diarrhea and incontinence, pseudo–obstruction (causing anorexia, nausea and vomiting), disturbance of drug absorp‐ tion, and urinary retention and incontinence. OIBD may also lead to inappropriate opioid dosing and in consequence, insufficient analgesia. As a result, OIBD significantly deteriorate patients' quality of life and compliance with their treatment. Approximately one-third of pa‐ tients treated with opioid analgesics do not adhere to the prescribed opioid regimen or sim‐ ply quit the treatment due to OIBD symptoms [2].

Several strategies have been advocated to prevent or treat OIBD. Use of traditional laxatives is limited by their effectiveness, yet conveys their own adverse effects. Other possibilities comprise an opioid switch or changing the opioid administration route. New therapies now target opioid receptors in the gut as they represent a main source of OIBD symptoms. A combination of an opioid and opioid antagonist (oxycodone/naloxone) in prolonged release tablets and purely peripherally acting opioid receptor antagonist (methylnaltrexone) availa‐ ble in subcutaneous injections are currently available treatment options. This chapter re‐ views the pathophysiological basis and possible treatment strategies for OIBD.

© 2013 Leppert; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **2. Pathophysiological mechanism of opioid–induced bowel dysfunction**

of secretomotor neurons in the epithelium of the gut [18] leads to the stool becomes hard and dry. In summary, OIBD is the consequence of reduced gastrointestinal motility, in‐

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Dysfunction of the upper gastrointestinal tract (esophagus, stomach and duodenum) often manifests as dyspepsia. Dyspepsia represents a constellation of symptoms rather than a sin‐ gle disease entity. Its diverse symptoms may be expressed as epigastric pain, anorexia, belching, heartburn, bloating, nausea and vomiting, post–prandial fullness, early satiety,

**•** *Structural* (*organic*) *dyspepsia* for which a structural change can be demonstrated, often due to acid–related disease such as a gastric ulcer. In advanced cancer patients, symptoms

**•** *Functional dysmotility* (*non–ulcer dyspepsia*) due to dysmotility and/or altered sensitivity of the upper GI tract affecting the esophagus, stomach and duodenum. Esophageal and gas‐

In cancer patients, it may be iatrogenic (e.g.; opioid–induced delayed gastric emptying) and associated with disease-related complications like hepatomegaly or massive ascites. Furthermore, paraneoplastic visceral autonomic neuropathy seems to play an important role. Opioids and other drugs such as anticholinergics, tricyclic antidepressants, benzodia‐ zepines, nitrates and calcium channel blockers may decrease lower esophageal sphincter tone and lead to reflux (GERD) that would be aggravated secondarily by delayed gastric emptying. Gastric secretory and motor activity may be also affected by chronic alcohol‐ ism, diabetes, uremia, anxiety and depression. Gastroparesis is a symptomatic chronic dis‐ order characterized by impaired gastric emptying in the absence of a structural cause. This occurs as a component of paraneoplastic syndromes, most commonly in the course of small cell lung, breast, ovarian cancer, Hodgkin disease or multiple myeloma. In addi‐ tion to opioid adversely affecting gastric emptying, other drugs such as anticholinergics, neuroleptics or tricyclic antidepressants can aggravate gastroparesis. Meanwhile, concur‐ rent conditions such as diabetes, prior gastric surgery, and neuromuscular disorders may further impair gastric emptying. Lastly, gastric or pancreatic tumors can inflict a mechani‐

Another component that might co-exist is gastroesophageal reflux disease (GERD) due to re‐

The prevalence of functional dyspepsia is high in the normal population (24–34%) and even higher in cancer patients (70%) [20]. Opioids adversely affect the esophagus. This class of drugs impairs esophageal inhibitory innervation and so induces spastic esophageal dysfunc‐

flux of gastric contents into the esophagus, causing mucosal damage and heartburn.

may arise from NSAID, corticosteroid and bisphosphonate administration.

creased absorption of fluids from the gut and decreased epithelial secretion.

**3. Dyspepsia**

and/or regurgitation [19].

cal outlet obstruction.

Two types of dyspepsia may be diagnosed:

troduodenal dysmotility can be differentiated.

Opioids produce widespread effects throughout the gastrointestinal tract though several central and peripheral mechanisms. Such effects are a mixture of inhibitory and excitatory actions. Opioid peptides and their receptors are found throughout the gastrointestinal tract, especially in the gastric antrum and proximal duodenum. The basis for OIBD is therefore complex. The peripheral opioid effect on μ–opioid receptors in the gut wall likely plays a major role, but central effects may also be important [3]. μ–opioid receptors at a high density reside in neurons of myenteric and submucosal plexus and immune cells in the lamina propria [4]. Opioid receptors (predominantly μ, also κ and δ) are located in the gut wall in the myenteric plexus and in the submucosal plexus. The former are responsible for gut mo‐ tility and the latter for secretion. These μ–opioid receptors are activated in the wall of the stomach, small and large intestine by both endogenous (e.g. enkephalins, endorphins and dynorphins) and exogenous (e.g. morphine, oxycodone, methadone) opioids and modify gastrointestinal function. Activation of μ–opioid receptors inhibits excitatory and inhibitory neural pathways within the enteric nervous system that coordinates motility. Inhibition of excitatory neural pathways depresses peristaltic contractions. On the other hand, the block‐ ade of inhibitory neural pathways increases gut muscle activity, elevates resting muscle tone, and results in spasm and non–propulsive motility patterns. These mechanisms give rise to delayed gastric emptying and slowed intestinal transit [5].

Activation of opioid receptors in the submucosa inhibits water and electrolyte secretion into the gut lumen and increases fluid absorption from the intestine and accelerates blood flow in the gut wall [6]. Opioids increase activity in the sympathetic nervous system and thereby decrease secretion. Endocrine cells located in the epithelium also may play a role in regulat‐ ing motor activity and secretion in the gut. Interms of motility, peripheral μ–opioid recep‐ tors inhibit intestinal transit independent of central μ–opioid receptors [7]. Moreover, opioids increase ileocaecal and anal sphincter tones and impair defecation reflex through re‐ duced sensitivity to distension and increased internal anal sphincter tone [8]. Morphine ad‐ ministration leads to sphincter contraction and to a decreased emptying of pancreatic juice and bile [9], which may impair digestion. The anal sphincter dysfunction is an important factor in the sensation of anal blockage [10,11].

The central mechanism of opioid effects on the gastrointestinal tract is supported by the re‐ sults of animal studies in which intracerebroventricular administration of morphine inhibit‐ ed GI propulsion [12]. This effect was reversed by intracerebroventricular administration of naloxone [13] and vagotomy [14]. Intrathecal administration of morphine reduced gastro‐ duodenal motility while intramuscular morphine gave additional effects. Thus, it seems that both central and peripheral opioid effects play a role in opioid GI effects [15]. The indirect evidence of both central and peripheral components of opioid effects on bowel function may be the observed 50–60% response rate to the treatment of OIBD with methylnaltrexone (MNTX), which displays only peripheral μ–opioid receptor antagonist effect in the treat‐ ment of patients with OIBD [16,17]. The stool remains in the gut lumen for a longer time, allowing greater absorption of fluid. Enhanced absorption combined with opioid inhibition of secretomotor neurons in the epithelium of the gut [18] leads to the stool becomes hard and dry. In summary, OIBD is the consequence of reduced gastrointestinal motility, in‐ creased absorption of fluids from the gut and decreased epithelial secretion.

## **3. Dyspepsia**

**2. Pathophysiological mechanism of opioid–induced bowel dysfunction**

Opioids produce widespread effects throughout the gastrointestinal tract though several central and peripheral mechanisms. Such effects are a mixture of inhibitory and excitatory actions. Opioid peptides and their receptors are found throughout the gastrointestinal tract, especially in the gastric antrum and proximal duodenum. The basis for OIBD is therefore complex. The peripheral opioid effect on μ–opioid receptors in the gut wall likely plays a major role, but central effects may also be important [3]. μ–opioid receptors at a high density reside in neurons of myenteric and submucosal plexus and immune cells in the lamina propria [4]. Opioid receptors (predominantly μ, also κ and δ) are located in the gut wall in the myenteric plexus and in the submucosal plexus. The former are responsible for gut mo‐ tility and the latter for secretion. These μ–opioid receptors are activated in the wall of the stomach, small and large intestine by both endogenous (e.g. enkephalins, endorphins and dynorphins) and exogenous (e.g. morphine, oxycodone, methadone) opioids and modify gastrointestinal function. Activation of μ–opioid receptors inhibits excitatory and inhibitory neural pathways within the enteric nervous system that coordinates motility. Inhibition of excitatory neural pathways depresses peristaltic contractions. On the other hand, the block‐ ade of inhibitory neural pathways increases gut muscle activity, elevates resting muscle tone, and results in spasm and non–propulsive motility patterns. These mechanisms give

Activation of opioid receptors in the submucosa inhibits water and electrolyte secretion into the gut lumen and increases fluid absorption from the intestine and accelerates blood flow in the gut wall [6]. Opioids increase activity in the sympathetic nervous system and thereby decrease secretion. Endocrine cells located in the epithelium also may play a role in regulat‐ ing motor activity and secretion in the gut. Interms of motility, peripheral μ–opioid recep‐ tors inhibit intestinal transit independent of central μ–opioid receptors [7]. Moreover, opioids increase ileocaecal and anal sphincter tones and impair defecation reflex through re‐ duced sensitivity to distension and increased internal anal sphincter tone [8]. Morphine ad‐ ministration leads to sphincter contraction and to a decreased emptying of pancreatic juice and bile [9], which may impair digestion. The anal sphincter dysfunction is an important

The central mechanism of opioid effects on the gastrointestinal tract is supported by the re‐ sults of animal studies in which intracerebroventricular administration of morphine inhibit‐ ed GI propulsion [12]. This effect was reversed by intracerebroventricular administration of naloxone [13] and vagotomy [14]. Intrathecal administration of morphine reduced gastro‐ duodenal motility while intramuscular morphine gave additional effects. Thus, it seems that both central and peripheral opioid effects play a role in opioid GI effects [15]. The indirect evidence of both central and peripheral components of opioid effects on bowel function may be the observed 50–60% response rate to the treatment of OIBD with methylnaltrexone (MNTX), which displays only peripheral μ–opioid receptor antagonist effect in the treat‐ ment of patients with OIBD [16,17]. The stool remains in the gut lumen for a longer time, allowing greater absorption of fluid. Enhanced absorption combined with opioid inhibition

rise to delayed gastric emptying and slowed intestinal transit [5].

factor in the sensation of anal blockage [10,11].

184 Dyspepsia - Advances in Understanding and Management

Dysfunction of the upper gastrointestinal tract (esophagus, stomach and duodenum) often manifests as dyspepsia. Dyspepsia represents a constellation of symptoms rather than a sin‐ gle disease entity. Its diverse symptoms may be expressed as epigastric pain, anorexia, belching, heartburn, bloating, nausea and vomiting, post–prandial fullness, early satiety, and/or regurgitation [19].

Two types of dyspepsia may be diagnosed:


In cancer patients, it may be iatrogenic (e.g.; opioid–induced delayed gastric emptying) and associated with disease-related complications like hepatomegaly or massive ascites. Furthermore, paraneoplastic visceral autonomic neuropathy seems to play an important role. Opioids and other drugs such as anticholinergics, tricyclic antidepressants, benzodia‐ zepines, nitrates and calcium channel blockers may decrease lower esophageal sphincter tone and lead to reflux (GERD) that would be aggravated secondarily by delayed gastric emptying. Gastric secretory and motor activity may be also affected by chronic alcohol‐ ism, diabetes, uremia, anxiety and depression. Gastroparesis is a symptomatic chronic dis‐ order characterized by impaired gastric emptying in the absence of a structural cause. This occurs as a component of paraneoplastic syndromes, most commonly in the course of small cell lung, breast, ovarian cancer, Hodgkin disease or multiple myeloma. In addi‐ tion to opioid adversely affecting gastric emptying, other drugs such as anticholinergics, neuroleptics or tricyclic antidepressants can aggravate gastroparesis. Meanwhile, concur‐ rent conditions such as diabetes, prior gastric surgery, and neuromuscular disorders may further impair gastric emptying. Lastly, gastric or pancreatic tumors can inflict a mechani‐ cal outlet obstruction.

Another component that might co-exist is gastroesophageal reflux disease (GERD) due to re‐ flux of gastric contents into the esophagus, causing mucosal damage and heartburn.

The prevalence of functional dyspepsia is high in the normal population (24–34%) and even higher in cancer patients (70%) [20]. Opioids adversely affect the esophagus. This class of drugs impairs esophageal inhibitory innervation and so induces spastic esophageal dysfunc‐ tion while impairing lower esophageal relaxation, leading to swallowing difficulties (dys‐ phagia). Opioids also reduce the lower esophageal sphincter (LES) pressure, thereby decreasing the barrier pressure between the stomach and the esophagus, producing acid-re‐ flux symptoms. This effect is reversed by naloxone. Opioids inhibit gastric emptying, a product of enhanced gastric relaxation and heightened pyloric tone. This decrease in gastric emptying results from both central and peripheral effects, although a peripheral μ–opioid receptor mechanism is dominant. Opioid administration increases duodenal motility by generating patterns of contractions resembling migrating motor complex (MMC) phase III patterns. Endorphins in humans decrease antral phasic pressure activity and increase pylor‐ ic phasic pressure activity and induce MMC III–like bursts of contractile activity in the prox‐ imal gut followed by motor quiescence. Exogenous and endogenous opioids impair gastric emptying [21, 22].

zole are used once daily in doses 20–40 mg, best given 30 minutes before breakfast. In cancer patients, prokinetic agents are commonly administered, aiming to counteract opioid–in‐

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Typically, metoclopramide is prescribed (commonly as 10 mg t.i.d.) for patients with func‐ tional dyspepsia, especially when symptoms arise from gastroparesis. Metoclopramide works mostly in the upper GI tract through blocking dopaminergic receptors. As metoclo‐ pramide also acts centrally, its use is associated with the added risk of extra–pyramidal ef‐ fects, particularly in younger patients and children. Metoclopramide also inhibits the cytochrome, CYP2D6 enzyme [25]. The most common adverse effects of metoclopramide are restlessness, drowsiness and fatigue. Concomitant use of antidepressants, such as tricyclics, selective serotonin reuptake inhibitors (SSRIs) and newer serotonin–noradrenalin reuptake inhibitors (venlafaxine, duloxetine), may aggravate the adverse effects of metoclopramide [26]. Extrapyramidal effects are unlikely to occur when using domperidone, which does not cross blood–brain barrier [27]. Cisapride is a 5HT4 receptor agonist, affecting the entire GI

Itopride works through peripheral blocking dopaminergic receptors. It inhibits acetylcholi‐ nesterase and so increases acetylcholine levels. Itopride works through the whole GI tract. It is devoid of activity at 5–HT4 and 5–HT3 receptors. Itopride is metabolized through monoox‐ idase system. Thus, it has no significant risk of pharmacokinetic interactions with other drugs. Itopride does not cross blood–brain barrier and in consequence does not induce ex‐

Prucalopride, a new prokinetic agent, is a highly selective 5HT4 receptor agonist that stimu‐ lates gut motility *in vitro* and *in vivo*. Prucalopride at 2–4 mg daily accelerates whole gut, gastric, small bowel and colonic transit in constipated patients [30]. The recommended dose is 1–2 mg once daily. Prucalopride is used in managing chronic constipation predominantly in women, but has not been evaluated in gastroparesis as yet [31]. Treatment is usually welltolerated; typical adverse effects are headaches (present in 25–30% of treated patients), nau‐ sea (12–24%), abdominal pain or cramps (16–23%) and diarrhea (12–19%) [32]. Both itopride

Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist that appears quite effective for chronic constipation and the irritable bowel syndrome [33,34]. It looks promis‐

Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, acts by specifically acti‐ vating chloride channels on the apical aspect of gastrointestinal epithelial cells, producing a chloride-rich fluid secretion. These secretions soften the stool, increase intestinal motility, and so promote spontaneous bowel movements. Lubiprostone thus has value in treating

General measures to be taken in patients with OIBD and OIC include the assessment and applying prophylactic measures matched to the patient's general condition [35]. Change of

duced motility disorders.

tract; however, its cardiotoxicity has limited use [28].

trapyramidal effects. The dose usually equals 50 mg t. i. d. [29]

and prucapolpride appear safe relative to cardiac function.

functional constipation.

ing in the treatment of gastroparesis and so may have a role in OBID.

**4.2. Oral and rectal laxatives for Opioid-induced Bowel Dysfunction**

The evaluation of patients with functional dyspepsia and gastroparesis is based on a careful history taking and physical examination that allow differentiating between functional and structural dyspepsia and GERD. The symptoms of gastroparesis, as quantified by the Gas‐ troparesis Cardinal Symptom Index (GCSI), consists of 9 symptoms, each graded from 0 (none) to 5 (very severe), divided into 3 subscales: postprandial fullness/early satiety, nau‐ sea/vomiting, and bloating [23]. Upper endoscopy is usually needed to exclude mechanical obstruction and to assess for mucosal lesions. It is recommended in patients with alarming symptoms e.g.; those suspected for gastrointestinal bleeding. Endoscopy may be also con‐ ducted when symptoms develop with NSAIDs administration and when treatment with an‐ tisecretory drugs or antacids is unsuccessful. Blood tests assessing complete blood count and biochemistry might be useful. An ultrasound or CT abdominal scan is helpful to assess for cancer spread. In some patients, solid phase gastric scintigraphic emptying studies or breath tests may be needed to confirm gastroparesis. Other investigations such as electro‐ gastrography, antroduodenal manometry are infrequently used in cancer patients.
