**4. Management of opioid–induced bowel dysfunction**

#### **4.1. The management of dyspepsia**

**a.** Non–pharmacological measures

Treatment should be directed at cause of symptoms. Functional dyspepsia may be treated with non–pharmacological measures and drugs. The former comprise explanation and edu‐ cation of patients and families. Advice on the diet may play an important role. Fatty foods should be avoided as lipids impair gastric emptying, while lipids entering the duodenum may aggravate impaired gastric accommodation and gastric hypersensitivity. Medications that may cause dyspepsia (e.g. NSAIDs) should be discontinued when possible [24].

**b.** Pharmacological approach

Pharmacological treatment is usually needed. First-line therapy for dyspepsia is usually acid suppression. Proton pomp inhibitors (PPIs) such as omeprazole, esomeprazole or pantopra‐ 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‐ duced motility disorders.

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

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.

Treatment should be directed at cause of symptoms. Functional dyspepsia may be treated with non–pharmacological measures and drugs. The former comprise explanation and edu‐ cation of patients and families. Advice on the diet may play an important role. Fatty foods should be avoided as lipids impair gastric emptying, while lipids entering the duodenum may aggravate impaired gastric accommodation and gastric hypersensitivity. Medications

Pharmacological treatment is usually needed. First-line therapy for dyspepsia is usually acid suppression. Proton pomp inhibitors (PPIs) such as omeprazole, esomeprazole or pantopra‐

that may cause dyspepsia (e.g. NSAIDs) should be discontinued when possible [24].

**4. Management of opioid–induced bowel dysfunction**

**4.1. The management of dyspepsia**

**a.** Non–pharmacological measures

**b.** Pharmacological approach

emptying [21, 22].

186 Dyspepsia - Advances in Understanding and Management

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

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

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 and prucapolpride appear safe relative to cardiac function.

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

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 functional constipation.

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

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 diet (increased food and fluid intake), more physical activity, assuming a sitting position during bowel movement and obtaining privacy during defecation process are recommend‐ ed [36]. Patients treated with opioids should be considered for prokinetic administration [37]. Any reversible causes such as hypercalcaemia should also be treated. Discontinuing or decreasing doses of drugs that may aggravate constipation (e.g. tricyclics, neuroleptics, anti‐ cholinergics) should also be considered. Patients and families should be educated about the means to prevent and treat OIBD [9].

terms of weekly bowel movement frequency, patient satisfaction, ease of defecation and re‐ duced constipation symptoms with similar treatment tolerance and slightly higher lactulose costs [46]. For palliative care patients, different laxative regimens have no real differences. Overall, there is limited efficacy of traditional laxatives; well-done randomised controlled

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The possibility of opioid switch for OIBD should be considered as one of the available treat‐ ment options. Opioids, which seem to be more often associated with constipation, are co‐ deine and dihydrocodeine (opioids for mild to moderate pain), morphine, oxycodone and hydromorphone (opioids for moderate to severe pain). These opioids may be switched to other opioids belonging to the same group but having less constipating effect: codeine or di‐ hydrocodeine may be switched to tramadol; morphine, oxycodone or hydromorphone to transdermal opioids (fentanyl, buprenorphine) or to methadone [48,49]. The most convinc‐ ing evidence supporting the benefits of the opioid switch as regards constipation relief comes from the morphine to transdermal fentanyl switch [50–53]. In contrast to clinical stud‐ ies, observational surveys do not provide evidence for advantages of transdermal fentanyl over other opioid analgesics with respect to bowel function. [54-55] Other studies report similar or less intense constipating effects with transdermal buprenorphine compared to CR morphine [56] and after a switch from morphine to methadone [57–59]. There may be a ben‐ efit to administering tramadol rather than small morphine doses [60–62] or dihydrocodeine [63] with respect to the constipation intensity. However, no differences were found in con‐ stipation in cancer patients with pain between transdermal opioids (buprenorphine and fen‐

Few clinical studies compared the efficacy of different laxatives [65] and controlled studies are lacking [66]. Certainly traditional laxatives do not target the cause of OIBD, which is pre‐ dominantly associated with opioid analgesics binding and activating μ–opioid receptors in the GI tract [67]. Treatment directed at the cause of OIBD involves either using a combina‐ tion of opioid analgesics with opioid receptor antagonists, which act both centrally and pe‐ ripherally, or administering opioid receptor antagonists, which act exclusively peripherally. An important advantage of this approach is the fact that it is targeted treatment of OIBD and that it may be combined with oral laxatives, if necessary. Finally, this approach may elimi‐

Apart from opioid antagonists with exclusively peripheral effects, opioid receptor antago‐ nists with a central mode of action are naloxone, naltrexone and nalmefene. The majority of studies performed so far have used immediate release formulation of oral naloxone (IR na‐ loxone). In spite of high IR naloxone efficacy in the treatment of OIBD, some patients experi‐ ence opioid withdrawal symptoms and attenuation of analgesia, rendering IR naloxone less useful when administered alone [68–70]. Nalmefene [71] and nalmefene glucuronide [72] be‐

tanyl) and oral controlled release hydromorphone [64].

**4.4. Targeted treatment of opioid–induced bowel dysfunction**

nate the need for rectal measures, which patients tolerate poorly.

trials are lacking [47].

**4.3. Opioid switch**

have similarly.

In most patients with OIBD, laxatives are necessary. The general recommendation is to com‐ bine orally administered osmotic agents – usually lactulose or macrogol (PEG – polyethy‐ lene glycol) which have an osmotic effect in the colon [10] with stimulants activating on neurons in the myenteric and submucosal plexus in colon and reducing absorption of water and electrolytes from the intraluminal contents: anthracenes (senna), polyphenolics (bisa‐ codyl) or sodium picosulphate. Unfortunately, these drugs exhibit limited efficacy in pa‐ tients suffering from OIBD. Moreover, they may cause several adverse effects and must be administered on a regular basis [38]. Other classes of laxatives are faecal lubricants (liquid paraffin), stool softeners (surfactants: sodium docusate); however, they are usually ineffec‐ tive when administered alone [39]. The use of bulk–forming agents such as fibre, bran, methylcellulose and psyllium seeds has limited role in patients with advanced constipation and warrant ingesting adequate fluids (at least 2 liters per day) [40–42]. Castor oil is not rec‐ ommended due to its sudden stimulating effect on bowel motility and the risk of developing severe abdominal cramps [43]. If oral laxatives are found to be ineffective, rectal treatment should be considered.

Rectal laxatives comprise suppositories increasing intestinal motility through direct stimula‐ tion of the nerve endings in the myenteric ganglia of the colon, thus inducing peristalsis (bi‐ sacodyl) or using osmotic drugs (glycerol), which act by irritating the rectal mucosa and also enhance the colonic motility that subsequently triggers the defecation reflex. The next step if these agents prove ineffective is rectal enemas, either as normal saline (100–200 ml) or phos‐ phates (120–150 ml).

The management of faecal impaction depends on the severity of symptoms (rectal pain, ab‐ dominal colicky pain, protruding hard faeces and faecal leakage). If the symptoms are not severe in case of soft faeces, administer bisacodyl 10–20 mg once daily either rectally or oral‐ ly until bowel movements are achieved. If hard faeces are present, use glycerol and bisacod‐ yl suppositories or osmotic enemas. Enemas of arachis oil (130 ml) or of decussate sodium (100 ml) followed by a phosphate enema next day may be appropriate. Macrogol (PEG) re‐ duces the need for digital disimpaction. Digital stool evacuation may be necessary in cases of severe symptoms, when neither oral nor rectal treatment gives a desired effect and faecal impaction is not relieved, causing significant distress to the patient. As the procedure is quite painful and distressing, it should be performed with great caution and only when nec‐ essary and sometimes necessitating intravenous sedation with midazolam combined with opioids plus topical analgesics [44].

Polyethylene glycol (PEG) and sodium picosulphate are more effective than lactulose in OIC in cancer pain patients [45]. PEG specifically appears to be more effective than lactulose in terms of weekly bowel movement frequency, patient satisfaction, ease of defecation and re‐ duced constipation symptoms with similar treatment tolerance and slightly higher lactulose costs [46]. For palliative care patients, different laxative regimens have no real differences. Overall, there is limited efficacy of traditional laxatives; well-done randomised controlled trials are lacking [47].

#### **4.3. Opioid switch**

diet (increased food and fluid intake), more physical activity, assuming a sitting position during bowel movement and obtaining privacy during defecation process are recommend‐ ed [36]. Patients treated with opioids should be considered for prokinetic administration [37]. Any reversible causes such as hypercalcaemia should also be treated. Discontinuing or decreasing doses of drugs that may aggravate constipation (e.g. tricyclics, neuroleptics, anti‐ cholinergics) should also be considered. Patients and families should be educated about the

In most patients with OIBD, laxatives are necessary. The general recommendation is to com‐ bine orally administered osmotic agents – usually lactulose or macrogol (PEG – polyethy‐ lene glycol) which have an osmotic effect in the colon [10] with stimulants activating on neurons in the myenteric and submucosal plexus in colon and reducing absorption of water and electrolytes from the intraluminal contents: anthracenes (senna), polyphenolics (bisa‐ codyl) or sodium picosulphate. Unfortunately, these drugs exhibit limited efficacy in pa‐ tients suffering from OIBD. Moreover, they may cause several adverse effects and must be administered on a regular basis [38]. Other classes of laxatives are faecal lubricants (liquid paraffin), stool softeners (surfactants: sodium docusate); however, they are usually ineffec‐ tive when administered alone [39]. The use of bulk–forming agents such as fibre, bran, methylcellulose and psyllium seeds has limited role in patients with advanced constipation and warrant ingesting adequate fluids (at least 2 liters per day) [40–42]. Castor oil is not rec‐ ommended due to its sudden stimulating effect on bowel motility and the risk of developing severe abdominal cramps [43]. If oral laxatives are found to be ineffective, rectal treatment

Rectal laxatives comprise suppositories increasing intestinal motility through direct stimula‐ tion of the nerve endings in the myenteric ganglia of the colon, thus inducing peristalsis (bi‐ sacodyl) or using osmotic drugs (glycerol), which act by irritating the rectal mucosa and also enhance the colonic motility that subsequently triggers the defecation reflex. The next step if these agents prove ineffective is rectal enemas, either as normal saline (100–200 ml) or phos‐

The management of faecal impaction depends on the severity of symptoms (rectal pain, ab‐ dominal colicky pain, protruding hard faeces and faecal leakage). If the symptoms are not severe in case of soft faeces, administer bisacodyl 10–20 mg once daily either rectally or oral‐ ly until bowel movements are achieved. If hard faeces are present, use glycerol and bisacod‐ yl suppositories or osmotic enemas. Enemas of arachis oil (130 ml) or of decussate sodium (100 ml) followed by a phosphate enema next day may be appropriate. Macrogol (PEG) re‐ duces the need for digital disimpaction. Digital stool evacuation may be necessary in cases of severe symptoms, when neither oral nor rectal treatment gives a desired effect and faecal impaction is not relieved, causing significant distress to the patient. As the procedure is quite painful and distressing, it should be performed with great caution and only when nec‐ essary and sometimes necessitating intravenous sedation with midazolam combined with

Polyethylene glycol (PEG) and sodium picosulphate are more effective than lactulose in OIC in cancer pain patients [45]. PEG specifically appears to be more effective than lactulose in

means to prevent and treat OIBD [9].

188 Dyspepsia - Advances in Understanding and Management

should be considered.

phates (120–150 ml).

opioids plus topical analgesics [44].

The possibility of opioid switch for OIBD should be considered as one of the available treat‐ ment options. Opioids, which seem to be more often associated with constipation, are co‐ deine and dihydrocodeine (opioids for mild to moderate pain), morphine, oxycodone and hydromorphone (opioids for moderate to severe pain). These opioids may be switched to other opioids belonging to the same group but having less constipating effect: codeine or di‐ hydrocodeine may be switched to tramadol; morphine, oxycodone or hydromorphone to transdermal opioids (fentanyl, buprenorphine) or to methadone [48,49]. The most convinc‐ ing evidence supporting the benefits of the opioid switch as regards constipation relief comes from the morphine to transdermal fentanyl switch [50–53]. In contrast to clinical stud‐ ies, observational surveys do not provide evidence for advantages of transdermal fentanyl over other opioid analgesics with respect to bowel function. [54-55] Other studies report similar or less intense constipating effects with transdermal buprenorphine compared to CR morphine [56] and after a switch from morphine to methadone [57–59]. There may be a ben‐ efit to administering tramadol rather than small morphine doses [60–62] or dihydrocodeine [63] with respect to the constipation intensity. However, no differences were found in con‐ stipation in cancer patients with pain between transdermal opioids (buprenorphine and fen‐ tanyl) and oral controlled release hydromorphone [64].

#### **4.4. Targeted treatment of opioid–induced bowel dysfunction**

Few clinical studies compared the efficacy of different laxatives [65] and controlled studies are lacking [66]. Certainly traditional laxatives do not target the cause of OIBD, which is pre‐ dominantly associated with opioid analgesics binding and activating μ–opioid receptors in the GI tract [67]. Treatment directed at the cause of OIBD involves either using a combina‐ tion of opioid analgesics with opioid receptor antagonists, which act both centrally and pe‐ ripherally, or administering opioid receptor antagonists, which act exclusively peripherally. An important advantage of this approach is the fact that it is targeted treatment of OIBD and that it may be combined with oral laxatives, if necessary. Finally, this approach may elimi‐ nate the need for rectal measures, which patients tolerate poorly.

Apart from opioid antagonists with exclusively peripheral effects, opioid receptor antago‐ nists with a central mode of action are naloxone, naltrexone and nalmefene. The majority of studies performed so far have used immediate release formulation of oral naloxone (IR na‐ loxone). In spite of high IR naloxone efficacy in the treatment of OIBD, some patients experi‐ ence opioid withdrawal symptoms and attenuation of analgesia, rendering IR naloxone less useful when administered alone [68–70]. Nalmefene [71] and nalmefene glucuronide [72] be‐ have similarly.

#### **4.5. Combined opioid receptor agonist with its antagonist**

One of methods to decrease the frequency of constipation in patients requiring strong opioids is using formulation composed of an opioid and opioid receptor antagonist. The formulation combining oxycodone and naloxone is available in the form of prolonged re‐ lease (PR) tablets containing both drugs in the ratio of 2:1 (PR oxycodone/PR naloxone 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg) [73]. The optimal 2:1 ratio of PR oxycodone/PR naloxone tablets was demonstrated in a phase II study rendering effective analgesia and improvement in bowel function with good treatment toleration in patients with severe chronic pain [74]. PR oxycodone/PR naloxone is registered for the indication of severe pain, which may only be successfully treated with opioid analgesics. In this for‐ mulation, naloxone counteracts the development of OIBD through inhibition of oxyco‐ done effect on opioid receptors in the gut wall [75]. The starting PR oxycodone/PR naloxone doses in opioid–naive patients is 5 mg/2.5 mg b.i.d. Patients unsuccessfully treated with opioids for mild to moderate pain (tramadol, codeine, dihydrocodeine) may start with the dose 10 mg/5 mg b.i.d. When rotating from other opioids for moderate to severe pain to PR oxycodone/PR naloxone, the starting dose is established individually depending on the amount of previously administered opioid, analgesia and adverse ef‐ fects. The maximal daily dose of PR oxycodone/PR naloxone recommended equals 40 mg/ 20 mg twice daily. However, in a study conducted in cancer patients with pain higher daily doses up to 120 mg/60 mg were effective and well–tolerated while symptoms of OIBD were decreased, compared to PR oxycodone administered alone [76].

to 120 mg/60 mg per day provides effective analgesia while improving bowel function [76]. Adverse effects of PR oxycodone/PR naloxone and PR oxycodone are similar; the frequency of diarrhea is slightly higher in PR oxycodone/PR naloxone compared to PR oxycodone ad‐ ministered alone (5.2% vs. 2.6%) [81]. However, PR oxycodone/PR naloxone less frequency induces nausea (6.3% vs. 10.5%), vomiting (1.3% vs. 4.3%), abdominal pain (1.3% vs. 4.3%) and dyspepsia (0.6% vs. 2.5%) in comparison to PR oxycodone administered alone [82]. These differences might be explained by naloxone antagonist effect on gastric and gut opioid receptors and in consequence, naloxone prokinetic properties [86]. PR oxycodone/PR naloxone studies were performed mainly in patients with chronic, non–malignant pain [80– 83,85,89]. Opioid switch to PR oxycodone/PR naloxone for cancer patients generally pro‐ vides adequate analgesia and improved bowel function [87], but in some requiring height‐ ened analgesia, very high doses of PR up to 240 mg per day oxycodone administered alone

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The contraindications for PR oxycodone/PR naloxone comprise bowel obstruction, acute ab‐ dominal conditions, diarrhea and an allergy to the drug. PR oxycodone/PR naloxone is available in several European countries. One pack contains 60 PR oxycodone/PR naloxone tablets of 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg strength. Direct treatment costs for PR oxycodone/PR naloxone in patients with moderate–to–severe non–malignant pain and opioid–induced constipation is slightly higher compared to oxycodone PR. When analysing constipation treatment costs and benefits of PR oxycodone/PR naloxone in terms of improved quality–adjusted life–years, PR oxycodone/PR naloxone appears to be cost–ef‐ fective option in the UK [90]. Government and other insurance schemes however may not

Methylnaltrexone (MNTX), a derivative of naltrexone, is a peripheral μ–opioid receptor an‐ tagonist, which does not cross blood–brain barrier [91]. Because of its low oral bioavailabili‐ ty, MNTX is administered subcutaneously or intravenously [92]. However, MNTX taken orally prevents the delay in oro–ceacal transit time that follows intravenous morphine ad‐ ministration [93]. MNTX plasma half–life equals 105 to 140 minutes. 50% is excreted un‐ changed in the urine. MNTX is a weak CYP2D6 inhibitor with no significant drug interactions [94]. MNTX is used to treat OIC in adult patients with advanced diseases when constipation does not respond to conventional oral laxatives. The drug is available in am‐ poules containing 12 mg MNTX bromide in the volume of 0.6 ml and is applied via subcuta‐ neous injections. The recommended single MNTX dose is 8 mg in patients with body weight 38–61 kg or 12 mg if the body mass is 62–114 kg [95]. Those falling outside of this range should receive a dose of 0.15 mg/kg. No dose adjustment is necessary for patients with mild to moderate hepatic or renal impairment. However, in patients with severe renal failure (creatinine clearance < 30 mL/min) the MNTX dose should be reduced by one–half [96].

A bowel movement within 4 h after MNTX injection is observed in 50–60% patients (the me‐ dian time to bowel movement after the drug administration is 30 minutes). If no therapeutic effect is observed, the injection may be repeated every other day. MNTX adverse effects

may be necessary[88].

reimburse PR oxycodone/PR naloxone tablets.

**4.6. Purely peripherally acting opioid receptor antagonists**

Following oral administration, oxycodone displays high bioavailability (60 – 87%) and pro‐ vides effective analgesia [77,78]. Naloxone exhibits low bioavailability after oral administra‐ tion (< 2%) and undergoes extensive first–pass metabolism in the liver with the formation of naloxone–3–glucuronide [79]. Analgesic effect is not reversed by naloxone and no symp‐ toms of opioid withdrawal occur. This effect of orally administered naloxone depends on normal liver function. Thus, any hepatic impairment should be carefully considered. In pa‐ tients suffering from decompensated liver disease, PR oxycodone/PR naloxone administra‐ tion is not recommended. There is a clinically observed difference between the administration of IR and PR formulations of naloxone. IR naloxone in some patients may at‐ tenuate analgesia or induce opioid withdrawal symptoms. The PR naloxone formulation prevents saturation of hepatic enzyme system responsible for naloxone metabolism and re‐ duces the risk of opioid antagonism in the CNS [3].

PR oxycodone/PR naloxone provides similar analgesic efficacy to oxycodone with improve‐ ment in bowel function, a lower consumption of laxatives and more frequent spontaneous bowel movements [82]. during treatment with PR oxycodone/PR naloxone in comparison to PR oxycodone therapy [80–82]. Long–term therapy (up to 52 weeks) with PR oxycodone/PR naloxone in daily doses up to 80 mg/40 mg appears effective and safe [83]. Analgesia is ef‐ fective while bowel function and quality of life improved with PR oxycodone/PR naloxone (20 mg/10 mg to 40 mg/20 mg) treatment in patients with severe neuropathic non–malignant pain [84]. Even at quite high doses, PR oxycodone/PR naloxone doses exhibited a benefit compared to PR oxycodone administered alone [85]. PR oxycodone/PR naloxone in doses up to 120 mg/60 mg per day provides effective analgesia while improving bowel function [76]. Adverse effects of PR oxycodone/PR naloxone and PR oxycodone are similar; the frequency of diarrhea is slightly higher in PR oxycodone/PR naloxone compared to PR oxycodone ad‐ ministered alone (5.2% vs. 2.6%) [81]. However, PR oxycodone/PR naloxone less frequency induces nausea (6.3% vs. 10.5%), vomiting (1.3% vs. 4.3%), abdominal pain (1.3% vs. 4.3%) and dyspepsia (0.6% vs. 2.5%) in comparison to PR oxycodone administered alone [82]. These differences might be explained by naloxone antagonist effect on gastric and gut opioid receptors and in consequence, naloxone prokinetic properties [86]. PR oxycodone/PR naloxone studies were performed mainly in patients with chronic, non–malignant pain [80– 83,85,89]. Opioid switch to PR oxycodone/PR naloxone for cancer patients generally pro‐ vides adequate analgesia and improved bowel function [87], but in some requiring height‐ ened analgesia, very high doses of PR up to 240 mg per day oxycodone administered alone may be necessary[88].

The contraindications for PR oxycodone/PR naloxone comprise bowel obstruction, acute ab‐ dominal conditions, diarrhea and an allergy to the drug. PR oxycodone/PR naloxone is available in several European countries. One pack contains 60 PR oxycodone/PR naloxone tablets of 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg strength. Direct treatment costs for PR oxycodone/PR naloxone in patients with moderate–to–severe non–malignant pain and opioid–induced constipation is slightly higher compared to oxycodone PR. When analysing constipation treatment costs and benefits of PR oxycodone/PR naloxone in terms of improved quality–adjusted life–years, PR oxycodone/PR naloxone appears to be cost–ef‐ fective option in the UK [90]. Government and other insurance schemes however may not reimburse PR oxycodone/PR naloxone tablets.

#### **4.6. Purely peripherally acting opioid receptor antagonists**

**4.5. Combined opioid receptor agonist with its antagonist**

190 Dyspepsia - Advances in Understanding and Management

One of methods to decrease the frequency of constipation in patients requiring strong opioids is using formulation composed of an opioid and opioid receptor antagonist. The formulation combining oxycodone and naloxone is available in the form of prolonged re‐ lease (PR) tablets containing both drugs in the ratio of 2:1 (PR oxycodone/PR naloxone 5 mg/2.5 mg, 10 mg/5 mg, 20 mg/10 mg, 40 mg/20 mg) [73]. The optimal 2:1 ratio of PR oxycodone/PR naloxone tablets was demonstrated in a phase II study rendering effective analgesia and improvement in bowel function with good treatment toleration in patients with severe chronic pain [74]. PR oxycodone/PR naloxone is registered for the indication of severe pain, which may only be successfully treated with opioid analgesics. In this for‐ mulation, naloxone counteracts the development of OIBD through inhibition of oxyco‐ done effect on opioid receptors in the gut wall [75]. The starting PR oxycodone/PR naloxone doses in opioid–naive patients is 5 mg/2.5 mg b.i.d. Patients unsuccessfully treated with opioids for mild to moderate pain (tramadol, codeine, dihydrocodeine) may start with the dose 10 mg/5 mg b.i.d. When rotating from other opioids for moderate to severe pain to PR oxycodone/PR naloxone, the starting dose is established individually depending on the amount of previously administered opioid, analgesia and adverse ef‐ fects. The maximal daily dose of PR oxycodone/PR naloxone recommended equals 40 mg/ 20 mg twice daily. However, in a study conducted in cancer patients with pain higher daily doses up to 120 mg/60 mg were effective and well–tolerated while symptoms of

OIBD were decreased, compared to PR oxycodone administered alone [76].

duces the risk of opioid antagonism in the CNS [3].

Following oral administration, oxycodone displays high bioavailability (60 – 87%) and pro‐ vides effective analgesia [77,78]. Naloxone exhibits low bioavailability after oral administra‐ tion (< 2%) and undergoes extensive first–pass metabolism in the liver with the formation of naloxone–3–glucuronide [79]. Analgesic effect is not reversed by naloxone and no symp‐ toms of opioid withdrawal occur. This effect of orally administered naloxone depends on normal liver function. Thus, any hepatic impairment should be carefully considered. In pa‐ tients suffering from decompensated liver disease, PR oxycodone/PR naloxone administra‐ tion is not recommended. There is a clinically observed difference between the administration of IR and PR formulations of naloxone. IR naloxone in some patients may at‐ tenuate analgesia or induce opioid withdrawal symptoms. The PR naloxone formulation prevents saturation of hepatic enzyme system responsible for naloxone metabolism and re‐

PR oxycodone/PR naloxone provides similar analgesic efficacy to oxycodone with improve‐ ment in bowel function, a lower consumption of laxatives and more frequent spontaneous bowel movements [82]. during treatment with PR oxycodone/PR naloxone in comparison to PR oxycodone therapy [80–82]. Long–term therapy (up to 52 weeks) with PR oxycodone/PR naloxone in daily doses up to 80 mg/40 mg appears effective and safe [83]. Analgesia is ef‐ fective while bowel function and quality of life improved with PR oxycodone/PR naloxone (20 mg/10 mg to 40 mg/20 mg) treatment in patients with severe neuropathic non–malignant pain [84]. Even at quite high doses, PR oxycodone/PR naloxone doses exhibited a benefit compared to PR oxycodone administered alone [85]. PR oxycodone/PR naloxone in doses up

Methylnaltrexone (MNTX), a derivative of naltrexone, is a peripheral μ–opioid receptor an‐ tagonist, which does not cross blood–brain barrier [91]. Because of its low oral bioavailabili‐ ty, MNTX is administered subcutaneously or intravenously [92]. However, MNTX taken orally prevents the delay in oro–ceacal transit time that follows intravenous morphine ad‐ ministration [93]. MNTX plasma half–life equals 105 to 140 minutes. 50% is excreted un‐ changed in the urine. MNTX is a weak CYP2D6 inhibitor with no significant drug interactions [94]. MNTX is used to treat OIC in adult patients with advanced diseases when constipation does not respond to conventional oral laxatives. The drug is available in am‐ poules containing 12 mg MNTX bromide in the volume of 0.6 ml and is applied via subcuta‐ neous injections. The recommended single MNTX dose is 8 mg in patients with body weight 38–61 kg or 12 mg if the body mass is 62–114 kg [95]. Those falling outside of this range should receive a dose of 0.15 mg/kg. No dose adjustment is necessary for patients with mild to moderate hepatic or renal impairment. However, in patients with severe renal failure (creatinine clearance < 30 mL/min) the MNTX dose should be reduced by one–half [96].

A bowel movement within 4 h after MNTX injection is observed in 50–60% patients (the me‐ dian time to bowel movement after the drug administration is 30 minutes). If no therapeutic effect is observed, the injection may be repeated every other day. MNTX adverse effects comprise abdominal pain (28% of the treated patients), flatulence (13%), nausea (11%), dizzi‐ ness (7%) and diarrhoea (5%) [16]. However, the administration of MNTX may be associated with an increased risk of gastrointestinal perforation in patients with diseases that decrease gut wall integrity (cancer, peptic ulceration and Ogilvie's syndrome) or on concomitant medications (NSAIDs, bevacizumab). GI perforation occur at different possible locations (duodenum, small and large bowel). A possible contributing factor might be the prokinetic effect of MNTX. It is not known if dose and duration of the treatment with MNTX relate to this complication [95]. As MNTX does not cross the blood–brain barrier, there is no attenua‐ tion of analgesia nor is there an opioid withdrawal syndrome [17]. The use of MNTX is con‐ traindicated in patients with mechanical bowel obstruction, in acute abdominal conditions and in case of allergy to the drug. MNTX may be used in palliative care patients with OIBD not amenable to the treatment with oral laxatives. Several clinical studies have demonstrat‐ ed the effectiveness of MNTX in patients with advanced diseases and with OIBD [16,17,95,96,98–100]. Peripherally active opioid receptor antagonists in the treatment of OIBD are effective and safe in [101-4]. Long–term efficacy and safety of opioid antagonists is not yet clearly established, in part due to a limited number of randomized studies [105-6].]. 20

At the first step traditional oral laxatives and/or PR oxycodone/PR naloxone may be consid‐ ered. PR oxycodone/PR naloxone targets the source of OIBD (prevention and treatment) as PR naloxone blocks opioid receptors in the gut and PR oxycodone provides effective analge‐ sia. PR oxycodone/PR naloxone may be considered in cancer pain patients who are at high risk of OIBD development such as those with GI tumors, patients who require combined treatment with opioids and other drugs disturbing normal bowel function, e.g. advanced cancer patients. At the second step subcutaneous administration of MNTX may be consid‐ ered when traditional oral laxatives are ineffective, which may allow avoiding invasive and

Dyspepsia and Opioid–Induced Bowel Dysfunction: The Role of Opioid Receptor Antagonists

http://dx.doi.org/10.5772/56624

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OIBD in patients diagnosed with chronic diseases is a challenging problem that health care providers often underestimate. This is particularly important in patients regularly receiving opioids for pain or other indications. Thanks to newly introduced drugs that target the cause of OIBD, a more effective therapy is available. The experience with MNTX and PR oxycodone/PR naloxone in patients suffering from OIBD is promising. Further clinical stud‐ ies are needed to develop more effective guidelines for the management of OIBD and to es‐ tablish more precisely the role of opioid receptor antagonists. The role of opioid receptor antagonists as potential antiemetic and prokinetic agents should be further explored as sug‐ gested by experimental studies in animals. The cost-benefit from new therapies must be carefully considered; overall resources may actually be saved from reduced use of tradition‐ al laxatives. The most important advantage of targeted therapies is to decrease patient suf‐ fering from OIBD, substantial reduce the need to perform invasive rectal procedures and

Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan,

[1] Ueberral MA, Mueller–Schwefe G. Opioid–induced constipation – a frequent and distressing side effect in daily practice affecting oral and transdermal opioid applica‐

often painful invasive procedures at step 3 of the ladder.

most importantly, improve quality of life.

Address all correspondence to: wojciechleppert@wp.pl

tions. Eur J Pain 2006; 10: S172.

**5. Conclusions**

**Author details**

Wojciech Leppert\*

Poland

**References**

The Expert Working Group of the Polish Association for Palliative Medicine developed a three step ladder for the management of OIC (Fig. 1) [43]. This updated version of the ladder takes into account new therapies directed at the underlying mechanism of OIBD [107]. Fig. 1. The three-step ladder of the management of opioid–induced constipation [43,107]

At the first step traditional oral laxatives and/or PR oxycodone/PR naloxone may be considered. PR oxycodone/PR naloxone targets the \* PAMORA–peripherally acting mu–opioid receptor antagonists (methylnaltrexone) indicated for patients who do not respond to traditional oral laxatives without bowel obstruction and acute abdominal illness; \*\* This procedure should be used only when other measures fail and the faecal impaction causes significant pain and distress for the patient. It should be proceeded by a sedative and analgesics (local and systemic) administration that provide effective relief of severe pain and distress associated with manual stool evacuation; sc – subcutaneous

receptors in the gut and PR oxycodone provides effective analgesia. PR oxycodone/PR naloxone may be considered in cancer pain patients who are at high risk of OIBD development such as those with GI tumors, patients who require combined treatment with opioids and other drugs disturbing normal bowel function, e.g. advanced cancer patients. At the second step subcutaneous administration of MNTX may be considered

source of OIBD (prevention and treatment) as PR naloxone blocks opioid **Figure 1.** The three-step ladder of the management of opioid–induced constipation [43,107]

At the first step traditional oral laxatives and/or PR oxycodone/PR naloxone may be consid‐ ered. PR oxycodone/PR naloxone targets the source of OIBD (prevention and treatment) as PR naloxone blocks opioid receptors in the gut and PR oxycodone provides effective analge‐ sia. PR oxycodone/PR naloxone may be considered in cancer pain patients who are at high risk of OIBD development such as those with GI tumors, patients who require combined treatment with opioids and other drugs disturbing normal bowel function, e.g. advanced cancer patients. At the second step subcutaneous administration of MNTX may be consid‐ ered when traditional oral laxatives are ineffective, which may allow avoiding invasive and often painful invasive procedures at step 3 of the ladder.
