Adv Ther (2010) 27(10):17. DOI 10.1007/s12325-010-0063-0
REVIEW
The Role of Opioid Receptor Antagonists in the Treatment of Opioid-Induced Constipation: a Review
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Opioid-induced constipation (OIC) is associated with negative impact of opioid analgesics on opioid receptors located in the gut wall. Until recently, OIC was treated symptomatically only, with different laxatives which did not target the pathophysiology of OIC. Recently, several opioid receptor antagonists have been introduced in the treatment of OIC. Methylnaltrexone (MNTX) is a peripheral mu-opioid receptor antagonist for subcutaneous administration, which does not evoke symptoms of opioid abstinence. MNTX is indicated for patients with OIC who are not amenable to therapy with oral laxatives. In clinical trials, the effectiveness of MNTX assessed as its ability to induce spontaneous bowel movement, is 50%‑60% of treated patients; MNTX demonstrates
significant superiority over placebo. Another product is combination of oral formulation of prolonged release oxycodone and prolonged release naloxone (PR oxycodone/PR naloxone), indicated for patients who require opioid administration for chronic pain and have already developed OIC, and for those who need opioid therapy and take the drug to prevent OIC. Naloxone administered orally displays local, antagonist effects on opioid receptors in the gut wall, negligible systemic bioavailability, and significantly reduces the oxycodone constipating effect. PR oxycodone/ PR naloxone has similar analgesic efficacy, but causes less constipation and less laxative consumption in comparison with patients treated with oxycodone alone. Both products are expensive, therefore their administration should be carefully considered. On the other hand, uncontrolled OIC and the necessity to perform rectal invasive procedures (enema, manual evacuation) lead not only to increased health care costs, but most importantly, cause severe patient suffering.
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ABSTRACT
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Received: April 1, 2010 / Published online: © Springer Healthcare 2010
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Wojciech Leppert
Wojciech Leppert () Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Osiedle Rusa 25 A, 61–245 Poznan, Poland. Email:
[email protected]
Keywords: constipation; laxatives; opioids; opioid-induced constipation; opioid receptor antagonists; treatment
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Adv Ther (2010) 27(10):17.
EPIDEMIOLOGY, ASSESSMENT, AND PATHOMECHANISM OF CONSTIPATION
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Constipation is defined as a decrease in frequency of bowel movements (less than 3 per week) or the following symptoms reported by patients: difficulties in bowel movement, hard stools, straining during defecation, and incomplete bowel movement.1 Opioid-induced constipation (OIC) is defined as a constipation which is induced by opioid administration. 2 Constipation is present in 10%-20% of a
healthy population and in approximately 50% of patients admitted to British hospices.3 OIC is developed by 80%-90% of cancer patients, and constitutes a significant clinical problem as it is often not amenable to symptomatic treatment, and in about 90% of patients it significantly decreases quality of life. 4 Constipation in patients with advanced diseases is induced by numerous causes, which comprise disease progression and its consequences (lack of appetite, weakness, low activity, hypercalcemia), drugs administered (opioids, anticholinergic drugs), and comorbidities5,6 (Table 1).
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Structural abnormalities • Bowel obstruction • Pelvic tumors • Radiation fibrosis • Diverticular disease • Colitis • Painful anorectal conditions (anal fissure, rectocoele, hemorrhoids, perianal abscess) • Hernia
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General • Advanced age • Inactivity • Anxiety • Depression • Confusion • Sedation • Lack of privacy
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Table 1. Causes of constipation in advanced cancer patients.5-9
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Dietary • Decreased food intake • Low-fibre diet • Poor fluid intake • Physical or social impediments
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Neurological disorders • Cerebral tumours • Spinal cord compression • Sacral nerve infiltration • Autonomic failure • Paraneoplastic neuropathy • Multiple sclerosis • Parkinson disease • Stroke
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Drugs • Opioid analgesics • Nonsteroidal anti-inflammatory drugs • Drugs with anticholinergic action (anticholinergics, antihistamines, phenothiazines, antidepressants, antiparkinsonian agents, haloperidol) • Antacids • Antiemetics (ondansetron) • Anticonvulsants • Antihypertensive drugs • Calcium and iron supplements • Diuretics • Chemotherapeutic agents: vinca alkaloids, cisplatin, taxanes, thalidomide
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Metabolic disturbances • Dehydration (fever, vomiting, polyuria, poor fluid intake, diuretics) • Hypercalcemia • Hypokalemia • Uremia • Diabetes • Hypothyroidism
Adv Ther (2010) 27(10):17.
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and pelvic investigations, and endoscopy of gastrointestinal (GI) tract should be considered. In the differential diagnosis bowel obstruction should be considered. Generally, all possible causes should be taken into account and the treatment should be multimodal. In case of OIC, all possible concomitant causes should also be considered.11 The assessment of constipation severity and intensity should be based on validated visualanalogue scales(VAS) or numerical rating scales (NRS). For the purpose of detailed assessment and monitoring of constipation treatment, the bowel function index (BFI, Figure 1) may be used.11,12 This tool comprises three numerical scales, all referring to the last 7 days; patients rate the ease of defecation, the feeling of incomplete bowel evacuation, and the patient’s personal
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Constipation can be diagnosed by historytaking with a focus placed on the frequency of bowel movements, stool consistency and color, concomitant symptoms, diet and amount of fluid intake, drugs administered (including laxatives), and by meticulous assessment of other symptoms.7-10 A physical examination should include abdominal palpation (to check for pathological mass, flatulence, pain, peritoneal symptoms), abdomen auscultation, and evaluation of gut peristalsis. Rectal examination is recommended in patients without bowel movement for over 3 days; the examination is contraindicated, however, in patients with neutropenia and thrombocytopenia— these patients should not be applied rectal suppositories and enemas. In case of diagnostic dilemma, additional laboratory tests, abdominal
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Figure 1. Bowel function index (BFI).11,12 Reprinted from European Journal of Pain, Vol.13, Meissner, et al., A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation, 56-64, Copyright (2009), with permission from Elsevier.
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Please complete all items in this assessment:
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1. Ease of defecation during the last 7 days according to patient assessment:
Ask the subject: “During the last 7 days, how would you rate your ease of defecation on a scale from 0 to 100, where 0 = easy or no difficulty and 100 = severe difficulty?”
If the subject requires clarification, ask: “During the last 7 days, how easy or difficult was it to have a bowel movement on a scale from 0 to 100, where 0 = easy or no difficulty and 100 = severe difficulty?”
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2. Feeling of incomplete bowel evacuation during the last 7 days according to patient assessment: Ask the subject: “During the last 7 days, how would you rate any feeling of incomplete bowel evacuation on a scale from 0 to 100, where 0 = no feeling of incomplete evacuation and 100 = a very strong feeling of incomplete evacuation?”
If the subject requires clarification, ask: “During the last 7 days, how strongly did you feel that you did not empty your bowels completely? Please indicate how strong this feeling was on a scale from 0 to 100, where 0 = not at all and 100 = very strong?”
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3. Personal judgment of patient regarding constipation during the last 7 days:
Ask the subject: “During the last 7 days, how would you rate your constipation on a scale from 0 to 100, where 0 = not at all and 100 = very strong?”
If the subject requires clarification, ask: “During the last 7 days, how would you rate how constipated you felt on a scale from 0 to 100, where 0 = not at all and 100 = very strong?”
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Adv Ther (2010) 27(10):17.
Apart from analgesia, opioids exert numerous adverse effects. These effects also appear in the GI tract and they are called opioid-induced bowel dysfunction (OIBD). The symptoms of OIBD are as follows: constipation, hard stool, incomplete bowel evacuation, straining during bowel movement, flatulence, and gastroesophageal reflux. In the case of long-term opioid therapy, these symptoms may lead to the development of more serious complications: bowel fecal impaction with overflow diarrhea and fecal incontinence, pseudo-obstruction which may cause anorexia, nausea, and vomiting, disturbance of drug absorption, urine retention,
It is also important to evaluate symptoms that accompany constipation with the use of the Patient Assessment of Constipation Symptoms (PAC-SYM, Figure 2).10
and urine incontinence. OIBD and especially OIC significantly deteriorate patients’ quality of life, and may lead to inappropriate opioid dosing and, in consequence, insufficient analgesia.14
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judgment of constipation intensity using a scale in the range of 0 (= not at all) to 100 (= very strong/severe). By averaging the results of the three scales, the mean is calculated (mean bowel function). A useful tool for monitoring the efficacy of constipation treatment is the modified Edmonton Symptom Assessment System (ESAS). To the ten original scales used for the assessment of pain, activity, nausea, depression, anxiety, drowsiness, appetite, sensation of well-being, shortness of breath, and one other symptom chosen by the patient, two items were added: constipation and vomiting.13
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Figure 2. The Patient Assessment of Constipation Symptoms (PAC-SYM).10 Reprinted from European Journal of Pain, Vol.10, Slappendel R, et al. Validation of the PAC-SYM questionnaire for opioid-induced constipation in patients with chronic low back pain, 209-217, Copyright (2006), with permission from Elsevier.
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How severe has each of these symptoms been in the last 2 weeks?
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1. Discomfort in your stomach.
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2. Pain in your stomach.
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3. Bloating in your stomach.
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4. Stomach cramps. 6. Rectal burning during or after a bowel movement.
10. Bowel movements that were too small.
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9. Bowel movements that were too hard.
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8. Incomplete bowel movement, like you did not “finish.”
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7. Rectal bleeding or tearing during or after a bowel movement.
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5. Painful bowel movements.
11. Straining or squeezing to try to pass bowel movements. 12. Feeling like you had to pass a bowel movement but you could not (“false alarm”). The instrument is composed of three domains: abdomial symptoms (four items: 1-4), rectal symptoms (three items: 5-7), and stool symptoms (five items: 8-12). Wording is as follows: Items are rated on a 5-point (0-4) Likert scale; responses are scored as 0 = absence of symptom, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe. The abdominal, rectal, and stool domain scores are the mean scores of each domain. The global score is the mean of all 12 items.
Adv Ther (2010) 27(10):17.
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(MNTX) (which display only peripheral mu-opioid receptor antagonist effect) treatment, in patients with OIC.24,25 OIC is the consequence of reduced GI motility, increased absorption of fluids from the gut, and decreased epithelial secretion; as a result, the stool remains in the gut lumen for a longer time, therefore, more fluid is reabsorbed and the stool becomes hard and dry. The above effects are also associated with opioid inhibition of secretomotor neurons in the epithelium of the gut.26 Moreover, opioids increase ileocaecal and anal sphincter tones, and impair defecation reflex through reduced sensitivity to distension and increased internal anal sphincter tone.7
Activation of opioid receptors inhibits water and electrolyte secretion into the gut lumen, and increases fluid absorption from the intestine and blood flow in the gut wall.18 Endocrine cells located in the epithelium might play a role in regulating motor activity and secretion in the gut. Studies performed in mice indicate that peripheral mu-opioid receptors inhibit the transit, independently of central mu-receptors.19 The thesis of a central mechanism is supported by the results of experimental studies in which, intracerebroventricular administration of morphine in the rat, inhibited GI propulsion.20 This effect was reversed by intracerebroventricular administration of naloxone21 and vagotomy.22 Intrathecal administration of morphine reduced gastroduodenal motility, and intramuscular morphine gave additional effects, thus, both central and peripheral mechanisms play a role.23 The indirect evidence of both central and peripheral components of OIC may be the overall 50%-60% response rate to methylnaltrexone
General measures to be taken in patients with constipation include the assessment of constipation risk and applying prophylactic measures matched to the patient’s general condition.8 Change of diet (increased food and fluid intake), more physical activity, sitting position during bowel movement, and privacy during defecation process are recommended.27 Massaging the abdomen gently may also help some patients. Which of the above guidelines should be applied depends on the general patient condition. Patients treated with opioids should be prophylactically supplemented with laxatives and prokinetics (metoclopramide or domperidone). 28 The metabolic, water, and electrolyte imbalance should be corrected and any reversible causes (eg, hypercalcemia, hypothyroidism) should also be treated. Discontinuing or decreasing doses of drugs that may be responsible for constipation development should also be considered. It is mandatory for effective constipation management to educate
GENERAL MEASURES
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Traditional Oral and Rectal Laxatives
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The pathomechanism of OIC is complex. It seems that the peripheral opioid effect on mu-opioid receptors in the gut wall play the main role here, but the central effects are also important. 15 The mu-opioid receptors are activated in the walls of the stomach, and small and large intestines. High density of mu-opioid receptors was found in neurons of myenteric and submucosal plexus, and in immune cells in the lamina propria.16 Activation of mu-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 blockade of inhibitory neural pathways increases GI muscle activity, elevates resting muscle tone, spasm, and nonpropulsive motility patterns. These mechanisms are responsible for delayed gastric emptying and slowing the intestinal transit.17
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Adv Ther (2010) 27(10):17.
direct stimulation of the nerve endings in the myenteric ganglia of the colon, thus inducing peristalsis (bisacodyl), or osmotic drugs (glycerol), which act by irritation of the mucosa in the rectum that enhances the motility of the colon and subsequently triggers the defecation reflex.2 The next step to be taken after these agents is rectal enema with normal saline (100200 mL) or phosphates (120-150 mL). If neither oral nor rectal treatment gives a desired effect and fecal impaction is not relieved, causing significant distress to the patient, it may be necessary to perform manual stool evacuation, which is a painful procedure.2 The procedure should be performed very carefully and only when necessary; before starting the procedure it is mandatory to administer opioid analgesics with local anesthetics and anxiolytics. 6 Controlled studies are lacking on the efficacy of different laxatives, with only a few clinical trials comparing this.34,35 This is an important clinical problem when establishing OIC management recommendations. Another issue is the fact that none of the traditional laxatives target the cause of OIC, which is predominantly associated with opioid analgesics binding and activating mu-opioid receptors in the GI tract.36
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patients and families about the ways to prevent and treat constipation.29 In the majority of patients with OIC, aside from prophylactic measures laxatives need to be administered. The general recommendation for the treatment of OIC is to combine oral administration of osmotic agents (most frequently lactulose or macrogol), which have an osmotic effect in the colon,30 with stimulants activating neurons in the myenteric and submucosal plexus in colon and reducing absorption of water and electrolytes from the intraluminal contents: anthracenes (senna), polyphenolics (bisacodyl), or sodium picosulphate.27 These drugs display limited efficacy in patients suffering from OIC; moreover, they may cause several adverse effects and must be administered on a regular basis.2 Other groups of laxatives are fecal lubricants (liquid paraffin), stool softeners (surfactants: sodium docusate); however, they are usually not effective in OIC when administered alone.5 The use of bulk-forming agents, such as, fibre, bran, methylcellulose, and psyllium seeds is limited to patients who are in a general good condition, receive enough fluids (at least 2 L per day), and do not suffer from anorexia/cachexia syndrome. The efficacy of these agents is doubtful (a 50% increase in bowel frequency requires a 450% increase in fibre intake). 31 Moreover, when oral intake of fluids is insufficient, a viscous mass may form in the GI tract and aggravate a partial bowel obstruction; significant allergy to these substances is also reported.9 For these reasons, bulk laxatives are not indicted for advanced cancer patients.32,33 Similarly, castor oil is not recommended due to its sudden stimulating effect on bowel motility and the risk of developing strong abdominal cramps.6 If the oral laxatives are found to be ineffective, rectal treatment is usually introduced. Rectal laxatives comprise suppositories, which increase intestinal motility through
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Opioid Switch
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The possibility of opioid switch in the treatment of OIC should be considered as one of the available treatment options. Opioids which seem to be more often associated with constipation are codeine 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 dihydrocodeine may be switched to tramadol; morphine, oxycodone,
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with buprenorphine and fentanyl, and higher activity of patients treated with hydromorphone. No differences in the consumption of laxatives or in the intensity of nausea were found between the patient groups. The patients treated with hydromorphone experienced vomiting that was more intense than that experienced by patients taking transdermal opioids; apart from the opioid, the cause of vomiting could be attributed to the primary tumour site, as in patients treated with hydromorphone, abdominal site was more often diagnosed as the primary site.50 This important problem could be solved in the course of randomized clinical studies, which would unequivocally show differences between the effects that different opioids exert on the GI tract. One of the obstacles preventing the exact identification of differences between the impacts of different opioids on GI function is the fact that a significant percentage of patients do not take laxatives as recommended by medical staff. Another difficulty in the assessment of influence of different opioids on bowel function is associated with a multiple etiology of constipation in patients with advanced disease. Patients are often concurrently treated with more than one opioid eg, transdermal fentanyl or buprenorphine is combined with morphine for breakthrough pain, which makes a comparison between the impacts of different opioids on GI function even more difficult.
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TARGETED TREATMENT OF OIC
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or hydromorphone to transdermal opioids (fentanyl, buprenorphine) or to methadone.37,38 Much of the evidence supporting the benefits of the opioid switch, as regards constipation relief, was accumulated for the morphineto-transdermal fentanyl switch. 39-41 Tassinari et al. performed a meta-analysis, comparing three randomized trials of transdermal opioids (fentanyl and buprenorphine) with slow-release oral morphine, in the treatment of moderate to severe cancer pain in 425 patients. A significant difference in favor of transdermal opioids was observed for constipation (OR = 0.38; P
