The opioid bowel syndrome: A review of pathophysiology and treatment

Mellar P. Davis, MD, FCCP

doi:10.5055/jom.2005.0035

Authors

Mellar P. Davis, MD, FCCP

DOI:

https://doi.org/10.5055/jom.2005.0035

Keywords:

opioid bowel syndrome, pathophysiology, prophylaxis, bowel dysfunction

Abstract

Opioids are responsible for 25 percent of constipation in terminally ill patients. Patients in pain require prophylaxis to prevent opioid bowel syndrome (OBS). Laxatives are the treatment of choice, but are marginally effective. The development of quaternary opioid receptor antagonists is a step toward target-specific therapy for opioidinduced bowel dysfunction. This review will discuss the pathophysiology and management of OBS.

Author Biography

Mellar P. Davis, MD, FCCP

Director of Research, the Harry R. Horvitz Center for Palliative Medicine, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, Ohio.

References

Kurz A, Sessler DI: Opioid-induced bowel dysfunction: Pathophysiology and potential new therapies. Drugs. 2003; 63(7): 649-671.

DeLuca A, Coupar IM: Insights into opioid action in the intestinal tract. Pharmacol Ther. 1996; 69(2): 103-115.

Tamayo AC, Diaz-Zuluaga PA: Management of opioidinduced bowel dysfunction in cancer patients. Support Care Cancer. 2004; 12: 613-618.

Bayguinov O, Sanders KM: Regulation of neural responses in the canine pyloric sphincter by opioids. Br J Pharmacol. 1993; 108(4): 1024-1030.

Hansen MB: The enteric nervous system II: Gastrointestinal functions. Pharmacol Toxicol. 2003; 92: 249-257.

Wood JD, Galligan JJ: Function of opioids in the enteric nervous system. Neurogastroenterol Motil. 2004; 16(2): 17-28.

Hansen MB: The enteric nervous system III: A target for pharmacological treatment. Pharmacol Toxicol. 2003; 93: 1-13.

Choi YS, Billings JA: Opioid antagonists: A review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage. 2002; 24(1): 71-90.

Holzer P: Opioids and opioid receptors in the enteric nervous system: From a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett. 2004; 361: 192-195.

Hansen MB: Neurohumoral control of gastrointestinal motility. Physiol Res. 2003; 52: 1-30.

Bauer AJ, Boeckxstaens GE: Mechanisms of postoperative ileus. Neurogastroenterol Motil. 2004; 16 (Suppl 2): 54-60.

Sternini C, Patierno S, Selmer S, et al.: The opioid system in the gastrointestinal tract. Neurogastroenterol Motil. 2004; 16(2): 3-16.

Sternini C: Receptors and transmission in the brain-gut axis: Potential for Novel Therapies. III. Mu-opioid receptors in the enteric nervous system. Am J Physiol Gastrointest Liver Physiol. 2001; 281: G8-G15.

Holzer P: Opioids and opioid receptors in the enteric nervous system: From a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett. 2004; 361: 192-195.

Gue M, Junien JL, Bueno L: The kappa agonist fedotozine modulates colonic distention-induced inhibition of gastric motility and emptying in dogs. Gastroenterology. 1994; 107(5): 1327-1334.

Sanger GJ, Tuladhar BR: The role of endogenous opioids in the control of gastrointestinal motility: Predictions from in vitro modeling. Neurogastroenterol Motil. 2004; 16(2): 38-45.

Poonyachoti S, Portoghese PS, Brown DR: Characterization of opioid receptors modulating neurogenic contractions of circular muscle from procine ileum and evidence that delta- and kappa-opioid receptors are coexpressed in myenteric neurons. J Pharmacol Exp Ther. 2001; 297: 69-77.

Camilleri M: Alvimopan, a selective peripherally acting μ-opioid antagonist. Neurogastroenterol Motil. 2005; 17: 157-165.

Bitar KN, Makhlouf GM: Selective presence of opiate receptors on intestinal circular muscle cells. Life Sci. 1985; 37(16): 1545-1550.

De Schepper HU, Cremonini F, Park MI, et al.: Opioids and the gut: Pharmacology and current clinical experience. Neurogastroenterol Motil. 2004; 16: 383-394.

Johnson SM, Costa M, Humphreys CM: Opioid mu and kappa receptors on axons of cholinergic excitatory motor neurons supplying the circular muscle of guinea-pig ileum. Naunyn Schmiedebergs Arch Pharmacol. 1988; 338(4): 397-400.

Johnson SM, Costa M, Humphreys CM, et al.: Inhibitory effects of opioids in a circular muscle-myenteric plexus preparation of guinea-pig ileum. Naunyn Schmiedebergs Arch Pharmacol. 1987; 336(4): 419-424.

Grider JR, Makhlouf GM: Identification of opioid receptors on gastric muscle cells by selective receptor protection. Am J Physiol. 1991; 260(1 Pt 1): G103-G107.

Yuan, Chun-Su: Gastric effects of mu-, delta- and kappa-opioid receptor agonists on brainstem unitary responses in the neonatal rat. Eur J Pharmacol. 1996; 314: 27-32.

Zhang L, Gu ZF, Pradhan T, et al.: Characterization of opioid receptors on smooth muscle cells from guinea pig stomach. Am J Physiol. 1992; 262(3 Pt 1): G461-G469.

Greenwood-Van Meerveld B, Gardner CJ, Little PJ, et al.: Preclinical studies of opioids and opioid antagonists on gastrointestinal function. Neurogastroenterol Motil. 2004; 16 Suppl 2: 46-53.

Fox DA, Burks TF: Roles of central and peripheral mu, delta and kappa opioid receptors in the mediation of gastric acid secretory effects in the rat. J Pharmacol Exp Ther. 1988; 244(2): 456-462.

Bauer AJ, Szurszewski JH: Effect of opioid peptides on circular muscle of canine duodenum. J Physiol. 1991; 434: 409-422.

Nishiwaki H, Saitoh N, Nishio H, et al.: Relationship between inhibitory effect of endogenous opioid via mu-receptors and muscarinic autoinhibition in acetylcholine release from myenteric plexus of guinea pig ileum. Jpn J Pharmacol. 1998; 77(4): 279-286.

Kojima Y, Takahashi T, Fujina M, et al.: Inhibition of cholinergic transmission by opiates in ileal myenteric plexus is mediated by kappa receptor. Involvement of regulatory inhibitory G protein and calcium N-channels. J Pharmacol Exp Ther. 1994; 268(2): 965-970.

Bruera E, Brenneis C, Michaud M, et al.: Continuous Sc infusion of metoclopramide for treatment of narcotic bowel syndrome. Cancer Treat Rep. 1987; 71(11): 1121-1122.

Baig MK, Wexner SD: Postoperative ileus: A review. Dis Colon Rectum. 2004; 47: 516-526.

Taguchi A, Sharma N, Saleem RM, et al.: Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001; 345(13): 935-940.

Schmidt WK: Alvimopan (ADL8-2698) is a novel peripheral opioid antagonist. Am J Surg. 2001; 182(5A Suppl): 27S-38S.

Goodman M, Low J, Wilkinson S: Constipation management in palliative care: A survey of practices in the United Kingdom. J Pain Symptom Manage. 2005; 29(3): 238-244.

Sykes NP: The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med. 1998; 12: 375-382.

Lederle FA, Busch DL, Mattox KM, et al.: Cost-effective treatment of constipation in the elderly: A randomized double-blind comparison of sorbitol and lactulose. Am J Med. 1990; 89(5): 597-601.

Petticrew M, Watt I, Sheldon T: A systematic review of the effectiveness of laxatives in the elderly. Health Technol Assess. 1997; 1(13): 1-52.

Agra Y, Sacristan A, Gonzalez M, et al.: Efficacy of senna versus lactulose in terminal cancer patients treated with opioids. J Pain Symptom Manage. 1998; 15(1): 1-7.

Attar A, Lemann M, Ferguson A, et al.: Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut. 1999; 44(2): 226-230.

Sykes NP: A volunteer model for the comparison of laxatives in opioid-related constipation. J Pain Symptom Manage. 1996; 11(6): 363-369.

Crowther AG: Management of constipation in terminally ill patients. J Int Med Res. 1978; 6(4): 348-350.

Ferguson A, Culbert P, Gillett H, et al.: New polyethylene glycol electrolyte solution for the treatment of constipation and faecal impaction. Ital J Gastroenterol Hepatol. 1999; 31 Suppl 3: S249-S252.

Freedman MD, Schwartz HJ, Roby R, et al.: Tolerance and efficacy of polyethylene glycol 3350/electrolyte solution versus lactulose in relieving opiate induced constipation: A doubleblinded placebo-controlled trial. J Clin Pharmacol. 1997; 37(10): 904-907.

Wong V, Sobala G, Losowsky M: A case of narcotic bowel syndrome successfully treated with clonidine. Postgrad Med J. 1994; 70(820): 138-140.

Daeninck PJ, Bruera E: Reduction in constipation and laxative requirements following opioid rotation to methadone: A report of four cases. J Pain Symptom Manage. 1999; 18(4): 303-309.

Cowan A: Buprenorphine: New pharmacological aspects. Int J Clin Pract Suppl 2003; 133: 3-8.

Joishy MD, Suresh K, Walsh D: The opioid-sparing effects of intravenous ketorolac as an adjuvant analgesic in cancer pain: Application in bone metastases and the OBS. J Pain Symptom Manage. 1998; 16(5): 334-339.

Mercadante S, Fulfaro F, Casuccio A: A randomized controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: Effects on dose-escalation and a pharmacoeconomic analysis. Eur J Cancer. 2002; 38(1): 1358-1363.

Radbruch L, Sabatowski R, Loick G, et al.: Constipation and the use of laxatives: A comparison between transdermal fentanyl and oral morphine. Palliat Med. 2000; 14(2): 111-119.

Allan L, Hays H, Jensen NH, et al.: Randomized crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001; 322(7295): 1154-1158.

Sykes NP: An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med. 1996; 10(2): 135-144.

Meissner W, Schmidt U, Hartmann M, et al.: Oral naloxone reverses opioid-associated constipation. Pain. 2000; 84: 105-109.

Liu M, Wittbrodt E: Low-dose oral naloxone reverses opioidinduced constipation and analgesia. J Pain Symptom Manage 2002; 23(1): 48-53.

Cheskin LJ, Chami TN, Johnson RE, et al.: Assessment of nalmephrene glucuronide as a selective gut opioid antagonist. Drug Alcohol Depend. 1995; 39: 151-154.

Yuan CS, Wei G, Foss JF, et al.: Effects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: A double-blind randomized placebo-controlled trial. J Pharmacol Exp Ther. 2002; 300(1): 118-123.

Yuan CS, Foss JF: Antagonism of gastrointestinal opioid effects. Reg Anesth Pain Med. 2000; 25(6): 639-642.

Yuan CS, Foss JF, O’Connor M, et al.: Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: A pilot study. Pain. 1999; 83: 631-635.

Yuan CS, Foss JF, O’Connor M, et al.: Methylnaltrexone for reversal of constipation due to chronic methadone use: A randomized controlled trial. JAMA. 2000; 283(3): 367-372.

Yuan CS, Foss JF: Oral methylnaltrexone for opioid-induced constipation. JAMA. 2000; 284(11): 1383-1384.

Foss JF, O’Connor MF, Yuan CS, et al.: Safety and tolerance of methylnaltrexone in healthy humans: A randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study. J Clin Pharmacol. 1997; 37(1): 25-30.

Foss JF: A review of the potential role of methylnaltrexone in opioid bowel dysfunction. Am J Surg. 2001; 182(5A Suppl): 19S-26S.

Barr WH, Nguyen P, Slattery M, et al.: ADL 8-2698 reverses opioid induced delay in colonic transit. Clin Pharmacol Ther. 2000; 67: 91.

Callaghan JT, Cerimele B, Nowak TV, et al.: Effect of the opioid antagonist LY246736 on gastrointestinal transit in human subjects. Gastroenterology. 1998; 114: G3015.

Liu SS, Hodgson PS, Carpenter RL, et al.: ADL 8-2698 a trans 3, 4 dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther. 2001; 69: 66-71.

Paulson DM, Kennedy DT, Donovick RA, et al.: Alvimopan: An oral, peripherally acting, μ-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction—a 21 day treatment randomized clinical trial. J Pain. 2005; 6(3): 184-192.

Wolff BG, Michelassi F, Gerkin TM, et al.: Alvimopan, a novel, peripherally acting mu opioid antagonist: Results of a multicentre, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004; 240(4): 728-734.