SPECIAL ARTICLEDevelopment of Peripheral Opioid Antagonists: New Insights Into Opioid Effects
Section snippets
GASTROINTESTINAL EFFECTS OF OPIOIDS
Although respiratory depression is the most dangerous adverse effect of opioids, constipation is a far more common problem for most patients who use opioids. Opioid-induced constipation is a symptom of a more general syndrome called opioid-induced bowel dysfunction (OBD), which includes inhibition of gastric emptying, peristalsis, and secretions, as well as increased tone of intestinal sphincters.7 Slowed gastrointestinal transit, increased fluid absorption, and desiccation of stool lead to
PHARMACOTHERAPY FOR OPIOID GASTROINTESTINAL EFFECTS
The gastrointestinal effects of morphine and similar substances involve both central and peripheral mechanisms; however, the actions at μ receptors in the gut wall appear to be the most important mechanisms.23, 24, 25 Thus, a logical goal of treatment is to block these gut receptors while sparing those receptors mediating analgesia.
The first attempts to accomplish this goal involved low doses of orally administered naloxone. Naloxone, a tertiary amine that is lipid soluble and easily crosses
Delayed Gastric Emptying
Effects of PAMORAs on gastric emptying have not been as well studied as effects on bowel motility, and the potential clinical implications of delayed emptying are rather different from implications of POI or constipation. Opioids decrease the tone of gastric smooth muscle and increase the tone of sphincters—and gastric emptying is a function of both these effects. As mentioned previously, a trial of alvimopan did not show any effect on gastric emptying.57 Two studies showed that MNTX attenuates
CELLULAR EFFECTS
Four lines of preclinical investigation indicate that PAMORAs may prove useful in areas that are far removed from the problems of constipation and ileus. Many patients who are critically ill, including those with large tumors, are given high doses of opioids under the assumption that these drugs do little harm, provided that ventilation is adequate. However, increasing experimental evidence shows that opioids can produce undesirable effects on the growth of tumors and on the spread of infection
THE NEW DRUGS: FINAL THOUGHTS
Although alvimopan and MNTX work by the same mechanism, major distinctions exist between them. One important difference is the route of administration. Methylnaltrexone has been tested in oral and parenteral forms, but FDA approval is based only on the injectable form for subcutaneous administration. Oral MNTX has been tested in small volunteer protocols, but there are no peer-reviewed publications of larger-scale trials. Alvimopan has been tested only in an oral form, and it is not clear if an
CONCLUSION
Peripherally acting μ-opioid receptor antagonists have been proven useful for the relief of opioid-induced gastrointestinal dysfunction. The development of PAMORAs—including MNTX and alvimopan—has provided important insights into the peripheral effects of opioids. Methylnaltrexone has been approved by the FDA, Health Canada, and the European Medicines Agency. In the United States, it has been approved for subcutaneous injection in patients with advanced illness who are receiving palliative
REFERENCES (93)
Oral morphine in chronic cancer pain
Pain
(1984)- et al.
Selective presence of opiate receptors on intestinal circular muscle cells
Life Sci
(1985) - et al.
Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation
J Pain Symptom Manage
(2002) - et al.
Assessment of nalmefene glucuronide as a selective gut opioid antagonist
Drug Alcohol Depend
(1995) - et al.
The use of quaternary narcotic antagonists in opiate research
Neuropharmacology
(1985) - et al.
Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists
Eur J Pharmacol
(1982) - et al.
Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine
Eur J Pharmacol
(1995) - 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) - et al.
Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study
J Pain Symptom Manage
(2008) - et al.
[(3)H]Alvimopan binding to the micro opioid receptor: comparative binding kinetics of opioid antagonists
Eur J Pharmacol
(2005)
Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study
Clin Gastroenterol Hepatol
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
Alvimopan, a peripherally acting mu-opioid receptor (PAM-OP) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain
Pain
Gastric effects of methylnaltrexone on μ, β, and δ opioid agonists induced brainstem unitary responses
Neuropharmacology
Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine
Drug Alcohol Depend
Can regional analgesia reduce the risk of recurrence after breast cancer? methodology of a multicenter randomized trial
Contemp Clin Trials
Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation
Microvasc Res
The contribution of opiate analgesics to the development of infectious complications in burn patients
Am J Surg
The isolation of morphine: first principles in science and ethics
Mol Interv
Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects
Ann Pharmacother
Pain relief without side effects: peripheral opiate antagonists
Mu-opioid antagonists for opioid-induced bowel dysfunction
Cochrane Database Syst Rev
FDA approves Relistor for opioid-induced constipation [press release]
FDA approves Entereg to help restore bowel function following surgery [press release]
Opioid-induced bowel dysfunction: pathophysiology and potential new therapies
Drugs
Gut motility and transit changes in patients receiving long-term methadone maintenance
J Clin Pharmacol
Side effects of morphine administration in cancer patients
Cancer Nurs
The relationship between opioid use and laxative use in terminally ill cancer patients
Palliat Med
Incidence, prevalence, and management of opioid bowel dysfunction
Am J Surg
Constipation and diarrhoea
Current management of opioid-related side effects
Oncology (Williston Park)
Palliative medicine in patients with advanced gastrointestinal and hepatic disease
Opioid-induced constipation compromises pain management and impacts patient quality of life [abstract A1490]
Anesthesiology
Utility assessments of opioid treatment for chronic pain
Pain Med
Review of postoperative ileus
Am J Surg
New therapies in the treatment of postoperative ileus after gastrointestinal surgery
Am J Ther
Sites of action of μ-, κ- and σ-opiate receptor agonists at the feline ileocecal sphincter
Am J Physiol
The central and peripheral influences of opioids on gastrointestinal propulsion
Annu Rev Pharmacol Toxicol
Peptide opioid antagonist separates peripheral and central opioid antitransit effects
J Pharmacol Exp Ther
Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites
J Pharmacol Exp Ther
Handbook of Equine Colic
Naloxone infusion after prophylactic epidural morphine: effects on incidence of postoperative side-effects and quality of analgesia
Can J Anaesth
Treatment of opioid-induced constipation with oral naloxone: a pilot study
Clin Pharmacol Ther
Using oral naloxone in management of opioid bowel dysfunction
Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats
J Pharmacol Exp Ther
Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial
JAMA
Cited by (0)
Dr Moss has patent interests in methylnaltrexone and serves as a consultant to Progenics Pharmaceuticals, which has the license for methylnaltrexone's development. Wyeth Pharmaceuticals entered into an agreement with Progenics in December 2005 to develop and commercialize methylnaltrexone for the treatment of patients with opioid-induced adverse effects. Dr Rosow has received research support from Progenics Pharmaceuticals.