Development of Peripheral Opioid Antagonists: New Insights Into Opioid Effects
2008; Elsevier BV; Volume: 83; Issue: 10 Linguagem: Inglês
10.4065/83.10.1116
ISSN1942-5546
Autores Tópico(s)Nausea and vomiting management
ResumoThe recent approval by the US Food and Drug Administration of 2 medications—methylnaltrexone and alvimopan—introduces a new class of therapeutic entities to clinicians. These peripherally acting μ-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence. The recent approval by the US Food and Drug Administration of 2 medications—methylnaltrexone and alvimopan—introduces a new class of therapeutic entities to clinicians. These peripherally acting μ-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence. People have used opioids for more than 4000 years. These substances have been intensely studied since the crystallization of morphine by Friedrich Wilhelm Sertürner in 1805.1Huxtable RJ Schwarz SKW The isolation of morphine: first principles in science and ethics.Mol Interv. 2001; 1: 189-191PubMed Google Scholar Opioids remain the most widely accepted medications for the treatment of patients with moderate to severe acute and chronic pain, but their analgesic effects are accompanied by numerous generally undesirable additional effects (Table 1). Although dangerous toxicity, including respiratory depression, occurs infrequently with opioid use, large numbers of patients experience such debilitating opioid adverse effects as constipation, urinary retention, and nausea and vomiting.TABLE 1Undesirable Effects of OpioidsDepression of ventilationNausea and vomitingSedationItchingDysphoriaConstipationHypotension, bradycardiaDelayed gastric emptyingIncreased skeletal muscle toneUrinary retentionSuppression of coughBiliary spasmSuppression of immune functionAddiction Open table in a new tab Ironically, the clinical management of pain with opioids has not benefited meaningfully from the explosion in knowledge of opioid receptor pharmacology. In 2008, some of our oldest opioids—including morphine and meperidine, which are selective for μ-opioid receptors—continue to be the mainstays of therapy. No analgesic that is selective for any of the other opioid receptors has proven to be an advance in safety or efficacy. Opioid effects may be central (ie, activating receptors in the central nervous system [CNS]) or peripheral (ie, activating receptors outside the CNS). Analgesia, respiratory depression, and miosis are examples of central effects. Depression of gastrointestinal motility—a peripheral effect—depends largely on receptors in the gut wall. Methylnaltrexone (MNTX, sold under the brand name RELISTOR [Progenics Pharmaceuticals, Tarrytown, NY; Wyeth Pharmaceuticals, Collegeville, PA]) and alvimopan (sold under the brand name Entereg; Adolor Corp, Exton, PA; GlaxoSmithKline, London, England) constitute a new class of therapeutic agents developed specifically for the management and prevention of peripheral opioid effects, primarily those affecting the gastrointestinal tract.2Yuan CS Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects.Ann Pharmacother. 2007 Jun; 41 (Epub 2007 May 15.): 984-993Crossref PubMed Scopus (73) Google Scholar, 3Moss J Foss J Pain relief without side effects: peripheral opiate antagonists.in: Schwartz AJ ASA Refresher Courses in Anesthesiology. Vol 33. Lippincott Williams and Wilkins, Philadelphia, PA2005: 175-186Google Scholar, 4McNicol ED Boyce D Schumann R Carr DB Mu-opioid antagonists for opioid-induced bowel dysfunction.Cochrane Database Syst Rev. 2008; : CD006332https://doi.org/10.1002/14651858Crossref PubMed Scopus (73) Google Scholar Drugs of this class, called peripherally acting μ-opioid receptor antagonists (PAMORAs), selectively block opioid effects that are mediated by μ receptors outside the CNS. Methylnaltrexone and alvimopan are compared in Table 2.TABLE 2Comparison Between Methylnaltrexone and AlvimopanCharacteristicMethylnaltrexoneAlvimopanApproved indicationOpioid-induced constipation in patients with advanced illness receiving palliative care, when response to laxatives has not been sufficientFacilitation of gut function after bowel resection and primary anastomosisDosage8 mg every other day (body weight, 38-62 kg)12 mg twice daily, starting preoperatively (limit, 15 doses total)12 mg every other day (body weight, 63-114 kg)AdministrationSubcutaneousOralAdverse effectsFlatulenceAnemiaAbdominal crampingDyspepsiaNauseaHypokalemiaVomitingBack pain Urinary retentionContraindicationsMechanical bowel obstructionOpiate use >1 wk Restricted to hospitalsWholesale cost/doseaInformation on cost per dose was obtained from Massachusetts General Hospital, Pharmacy Department.$38.54$61.88a Information on cost per dose was obtained from Massachusetts General Hospital, Pharmacy Department. Open table in a new tab The ability of PAMORAs, when given with opioids, to block such gastrointestinal effects as constipation, while preserving analgesia, was the basis for their initial clinical use. Methylnaltrexone, administered subcutaneously, has recently been approved by the US Food and Drug Administration (FDA),5US Food and Drug Administration FDA approves Relistor for opioid-induced constipation [press release]. US Food and Drug Administration, Rockville, MDApril 24, 2008http://www.fda.gov/bbs/topics/NEWS/2008/NEW01826.htmlGoogle Scholar as well as by Health Canada and the European Medicines Agency. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapyhas not been sufficient. Alvimopan has recently been approved by the FDA to accelerate recovery from postoperative gastrointestinal dysfunction after bowel resection and primary anastomosis.6US Food and Drug Administration FDA approves Entereg to help restore bowel function following surgery [press release]. US Food and Drug Administration, Rockville, MDMay 20, 2008http://www.fda.gov/bbs/topics/NEWS/2008/NEW01838.htmlGoogle Scholar Beyond their role in therapeutics, PAMORAs may also prove useful in characterizing (and possibly managing) other adverse effects of opioids, such as urinary retention, nausea, and pruritus. Our review of the literature on the use of PAMORAs identifies which adverse effects are central and which are peripheral. Recent laboratory studies using PAMORAs suggest that opioids acting through μ receptors outside of the CNS may have previously unknown and intriguing roles in fundamental aspects of cellular pathophysiologic mechanisms. We briefly review how opioid receptors in nonneuronal tissue may affect a surprising and diverse group of cellular processes, including angiogenesis, viral and bacterial infection, and vascular permeability. 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.7Kurz A Sessler DI Opioid-induced bowel dysfunction: pathophysiology and potential new therapies.Drugs. 2003; 63: 649-671Crossref PubMed Scopus (475) Google Scholar Slowed gastrointestinal transit, increased fluid absorption, and desiccation of stool lead to constipation. Over time, patients who become opioid tolerant require larger doses for pain relief, but they develop little tolerance to OBD.8Yuan CS Foss JF O'Connor M Moss J Roizen MF Gut motility and transit changes in patients receiving long-term methadone maintenance.J Clin Pharmacol. 1998; 38: 931-935Crossref PubMed Scopus (51) Google Scholar As a result, OBD is a clinical problem for as many as 60% to 90% of patients who receive opioids for chronic metastatic malignancy9Walsh TD Oral morphine in chronic cancer pain.Pain. 1984; 18: 1-11Abstract Full Text PDF PubMed Scopus (103) Google Scholar, 10Vanegas G Ripamonti C Sbanotto A De Conno F Side effects of morphine administration in cancer patients.Cancer Nurs. 1998; 21: 289-297Crossref PubMed Scopus (58) Google Scholar, 11Sykes NP The relationship between opioid use and laxative use in terminally ill cancer patients.Palliat Med. 1998; 12: 375-382Crossref PubMed Scopus (136) Google Scholar or chronic noncancer pain.12Pappagallo M Incidence, prevalence, and management of opioid bowel dysfunction.Am J Surg. 2001; 182: 11S-18SAbstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar Constipation is often refractory to stool softeners and laxatives, and it may limit effective pain control.13Sykes N Constipation and diarrhoea.in: Doyle D Hanks G Cherry N Calman K Oxford Textbook of Palliative Medicine. 3rd ed. Oxford University Press, New York, NY2004: 483-496Google Scholar, 14O'Mahony S Coyle N Payne R Current management of opioid-related side effects.Oncology (Williston Park). 2001; 15: 61-73PubMed Google Scholar, 15Marr L Weissman DE Palliative medicine in patients with advanced gastrointestinal and hepatic disease.in: Feldman M Friedman LS Brandt LJ Sleisenger & Fordtran's Gastrointestinal and Liver Disease. 8th ed. Saunders Elsevier, Philadelphia, PA2006: 2863-2873Google Scholar, 16Leslie J Bell T Annunziata K Freedman D Opioid-induced constipation compromises pain management and impacts patient quality of life [abstract A1490].Anesthesiology. 2006; 105 (Accessed August 22, 2008.): A1490http://www.asaabstract.com/strands/asaabstracts/abstract.htm;jsessionid=78ECA0E5C905576B57086BB175AA98ED?year=2006&index=3&absnum=1305Google Scholar Patients may actually prefer pain to severe constipation.17Schmier JK Palmer CS Flood EM Gourlay G Utility assessments of opioid treatment for chronic pain.Pain Med. 2002; 3: 218-230Crossref PubMed Scopus (29) Google Scholar A second related clinical problem is postoperative ileus (POI), the inhibition of bowel function after surgery.18Kehlet H Holte K Review of postoperative ileus.Am J Surg. 2001; 182: 3S-10SAbstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 19Maron DJ Fry RD New therapies in the treatment of postoperative ileus after gastrointestinal surgery.Am J Ther. 2008; 15: 59-65Crossref PubMed Scopus (28) Google Scholar Postoperative ileus results in bloating, distention, pain, nausea, and inability to resume oral feeding. In severe cases, paralytic POI can persist for many days after surgery and is often a primary reason for delay of hospital discharge. The etiology of POI is multifactorial and may include opioid administration, direct trauma, manipulation of the bowel during surgery, inflammatory mediators, electrolyte disturbances, and other metabolic effects of anesthesia and surgery. A portion of the inhibitory effect in POI is thought to involve sympathetic reflexes mediated by the release of endogenous opioid peptides in the enteric nervous system.20Bitar KN Makhlouf GM Selective presence of opiate receptors on intestinal circular muscle cells.Life Sci. 1985; 37: 1545-1550Crossref PubMed Scopus (48) Google Scholar, 21Choi 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: 71-90Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 22Ouyang A Vos P Cohen S Sites of action of μ-, κ- and σ-opiate receptor agonists at the feline ileocecal sphincter.Am J Physiol. 1988; 254: G224-G231PubMed Google Scholar, 23Manara L Bianchetti A The central and peripheral influences of opioids on gastrointestinal propulsion.Annu Rev Pharmacol Toxicol. 1985; 25: 249-273Crossref PubMed Google Scholar It is well accepted that the μ-opioid receptors modulate gut effects24Shook JE Pelton JT Hruby FJ Burks TF Peptide opioid antagonist separates peripheral and central opioid antitransit effects.J Pharmacol Exp Ther. 1987; 243: 492-500PubMed Google Scholar and that endogenous opioid peptides directly influence gut motility.23Manara L Bianchetti A The central and peripheral influences of opioids on gastrointestinal propulsion.Annu Rev Pharmacol Toxicol. 1985; 25: 249-273Crossref PubMed Google Scholar, 25Manara L Bianchi G Ferretti P Tavani A Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites.J Pharmacol Exp Ther. 1986; 237: 945-949PubMed Google Scholar At least three lines of evidence support a direct role for both endogenous and exogenous opioids in the etiology of POI. First, endogenous opioid peptides have been implicated in the pathophysiologic mechanisms of an animal syndrome, equine colic, which is the second leading cause of mortality in horses. The symptoms of equine colic mimic those of POI, and marked elevations in levels of serum endorphins have been observed in horses with this syndrome.26White NA Edwards G Handbook of Equine Colic. Butterworth-Heinemann, Oxford, UK1999Google Scholar In the second line of evidence, the role of exogenous opioids in POI has been demonstrated by comparing different analgesic regimens. Kehlet and Holte18Kehlet H Holte K Review of postoperative ileus.Am J Surg. 2001; 182: 3S-10SAbstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar conducted a remarkableseries of clinical studies on the management of postoperative pain with multiple analgesic therapies in combination with thoracic epidural anesthesia (ie, multimodal therapy). Studies of multimodal analgesia after laparotomy show that analgesic combinations that omit opioids reliably improve bowel function and shorten recovery time for patients.18Kehlet H Holte K Review of postoperative ileus.Am J Surg. 2001; 182: 3S-10SAbstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar The third line of evidence involves the prevention of POI with alvimopan (data reviewed in “Management of Postoperative Ileus”). This evidence is consistent with a role for both endogenous and exogenous opioids in POI. 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.23Manara L Bianchetti A The central and peripheral influences of opioids on gastrointestinal propulsion.Annu Rev Pharmacol Toxicol. 1985; 25: 249-273Crossref PubMed Google Scholar, 24Shook JE Pelton JT Hruby FJ Burks TF Peptide opioid antagonist separates peripheral and central opioid antitransit effects.J Pharmacol Exp Ther. 1987; 243: 492-500PubMed Google Scholar, 25Manara L Bianchi G Ferretti P Tavani A Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites.J Pharmacol Exp Ther. 1986; 237: 945-949PubMed Google Scholar 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 membranes, undergoes extensive first-pass metabolism, with only 2% systemic bioavailability. In theory, relatively large amounts of naloxone must reach the gut before enough is absorbed to reverse central effects of opioids. In several small trials, naloxone and similar tertiary opioid antagonists successfully reversed the constipating effects of opioids.27Gowan JD Hurtig JB Fraser RA Torbicki E Kitts J Naloxone infusion after prophylactic epidural morphine: effects on incidence of postoperative side-effects and quality of analgesia.Can J Anaesth. 1988; 35: 143-148Crossref PubMed Scopus (48) Google Scholar, 28Culpepper-Morgan JA Inturrisi CE Portenoy RK et al.Treatment of opioid-induced constipation with oral naloxone: a pilot study.Clin Pharmacol Ther. 1992; 52: 90-95Crossref PubMed Scopus (172) Google Scholar, 29Cheskin LJ Chami TN Johnson RE Jaffe JH Assessment of nalmefene glucuronide as a selective gut opioid antagonist.Drug Alcohol Depend. 1995; 39: 151-154Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 30Sykes NP Using oral naloxone in management of opioid bowel dysfunction.in: Yuan CS Handbook of Opioid Bowel Syndrome. Haworth Medical Press, New York, NY2005: 175-195Google Scholar Unfortunately, precise titration of these antagonists has proved difficult. Because these compounds act both centrally and peripherally, they can reverse analgesia or precipitate withdrawal.27Gowan JD Hurtig JB Fraser RA Torbicki E Kitts J Naloxone infusion after prophylactic epidural morphine: effects on incidence of postoperative side-effects and quality of analgesia.Can J Anaesth. 1988; 35: 143-148Crossref PubMed Scopus (48) Google Scholar, 28Culpepper-Morgan JA Inturrisi CE Portenoy RK et al.Treatment of opioid-induced constipation with oral naloxone: a pilot study.Clin Pharmacol Ther. 1992; 52: 90-95Crossref PubMed Scopus (172) Google Scholar, 29Cheskin LJ Chami TN Johnson RE Jaffe JH Assessment of nalmefene glucuronide as a selective gut opioid antagonist.Drug Alcohol Depend. 1995; 39: 151-154Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 30Sykes NP Using oral naloxone in management of opioid bowel dysfunction.in: Yuan CS Handbook of Opioid Bowel Syndrome. Haworth Medical Press, New York, NY2005: 175-195Google Scholar In the United States, 2 PAMORAs have been approved by the FDA—MNTX, as a subcutaneous injection for opioid-induced constipation in patients receiving palliative care, and oral alvimopan, for gastrointestinal recovery after bowel surgery with primary anastomosis. Clinical studies of these medications have greatly increased our understanding of the effects of opioids in the gut and in other organs. Preclinical Pharmacology. Methylnaltrexone, a quaternary amine and a derivative of the opioid antagonist naltrexone, was developed by the late Leon Goldberg, a pharmacologist at the University of Chicago, with the specific goal of treating patients with opioid-induced constipation. The chemical structures of MNTX and naltrexone are compared in Figure 1. Goldberg reasoned that this permanently charged, polar molecule would function at opioid receptors in the gastrointestinal tract but would not penetrate the blood-brain barrier.31Brown DR Goldberg LI The use of quaternary narcotic antagonists in opiate research.Neuropharmacology. 1985; 24: 181-191Crossref PubMed Scopus (223) Google Scholar, 32Russell J Bass P Goldberg LI Schuster CR Merz H Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists.Eur J Pharmacol. 1982; 78: 255-261Crossref PubMed Scopus (177) Google Scholar Methylnaltrexone is produced as a water-soluble powder for its injectable formulation. It is a competitive antagonist that is relatively selective for μ receptors and has no intrinsic opioid-agonist properties.33Gmerek DE Cowan A Woods JH Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats.J Pharmacol Exp Ther. 1986; 236: 8-13PubMed Google Scholar In vitro studies of human and guinea pig gut tissue show that MNTX has one third the potency of naloxone in reversing morphine-induced inhibition of contraction.33Gmerek DE Cowan A Woods JH Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats.J Pharmacol Exp Ther. 1986; 236: 8-13PubMed Google Scholar, 34Yuan CS Foss JF Moss J Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine.Eur J Pharmacol. 1995; 276: 107-111Crossref PubMed Scopus (68) Google Scholar In these studies, 97% of morphine's effect on intestinal motility could be reversed by MNTX administered on gut tissue. Pharmacokinetics. Interestingly, administration of MNTX alone in a human small intestine preparation increased smooth muscle contraction by 30%, suggesting the reversal of endogenous opioid activity.34Yuan CS Foss JF Moss J Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine.Eur J Pharmacol. 1995; 276: 107-111Crossref PubMed Scopus (68) Google Scholar When injected subcutaneously, MNTX neither reversed analgesia in rats33Gmerek DE Cowan A Woods JH Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats.J Pharmacol Exp Ther. 1986; 236: 8-13PubMed Google Scholar nor precipitated withdrawal in animals that were physically dependent on morphine.32Russell J Bass P Goldberg LI Schuster CR Merz H Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists.Eur J Pharmacol. 1982; 78: 255-261Crossref PubMed Scopus (177) Google Scholar Peak plasma concentration and area under the concentration-time curve for MNTX are proportional to dose after intravenous or subcutaneous administration in human volunteers.35Yuan 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: 367-372Crossref PubMed Scopus (243) Google Scholar Time to peak is approximately 30 minutes after subcutaneous dosing.36Yuan CS Foss JF O'Connor M et al.Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.Clin Pharmacol Ther. 2000; 67: 398-404Crossref PubMed Scopus (83) Google Scholar After oral administration, extremely low plasma concentrations of MNTX are observed; enteric coating reduces the concentrations further, suggesting that a small amount of the drug may be absorbed in the upper gastrointestinal tract. No correlation exists between drug effects and plasma concentrations after doses of 3.2 mg/kg or 6.4 mg/kg of enteric-coated MNTX.36Yuan CS Foss JF O'Connor M et al.Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.Clin Pharmacol Ther. 2000; 67: 398-404Crossref PubMed Scopus (83) Google Scholar Methylnaltrexone undergoes a moderate distribution (volume of distribution = 1.1 L/kg), and its terminal elimination half-life is 8 hours. Administration of MNTX at a dose of 0.3 mg/kg every 6 hours, for a total of 12 doses, did not result in accumulation or toxicity in healthy human volunteers.37Yuan CS Doshan H Charney MR et al.Tolerability, gut effects, and pharmacokinetics of methylnaltrexone following repeated intravenous administration in humans.J Clin Pharmacol. 2005; 45: 538-546Crossref PubMed Scopus (81) Google Scholar Approximately 85% of a dose is eliminated in the urine as unchanged drug. Unlike rats and mice, humans do not demethylate MNTX to the centrally active antagonist, naltrexone.38Kotake AN Kuwahara SK Burton E McCoy CE Goldberg LI Variations in demethylation of N-methylnaltrexone in mice, rats, dogs, and humans.Xenobiotica. 1989; 19: 1247-1254Crossref PubMed Scopus (59) Google Scholar Intestinal Motility. In studies with morphine-treated volunteers, intravenous MNTX shortened oral-cecal transit time (OCTT) with no effect on analgesia. These effects of MNTX were initially assessed in a crossover experiment involving 12 volunteers who were given intravenous placebo, morphine (0.05 mg/kg), or MNTX (0.45 mg/kg) plus morphine (0.05 mg/kg).39Yuan CS Foss JF O'Connor M Toledano A Roizen MF Moss J Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.Clin Pharmacol Ther. 1996; 59: 469-475Crossref PubMed Scopus (182) Google Scholar Mean OCTTs (measured by the lactulose hydrogen breath test) were 105, 163, and 106 minutes for placebo, morphine, and MNTX/morphine, respectively (Figure 2). These results demonstrate a nearly complete reversal of the opiate effect on OCTT. Pain was also measured in these patients using the cold pressor test.39Yuan CS Foss JF O'Connor M Toledano A Roizen MF Moss J Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.Clin Pharmacol Ther. 1996; 59: 469-475Crossref PubMed Scopus (182) Google Scholar Like naloxone, intravenously administered MNTX almost completely reversed gastrointestinal effects; however, unlike naloxone, it did not alter the analgesic effect of morphine. This study was the first demonstration in humans that opioid effects on the gastrointestinal tract are mainly peripherally mediated.39Yuan CS Foss JF O'Connor M Toledano A Roizen MF Moss J Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.Clin Pharmacol Ther. 1996; 59: 469-475Crossref PubMed Scopus (182) Google Scholar Another study with volunteer subjects confirmed that MNTX does not reverse opioid-mediated ventilatory depression, a centrally mediated opioid effect.40Amin HM Sopchak AM Foss JF Esposito BF Roizen MF Camporesi EM Efficacy of methylnaltrexone versus naloxone for reversal of morphine-induced depression of hypoxic ventilatory response.Anesth Analg. 1994; 78: 701-705Crossref PubMed Scopus (32) Google Scholar These results are important because they show that MNTX cannot be used, like naloxone, to treat patients with opioid overdose. Subcutaneous and Oral Administration. Many patients who have advanced illness, such as the late stages of cancer or AIDS, are given large doses of opioids in home or hospice settings. For this reason, both subcutaneous and oral dosage forms of MNTX that would be practical to use outside of a hospital were needed. Subcutaneous administration of MNTX at doses of 0.1 mg/kg or 0.3 mg/kg was reported to reverse completely the delay in intestinal transit caused by morphine (0.05 mg/kg).41Yuan CS Wei G Foss JF O'Connor M Karrison T Osinski J Effects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial.J Pharmacol Exp Ther. 2002; 300: 118-123Crossref PubMed Scopus (113) Google Scholar When the efficacy of orally administered MNTX was tested, doses as high as 19.2 mg/kg were required to produce complete reversal of intestinal transit delay.42Yuan CS Foss JF Osinski J Toledano A Roizen MF Moss J The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time.Clin Pharmacol Ther. 1997; 61: 467-475Crossref PubMed Scopus (117) Google Scholar An enteric-coated oral preparation was subsequently developed to reduce gastric absorption and release MNTX only in the small and large intestine. Using this formulation, Yuan et al36Yuan CS Foss JF O'Connor M et al.Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.Clin Pharmacol Ther. 2000; 67: 398-404Crossref PubMed Scopus (83) Google Scholar achieved a complete reversal of intestinal transit delay with an MNTX dose of only 3.2 mg/kg. Because the enteric-coated preparation had greater potency but lower systemic bioavailability than the non-enteric-coated formulation, these results are consistent with a site of action in the colonic lumen.36Yuan CS Foss JF O'Connor M et al.Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.Clin Pharmacol Ther. 2000; 67: 398-404Crossref PubMed Scopus (83) Google Scholar Opioid Bowel Dysfunction in Methadone Maintenance. Therapy
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