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Development of Peripheral Opioid Antagonists: New Insights Into Opioid Effects

      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.
      CCR5 (chemokine receptor 5), CNS (central nervous system), CTZ (chemoreceptor trigger zone), FDA (Food and Drug Administration), HIV (human immunodeficiency virus), ICU (intensive care unit), MNTX (methylnaltrexone), OBD (opioid-induced bowel dysfunction), OCTT (oralcecal transit time), PAMORA (peripherally acting μ-opioid receptor antagonist), POI (postoperative ileus), VEGF (vascular endothelial growth factor)
      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.
      • Huxtable RJ
      • Schwarz SKW
      The isolation of morphine: first principles in science and ethics.
      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 Opioids
      Depression of ventilationNausea and vomiting
      SedationItching
      DysphoriaConstipation
      Hypotension, bradycardiaDelayed gastric emptying
      Increased skeletal muscle toneUrinary retention
      Suppression of coughBiliary spasm
      Suppression of immune functionAddiction
      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.
      • Yuan CS
      Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects.
      • Moss J
      • Foss J
      Pain relief without side effects: peripheral opiate antagonists.
      • McNicol ED
      • Boyce D
      • Schumann R
      • Carr DB
      Mu-opioid antagonists for opioid-induced bowel dysfunction.
      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 Alvimopan
      CharacteristicMethylnaltrexoneAlvimopan
      Approved 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 anastomosis
      Dosage8 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)
      AdministrationSubcutaneousOral
      Adverse effectsFlatulenceAnemia
      Abdominal crampingDyspepsia
      NauseaHypokalemia
      VomitingBack pain Urinary retention
      ContraindicationsMechanical bowel obstructionOpiate use >1 wk Restricted to hospitals
      Wholesale cost/dose
      Information on cost per dose was obtained from Massachusetts General Hospital, Pharmacy Department.
      $38.54$61.88
      a Information on cost per dose was obtained from Massachusetts General Hospital, Pharmacy Department.
      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),
      • US Food and Drug Administration
      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.
      • US Food and Drug Administration
      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.

      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.
      • Kurz A
      • Sessler DI
      Opioid-induced bowel dysfunction: pathophysiology and potential new therapies.
      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.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • Moss J
      • Roizen MF
      Gut motility and transit changes in patients receiving long-term methadone maintenance.
      As a result, OBD is a clinical problem for as many as 60% to 90% of patients who receive opioids for chronic metastatic malignancy
      • Walsh TD
      Oral morphine in chronic cancer pain.
      • Vanegas G
      • Ripamonti C
      • Sbanotto A
      • De Conno F
      Side effects of morphine administration in cancer patients.
      • Sykes NP
      The relationship between opioid use and laxative use in terminally ill cancer patients.
      or chronic noncancer pain.
      • Pappagallo M
      Incidence, prevalence, and management of opioid bowel dysfunction.
      Constipation is often refractory to stool softeners and laxatives, and it may limit effective pain control.
      • Sykes N
      Constipation and diarrhoea.
      • O'Mahony S
      • Coyle N
      • Payne R
      Current management of opioid-related side effects.
      • Marr L
      • Weissman DE
      Palliative medicine in patients with advanced gastrointestinal and hepatic disease.
      • Leslie J
      • Bell T
      • Annunziata K
      • Freedman D
      Opioid-induced constipation compromises pain management and impacts patient quality of life [abstract A1490].
      Patients may actually prefer pain to severe constipation.
      • Schmier JK
      • Palmer CS
      • Flood EM
      • Gourlay G
      Utility assessments of opioid treatment for chronic pain.
      A second related clinical problem is postoperative ileus (POI), the inhibition of bowel function after surgery.
      • Kehlet H
      • Holte K
      Review of postoperative ileus.
      • Maron DJ
      • Fry RD
      New therapies in the treatment of postoperative ileus after gastrointestinal surgery.
      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.
      • Bitar KN
      • Makhlouf GM
      Selective presence of opiate receptors on intestinal circular muscle cells.
      • Choi YS
      • Billings JA
      Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation.
      • Ouyang A
      • Vos P
      • Cohen S
      Sites of action of μ-, κ- and σ-opiate receptor agonists at the feline ileocecal sphincter.
      • Manara L
      • Bianchetti A
      The central and peripheral influences of opioids on gastrointestinal propulsion.
      It is well accepted that the μ-opioid receptors modulate gut effects
      • Shook JE
      • Pelton JT
      • Hruby FJ
      • Burks TF
      Peptide opioid antagonist separates peripheral and central opioid antitransit effects.
      and that endogenous opioid peptides directly influence gut motility.
      • Manara L
      • Bianchetti A
      The central and peripheral influences of opioids on gastrointestinal propulsion.
      • Manara 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.
      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.
      • White NA
      • Edwards G
      In the second line of evidence, the role of exogenous opioids in POI has been demonstrated by comparing different analgesic regimens. Kehlet and Holte
      • Kehlet H
      • Holte K
      Review of postoperative ileus.
      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.
      • Kehlet H
      • Holte K
      Review of postoperative ileus.
      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.

      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.
      • Manara L
      • Bianchetti A
      The central and peripheral influences of opioids on gastrointestinal propulsion.
      • Shook JE
      • Pelton JT
      • Hruby FJ
      • Burks TF
      Peptide opioid antagonist separates peripheral and central opioid antitransit effects.
      • Manara 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.
      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.
      • Gowan 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.
      • Culpepper-Morgan JA
      • Inturrisi CE
      • Portenoy RK
      • et al.
      Treatment of opioid-induced constipation with oral naloxone: a pilot study.
      • Cheskin LJ
      • Chami TN
      • Johnson RE
      • Jaffe JH
      Assessment of nalmefene glucuronide as a selective gut opioid antagonist.
      • Sykes NP
      Using oral naloxone in management of opioid bowel dysfunction.
      Unfortunately, precise titration of these antagonists has proved difficult. Because these compounds act both centrally and peripherally, they can reverse analgesia or precipitate withdrawal.
      • Gowan 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.
      • Culpepper-Morgan JA
      • Inturrisi CE
      • Portenoy RK
      • et al.
      Treatment of opioid-induced constipation with oral naloxone: a pilot study.
      • Cheskin LJ
      • Chami TN
      • Johnson RE
      • Jaffe JH
      Assessment of nalmefene glucuronide as a selective gut opioid antagonist.
      • Sykes NP
      Using oral naloxone in management of opioid bowel dysfunction.
      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.

      Methylnaltrexone

      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.
      • Brown DR
      • Goldberg LI
      The use of quaternary narcotic antagonists in opiate research.
      • Russell J
      • Bass P
      • Goldberg LI
      • Schuster CR
      • Merz H
      Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists.
      Figure thumbnail gr1
      FIGURE 1Chemical structures of naltrexone (left) and methylnaltrexone (right).
      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.
      • Gmerek DE
      • Cowan A
      • Woods JH
      Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats.
      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.
      • Gmerek DE
      • Cowan A
      • Woods JH
      Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats.
      • Yuan CS
      • Foss JF
      • Moss J
      Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine.
      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.
      • Yuan CS
      • Foss JF
      • Moss J
      Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine.
      When injected subcutaneously, MNTX neither reversed analgesia in rats
      • Gmerek DE
      • Cowan A
      • Woods JH
      Independent central and peripheral mediation of morphine-induced inhibition of gastrointestinal transit in rats.
      nor precipitated withdrawal in animals that were physically dependent on morphine.
      • Russell J
      • Bass P
      • Goldberg LI
      • Schuster CR
      • Merz H
      Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists.
      Peak plasma concentration and area under the concentration-time curve for MNTX are proportional to dose after intravenous or subcutaneous administration in human volunteers.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.
      Time to peak is approximately 30 minutes after subcutaneous dosing.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.
      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.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.
      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.
      • Yuan CS
      • Doshan H
      • Charney MR
      • et al.
      Tolerability, gut effects, and pharmacokinetics of methylnaltrexone following repeated intravenous administration in humans.
      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.
      • Kotake AN
      • Kuwahara SK
      • Burton E
      • McCoy CE
      • Goldberg LI
      Variations in demethylation of N-methylnaltrexone in mice, rats, dogs, and humans.
      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).
      • Yuan 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.
      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.
      • Yuan 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.
      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.
      • Yuan 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.
      Another study with volunteer subjects confirmed that MNTX does not reverse opioid-mediated ventilatory depression, a centrally mediated opioid effect.
      • Amin 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.
      These results are important because they show that MNTX cannot be used, like naloxone, to treat patients with opioid overdose.
      Figure thumbnail gr2
      FIGURE 2Oral-cecal transit time (OCTT) in 12 volunteers given placebo, morphine (MS), or intravenous methylnaltrexone (MNTX) plus MS. The dashed line represents the mean response. From Clin Pharmacol Ther,
      • Yuan 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.
      with permission.
      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).
      • Yuan 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.
      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.
      • Yuan 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.
      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 al
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.
      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.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Effects of enteric coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.
      Opioid Bowel Dysfunction in Methadone Maintenance. Therapy using MNTX in opioid-tolerant volunteers represents a complex problem of dose titration. Opioid abusers who receive long-term methadone maintenance treatment for addiction are prone to having severe OBD. These volunteers typically defecate infrequently—perhaps only once or twice a week—and OCTT is markedly prolonged.
      The use of MNTX has been investigated in 3 protocols relevant to this opioid-abuser population.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • Osinski J
      • Roizen MF
      • Moss J
      Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study.
      • Yuan CS
      • Foss JF
      Oral methylnaltrexone for opioid-induced constipation [letter].
      In a pilot trial, intravenous MNTX produced an extremely rapid onset of laxation.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • Osinski J
      • Roizen MF
      • Moss J
      Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study.
      This trial confirmed that opioid abusers are sensitive to opioid antagonists, suggesting that lower doses of MNTX should be used in this population. A second study was performed with 22 volunteers who hadused methadone long term at dosages of 30 to 100 mg/d.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.
      In this proof-of-concept trial, volunteers were given MNTX intravenously on an ascending dose schedule. Both OCTT and laxation were recorded, and signs of withdrawal were monitored. By the second day, all MNTX-treated volunteers but none of the members of the placebo group responded with laxation. Laxation typically occurred within 1 minute, and the MNTX dose required was only 0.1 mg/kg—roughly one-fifth the dose needed to reverse opioid-induced prolongation of OCTT in healthy volunteers.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.
      These findings demonstrate that receptors in the gut, as well as in the brain, had become hypersensitive to opioid antagonists.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • et al.
      Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.
      Oral-cecal transit time was normalized with the use of MNTX. Other than mild to moderate cramping, no volunteer showed psychological or physical signs of opioid withdrawal. A subsequent trial examined oral administration of MNTX in 12 volunteers who were treated with methadone maintenance.
      • Yuan CS
      • Foss JF
      Oral methylnaltrexone for opioid-induced constipation [letter].
      Laxation occurred in 11 of the volunteers—but only after a delay that depended on the dose of MNTX. After oral MNTX doses of 0.3, 1, and 3 mg/kg, bowel movement occurred after an average delay of 18, 8.7, and 5.2 hours, respectively.
      Methylnaltrexone has also been developed in a subcutaneous formulation designed to avoid the long delay associated with oral dosing, as well as to eliminate the need for vascular access with intravenous dosing. Subcutaneous administration has been shown to be effective in reversing morphine-induced changes in OCTT.
      • Yuan 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.
      Peak plasma concentration of MNTX was achieved within only 15 minutes. Taken together, these studies show that the route of antagonist administration can significantly affect the speed of onset.
      Opioid Bowel Dysfunction in Advanced Illness. The clinical development program for MNTX was targeted particularly at patients with advanced illness. Such patients often have medical comorbidities, and their doses of opioids may be very high. In a phase 2b study of 33 patients with opioid-induced constipation who were receiving palliative care, subcutaneous injection of MNTX produced dose-related laxation, usually within 1 hour.
      • Portenoy RK
      • Thomas J
      • Moehl Boatwright ML
      • 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.
      More than 70% of the treated patients responded favorably to MNTX, and there was no evidence of withdrawal.
      Two pivotal phase 3 clinical trials of subcutaneous MNTX have been completed in patients with advanced illness. The first study (MNTX 301) was a multicenter trial that evaluated a single subcutaneous administration of MNTX (0.15 mg/kg or 0.3 mg/kg) in 154 patients with advanced illness.
      • Thomas J
      • Lipman A
      • Slatkin N
      • et al.
      A phase III double-blind placebo-controlled trial of methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness (AMI) [abstract 8003].
      The majority of these patients had advanced cancer, though some had severe chronic obstructive pulmonary disease, amyotrophic lateral sclerosis, or AIDS. Sixty-two percent of the patients laxated within 4 hours of their first MNTX injection, compared with 13% of the patients given placebo (P<.001). Most patients responded within 1 hour of treatment, allowing a measure of predictability among these medically complex patients. Both doses of MNTX were effective, but the incidence of flatulence and abdominal cramping was higher in the high-dose group.
      A follow-up phase 3 trial (MNTX 302) examined the effect of the lower subcutaneous MNTX dose (0.15 mg/kg) administered every other day for 1 week, with the option of doubling the dose as needed during a second week
      • Thomas J
      • Lipman A
      • Slatkin N
      • et al.
      A phase III double-blind placebo-controlled trial of methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness (AMI) [abstract 8003].
      • Thomas J
      • Wang W
      • Yan N
      • et al.
      Analysis of response to methylnaltrexone by response to previous dose in advanced illness patients with opioid-induced constipation [abstract 9626].
      • Thomas J
      • Karver S
      • Cooney GA
      • et al.
      Methylnaltrexone for opioid-induced constipation in advanced illness.
      • Berde C
      • Nurko S
      Opioid side effects-mechanism-based therapy [editorial].
      (Figure 3). Of patients given MNTX, 48% had laxation responses within 4 hours of the initial dose, compared with only 16% of those given placebo (P<.001). Overall, more than 46% of the patients responded favorably to the initial dose of subcutaneously injected MNTX, and more than 75% of the patients responded to one of the first 3 doses.
      • Thomas J
      • Wang W
      • Yan N
      • et al.
      Analysis of response to methylnaltrexone by response to previous dose in advanced illness patients with opioid-induced constipation [abstract 9626].
      The median time to response was 30 minutes. Doses were stable during the 2-week trial and subsequent open-label extension.
      Figure thumbnail gr3
      FIGURE 3Laxation responses among patients with opioid-induced bowel dysfunction and advanced illness who were given either subcutaneous methylnaltrexone (0.15 mg/kg every other day for 1 week, with option of doubling dose in second week) or placebo. A, Primary efficacy measures: laxation within 4 hours after the first dose and laxation within 4 hours after 2 or more of the first 4 doses (P<.001); B, Rescue-free laxation within 4 hours after each dose during a 13-day period (P<.005). On days 9, 11, and 13, variations in doses were permitted on the basis of efficacy and adverse events; C, Kaplan-Meier curves for the time to laxation within 4 hours after the first dose (P<.001). From N Engl J Med,
      • Thomas J
      • Karver S
      • Cooney GA
      • et al.
      Methylnaltrexone for opioid-induced constipation in advanced illness.
      with permission from the Massachusetts Medical Society. © 2008. All rights reserved.
      Aside from the expected abdominal cramping and flatulence, few adverse effects were observed; no patient in these phase 3 trials experienced opioid withdrawal.
      • Thomas J
      • Karver S
      • Cooney GA
      • et al.
      Methylnaltrexone for opioid-induced constipation in advanced illness.
      • Berde C
      • Nurko S
      Opioid side effects-mechanism-based therapy [editorial].
      Dropout rates were similar for patients in both the treatment and control groups.
      A phase 2b clinical trial of MNTX in an oral formulation was recently completed.
      This study, involving 122 patients, found that a single daily dose of an oral form of MNTX effectively promoted laxation in individuals receiving opioids for chronic nonmalignant pain. Details of this trial have yet to be published.
      Postoperative Ileus. The 3 trials of MNTX for the prevention of POI conducted to date have reported inconsistent results. The first was a phase 2 trial of intravenous MNTX in 65 patients who had colectomies. Compared with placebo, MNTX-treated patients had a 20-hour improvement in their mean time to first laxation (P<.04).
      • Viscusi E
      • Rathmell J
      • Alexxandro F
      • Gan TJ
      • Israel RJ
      A double-blind, randomized, placebo-controlled trial of methylnaltrexone (MNTX) for post-operative bowel dysfunction in segmental colectomy patients [abstract A893].
      The mean time to become eligible for hospital discharge was 33 hours earlier for patients given MNTX than for those given placebo (P<.05).
      • Viscusi E
      • Rathmell J
      • Alexxandro F
      • Gan TJ
      • Israel RJ
      A double-blind, randomized, placebo-controlled trial of methylnaltrexone (MNTX) for post-operative bowel dysfunction in segmental colectomy patients [abstract A893].
      However, two subsequent multinational phase 3 trials of intravenous MNTX did not show statistical significance for their primary end points. The data for these studies have not yet been published, and the reasons for the discrepancy with the phase 2 trial results are unclear.

      Alvimopan

      Preclinical Pharmacology. Alvimopan, formerly known as ADL 8-2698, is a zwitterion (ie, molecule with both positive and negative regions of charge) that has a relatively large molecular weight (Figure 4). As would be expected for a large, polar molecule, alvimopan does not enter the CNS easily, and it produces strong peripheral opioid antagonism without affecting such central effects as analgesia.
      Figure thumbnail gr4
      FIGURE 4Chemical structure of alvimopan.
      In a study using cloned μ receptors, alvimopan had very high binding affinity, which may account for the relatively long duration of its antagonist effect.
      • Cassel JA
      • Daubert JD
      • DeHaven RN
      [(3)H]Alvimopan binding to the micro opioid receptor: comparative binding kinetics of opioid antagonists.
      After oral administration to animals, alvimopan was poorly absorbed, with an absolute bioavailability of only 0.03%. Plasma pharmacokinetic data for alvimopan is derived from studies of intravenous administration to rabbits and dogs. These data indicate first-order elimination for alvimopan (ie, the amount of drug eliminated is directly proportional to the serum drug concentration), with a half-life of approximately 10 minutes.
      • Zimmerman DM
      • Gidda JS
      • Cantrell BE
      • Schoepp DD
      • Johnson BG
      • Leander JD
      Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine opioid antagonist for the treatment of gastrointestinal motility disorders.
      • Schmidt WK
      Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist.
      Pharmacokinetics. Alvimopan is available only in an oral preparation. In contrast to its minimal bioavailability in animals, systemic absorption of alvimopan in humans is approximately 6%.
      • Foss JF
      • Fisher DM
      • Schmith VD
      Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials.
      Absorption is greater with fasting, after surgery, and in younger patients. Alvimopan is biotransformed to a metabolite designated as ADL-08-0011, which functions as an opioid antagonist. The fact that levels of this metabolite are decreased by administration of antibiotics indicates that gut bacteria affect biotransformation. Approximately 8% of the metabolite is absorbed; the clinical relevance of this compound is unknown.
      • Foss JF
      • Fisher DM
      • Schmith VD
      Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials.
      Effects on Intestinal Motility. In healthy volunteers, the use of radiolabeled markers showed that alvimopan reversed the prolongation of OCTT produced by oral loperamide. Repeated doses sustained this antagonist effect for longer than 4 days.
      • Schmidt WK
      Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist.
      Alvimopan also reversed morphine's effects on gastrointestinal motility. In a study involving 14 volunteers, the use of intravenous morphine (0.05 mg/kg) increased gastrointestinal transit time from 69 minutes to 103 minutes (P=.005).
      • Liu SS
      • Hodgson PS
      • Carpenter RL
      • Fricke Jr, JR
      ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia.
      When alvimopan was administered orally to the volunteers at a dose of 4 mg, this effect of morphine was completely prevented (P=.004). In a follow-up protocol, alvimopan (4 mg) or placebo was administered to 45 patients who had been given morphine for pain after dental surgery. There was no difference between the alvimopan and placebo groups in central effects, including pupil constriction and analgesia.
      • Liu SS
      • Hodgson PS
      • Carpenter RL
      • Fricke Jr, JR
      ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia.
      In a placebo-controlled study, 36 of 72 enrolled volunteers were given codeine (30 mg 4 times daily) and 36 were given alvimopan (12 mg twice daily).
      • Gonenne J
      • Camilleri M
      • Ferber I
      • et al.
      Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study.
      Codeine prolonged both gastric emptying and small bowel transit time. Alvimopan completely reversed codeine's effect on the small bowel, but it did not antagonize the reduction in gastric emptying.
      • Gonenne J
      • Camilleri M
      • Ferber I
      • et al.
      Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study.
      The explanation for alvimopan's lack of effect on gastric emptying is unclear; it may be because blocking the gastric effect requires systemic absorption of the antagonist.
      Management of Postoperative Ileus. In a pivotal phase 2/phase 3 trial, 78 patients who had abdominal or gynecologic surgery were randomized to receive alvimopan (1 mg or 6 mg) or a placebo 2 hours before surgery and then twice daily until hospital discharge, for a maximum of 7 days.
      • Taguchi A
      • Sharma N
      • Saleem RM
      • et al.
      Selective postoperative inhibition of gastrointestinal opioid receptors.
      Patient-controlled analgesia with morphine or meperidine was used for postoperative analgesia. Alvimopan produced a substantial improvement in time to first flatus, time to first bowel movement, and time to be ready for hospital discharge (Figure 5).
      • Taguchi A
      • Sharma N
      • Saleem RM
      • et al.
      Selective postoperative inhibition of gastrointestinal opioid receptors.
      These effects were most prominent with the higher dose. No statistical differences in opioid use or pain scores were reported among the 3 study groups. Interestingly, postoperative nausea, vomiting, and overall incidence of all gastrointestinal adverse effects were significantly reduced with use of alvimopan.
      • Taguchi A
      • Sharma N
      • Saleem RM
      • et al.
      Selective postoperative inhibition of gastrointestinal opioid receptors.
      Figure thumbnail gr5
      FIGURE 5Kaplan-Meier estimates of probability of reaching end points among 78 patients with postoperative ileus who were given alvimopan (ADL 8-2698, 1 mg or 6 mg) or placebo 2 hours before surgery and then twice daily until hospital discharge, for a maximum of 7 days. Significant differences were observed among the groups in time to first passage of flatus (P=.03), time to first bowel movement (P=.01), and time until patient was ready for discharge (P=.03). From N Engl J Med,
      • Taguchi A
      • Sharma N
      • Saleem RM
      • et al.
      Selective postoperative inhibition of gastrointestinal opioid receptors.
      with permission from the Massachusetts Medical Society. © 2001. All rights reserved.
      The alvimopan phase 3 program investigated the prevention of POI with doses of 6 mg or 12 mg twice daily in 6 large trials. The results of four studies have been formally published,
      • Wolff BG
      • Michelassi F
      • Gerkin TM
      • et al.
      Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus.
      • Delaney CP
      • Weese JL
      • Hyman NH
      • Alvimopan Postoperative Ileus Study Group
      • et al.
      Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      • Viscusi ER
      • Goldstein S
      • Witkowski T
      • et al.
      Alvimopan, a peripherally acting μ-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20 (3): 537].
      but data on all studies are available from FDA online presentations.
      Patients in these studies underwent either segmental bowel resection or total abdominal hysterectomy. One of the primary end points was termed GI-3, which was defined as the elapsed time until first solid food, flatus, or stool—whichever occurred last. The results for GI-3 were positive overall, although not consistently, and the 12-mg dose of alvimopan was not always more efficacious than the 6-mg dose of the drug.
      Two explanations for the inconsistent results in the alvimopan phase 3 program are likely
      • Wolff BG
      • Michelassi F
      • Gerkin TM
      • et al.
      Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus.
      • Delaney CP
      • Weese JL
      • Hyman NH
      • Alvimopan Postoperative Ileus Study Group
      • et al.
      Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      • Viscusi ER
      • Goldstein S
      • Witkowski T
      • et al.
      Alvimopan, a peripherally acting μ-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20 (3): 537].
      : the inclusion of patients who had undergone hysterectomies (who do not usually have a problem with POI) and the use of GI-3, a composite end point (which lumped together very different phenomena). GI-2 (see Table 3 for definition) was a more consistent measurement. In one of the phase 3 trials that did not show statistical significance, many of the patients receivedsmall or minimal amounts of opiates. Some of the GI-2 data for patients who received the 12-mg dose of alvimopan, as presented to the FDA Gastrointestinal Drugs Advisory Committee, are shown in Table 3.
      TABLE 3Time to GI-2 for Patients Undergoing Bowel Resection in Phase 3 Postoperative Ileus Studies
      CI = confidence interval; GI-2 = composite end point of first time to tolerate solid food or first bowel movement, whichever occurred last; HR = hazard ratio.
      Time to GI-2
      Study No.Treatment
      Alvimopan dosage was 12 mg twice daily.
      No. of patients50th percentile (d)Change from placebo (d)75th percentile (d)Change from placebo (d)HR (95% CI)P value
      302
      • Delaney CP
      • Weese JL
      • Hyman NH
      • Alvimopan Postoperative Ileus Study Group
      • et al.
      Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.
      Placebo994.8−0.75.9−0.81.40 (1.04-1.89).029
      Alvimopan984.15.1
      308
      • Viscusi ER
      • Goldstein S
      • Witkowski T
      • et al.
      Alvimopan, a peripherally acting μ-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20 (3): 537].
      Placebo1424.9−0.56.3−0.91.37 (1.06-1.76).017
      Alvimopan1394.45.4
      313
      • Wolff BG
      • Michelassi F
      • Gerkin TM
      • et al.
      Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus.
      Placebo1424.9−0.96.3−1.21.63 (1.26-2.10)<.001
      Alvimopan1604.05.1
      001
      Placebo2294.0−0.15.7−0.81.30 (1.07-1.58).008
      Alvimopan2383.94.9
      314
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      Placebo3124.0−0.75.5−0.91.53 (1.29-1.82)<.001
      Alvimopan3173.34.6
      a CI = confidence interval; GI-2 = composite end point of first time to tolerate solid food or first bowel movement, whichever occurred last; HR = hazard ratio.
      b Alvimopan dosage was 12 mg twice daily.
      Neither alvimopan nor MNTX was consistently better than placebo in the large international trials of POI, although the data from all trials suggest a greater effect from alvimopan. Do the 2 antagonists truly differ in efficacy for POI? One possible confounding factor may be the very different doses used in the trials of these 2 drugs. Alvimopan was studied at relatively high doses that were appropriate for surgical patients who did not take opioids long term. In contrast, MNTX was studied at low doses that were previously shown to be safe and effective for patients who had substantial previous exposure to opioids. Patients taking opioids long term are much more sensitive to the effects of antagonists than those who are opioid naive. In addition, results from a large international trial of alvimopan in POI
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      suggest that variations in surgical practice and opiate use may have contributed to statistically nonsignificant results. In a post hoc analysis, patients who received more postoperative morphine than other patients were more likely to benefit from alvimopan.
      Faster recovery of gastrointestinal function can lead to shorter hospital stays for patients, an effect that may produce economic benefit by lowering hospital costs. The times to hospital discharge for patients receiving alvimopan (12 mg) vs placebo for the 5 studies involving bowel resection, as presented to the FDA Gastrointestinal Drugs Advisory Committee, are summarized in Table 4. Taken as a whole, the alvimopan phase 3 studies support an important role for alvimopan in treating patients with POI.
      • Wolff BG
      • Michelassi F
      • Gerkin TM
      • et al.
      Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus.
      • Delaney CP
      • Weese JL
      • Hyman NH
      • Alvimopan Postoperative Ileus Study Group
      • et al.
      Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      • Viscusi ER
      • Goldstein S
      • Witkowski T
      • et al.
      Alvimopan, a peripherally acting μ-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20 (3): 537].
      TABLE 4Time to Hospital Discharge for Patients Undergoing Bowel Resection in Phase 3 Postoperative Ileus Studies
      CI = confidence interval; HR = hazard ratio.
      Study No.Treatment
      Alvimopan dosage was 12 mg twice daily.
      No. of patientsTime to discharge 75th percentile (d)Change from placebo (d)HR (95% CI)P value
      302
      • Delaney CP
      • Weese JL
      • Hyman NH
      • Alvimopan Postoperative Ileus Study Group
      • et al.
      Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.
      Placebo994.71.52 (1.11-2.09)
      Alvimopan984.1−0.6.010
      308
      • Viscusi ER
      • Goldstein S
      • Witkowski T
      • et al.
      Alvimopan, a peripherally acting μ-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20 (3): 537].
      Placebo1424.91.40 (1.09-1.78)
      Alvimopan1394.6−0.3.008
      313
      • Wolff BG
      • Michelassi F
      • Gerkin TM
      • et al.
      Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus.
      Placebo1424.71.54 (1.20-1.96)
      Alvimopan1604.0−0.7<.001
      001
      Placebo2295.71.11 (0.92-1.35)
      Alvimopan2385.70.0.287
      314
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      Placebo3123.81.38 (1.17-1.63)
      Alvimopan3173.4−0.4<.001
      a CI = confidence interval; HR = hazard ratio.
      b Alvimopan dosage was 12 mg twice daily.
      The adverse event profile for alvimopan in these POI trials
      • Wolff BG
      • Michelassi F
      • Gerkin TM
      • et al.
      Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus.
      • Delaney CP
      • Weese JL
      • Hyman NH
      • Alvimopan Postoperative Ileus Study Group
      • et al.
      Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      • Viscusi ER
      • Goldstein S
      • Witkowski T
      • et al.
      Alvimopan, a peripherally acting μ-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20 (3): 537].
      was largely unremarkable, and serious adverse events were almost always related to the surgical procedures rather than to medications. Despite the fact that alvimopan would be expected to increase bowel motility, no increase in anastomotic leakage was observed. The most common adverse reactions reported in the alvimopan phase 3 POI trials (incidence >3%) were nonspecific phenomena, includinganemia, dyspepsia, hypokalemia, back pain, and urinary retention.
      • Wolff BG
      • Michelassi F
      • Gerkin TM
      • et al.
      Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting μ opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus.
      • Delaney CP
      • Weese JL
      • Hyman NH
      • Alvimopan Postoperative Ileus Study Group
      • et al.
      Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.
      • Büchler MW
      • Seiler CM
      • Monson JRT
      • et al.
      Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.
      • Viscusi ER
      • Goldstein S
      • Witkowski T
      • et al.
      Alvimopan, a peripherally acting μ-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published correction appears in Surg Endosc. 2006;20 (3): 537].
      It is clear that patients undergoing open bowel resections who are treated with alvimopan are ready for discharge substantially earlier than patients given placebo. However, this advantage is not seen for patients who have had a simple hysterectomy (data not shown). The potential of alvimopan to reduce length of hospital stay is an important finding, but many other variables will determine whether this results in cost savings for the institution.
      Opioid Bowel Dysfunction in Patients With Chronic Pain and Addiction. The use of alvimopan has been evaluated in 5 clinical trials involving patients who had OBD (chiefly constipation) and who were receiving long-term opioid treatment, but the results from most of these studies remain unpublished.
      • 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.
      • Webster L
      • Jansen JP
      • Peppin J
      • et al.
      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.
      Four of the studies enrolled patients with noncancer pain (with one of these studies including a small group of addicts who were receiving methadone maintenance therapy), and the fifth study enrolled patients with cancer-related pain. Results of one phase 2 clinical trial were promising,
      • Webster L
      • Jansen JP
      • Peppin J
      • et al.
      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.
      but the remaining trials failed to show a consistent beneficial effect of alvimopan in the clinical setting of OBD. The trial of 233 patients with chronic cancer pain found that 0.5 mg to 1 mg twice daily did not increase the frequency of spontaneous complete bowel movements. There were two phase 3 trials of patients with chronic pain: the first (522 patients) concluded that alvimopan worked, whereas the second (485 patients) failed to reach significance. It should be noted that a placebo rate of greater than 50% was seen in the latter study. This high placebo rate suggests a problem in trial design or implementation. Placebo rates in the phase 3 trials of MNTX for advanced illness were half of those observed in the chronic pain trials with alvimopan.
      Recent Safety Issues. An additional large study was carried out to examine the long-term efficacy and safety of alvimopan vs placebo in treating patients with OBD.
      A preliminary analysis of the safety data from this study revealed serious adverse events, which were confirmed when the study completed enrollment. Most troubling were reports of serious cardiovascular toxicity (although levels reported were not statistically significant): 7 of 538 patients in the alvimopan group had myocardial infarctions vs 0 of 267 patients in the placebo group. According to reports submitted to the FDA Gastrointestinal Drugs Advisory Committee, these cardiovascular events were seen in patients who were at high risk for cardiovascular disease or who had established cardiovascular disease, and most events occurred during the first 12 weeks of treatment.
      The adverse cardiovascular effects of alvimopan use were unexpected; no comparable toxicity had ever been observed when patients were given much higher doses of alvimopan for chronic POI. There is no reason to suspect that these adverse effects are endemic to the PAMORA drug class. No cardiovascular problems have been encountered with MNTX or with high doses of naltrexone given for long-term addiction.
      Given the nature of alvimopan and the drug's extremely low systemic exposure, the observed cardiovascular problems were likely not true toxic effects of alvimopan. Although the cardiovascular effects observed in the long-term alvimopan study were not statistically significant, the FDA took a very conservative approach in its recent approval of alvimopan. Until more is known about the drug's risk/benefit profile, the FDA is qualifying its approval of alvimopan with a Risk Evaluation and Mitigation Strategy, which is historically reserved for a small number of drugs about which the FDA has special concerns. Alvimopan is the first new molecular entity included in this strategy, which was adopted by the US Congress in the Food and Drug Administration Amendments Act of 2007.
      • US Food and Drug Administration
      Alvimopan is approved with the following restrictions.
      • US Food and Drug Administration
      It may be given to patients to restore bowel function postoperatively, but only to adults who have undergone large or small bowel resection. In order to prevent off-label use, a black box warning is included in the package insert, noting the drug's approval for short-term hospital use in institutions that have met requirements for the Entereg Access Support and Education program. Alvimopan is indicated only in hospitalized patients, for a total of no more than 15 doses per patient. In addition, alvimopan should not be used in patients who have received opiates for more than 1 week. This last restriction was included because data presented to the FDA indicated that the 12-mg dose of alvimopan can actually be painful for patients receiving long-term opioid therapy.

      EFFICACY OF PAMORAS IN ATTENUATING OTHER OPIOID-INDUCED ADVERSE EFFECTS

      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.
      • Gonenne J
      • Camilleri M
      • Ferber I
      • et al.
      Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study.
      Two studies showed that MNTX attenuates morphine-induced delay of gastric emptying, suggesting that gastric emptying is a peripheral effect of opioids.
      • Murphy DB
      • Sutton JA
      • Prescott LF
      • Murphy MB
      Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.
      • Yuan CS
      • Foss J
      • O'Connor M
      • Roizen M
      • Moss J
      Effects of low-dose morphine on gastric emptying in healthy volunteers.
      Eleven healthy volunteers were given placebo, morphine (0.09 mg/kg), or a combination of morphine and MNTX, and the rate of gastric emptying was measured by tests of bioimpedance and acetaminophen absorption.
      • Murphy DB
      • Sutton JA
      • Prescott LF
      • Murphy MB
      Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.
      The time for 50% emptying was 5.5, 21.0, and 7.4 minutes after administration of placebo, morphine, and morphine/MNTX, respectively. Morphine delayed acetaminophen transfer from stomach to proximal jejeunum and decreased acetaminophen peak plasma concentration.
      • Murphy DB
      • Sutton JA
      • Prescott LF
      • Murphy MB
      Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.
      • Yuan CS
      • Foss J
      • O'Connor M
      • Roizen M
      • Moss J
      Effects of low-dose morphine on gastric emptying in healthy volunteers.
      These effects were also prevented by MNTX.
      • Murphy DB
      • Sutton JA
      • Prescott LF
      • Murphy MB
      Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.
      • Yuan CS
      • Foss J
      • O'Connor M
      • Roizen M
      • Moss J
      Effects of low-dose morphine on gastric emptying in healthy volunteers.
      These preliminary data indicate 3 main ways in which MNTX could be helpful for certain patient populations receiving opioids. First, by decreasing the volume of gastric contents, MNTX may decrease the risk of regurgitation and pulmonary aspiration. This effect may be of particular relevance for patients undergoing general anesthesia, because the esophageal sphincter is relaxed, and protective airway reflexes are absent. Second, by increasing the rate at which an orally administered drug (eg, acetaminophen) passes into the proximal small bowel, MNTX may increase that drug's rate of absorption and peak concentration. Third, by decreasing gastric residuals, MNTX may increase the rate at which enteral feedings can be administered to patients who are taking large doses of opioids—an effect that may be of great importance for patients in the intensive care unit (ICU). No controlled studies of the effects of MNTX on enteral nutrition have been conducted. However, one case report describes the successful use of MNTX to initiate feedings in a patient with a 30% burn.

      Woo M, O'Connor MF, Yuan C-S, Moss J. Reversal of opioid-induced gastric dysfunction in a critically ill burn patient after methylnaltrexone. Anesth Analg. In press.

      Nausea and Vomiting

      Nausea and vomiting are well-known adverse effects of opioids that may have both peripheral and central components. The mechanisms involved in this association are complex. Low doses of opioids stimulate vomiting by binding to receptors in the chemoreceptor trigger zone (CTZ), whereas higher doses of opioids may suppress vomiting by acting at receptor sites deeper in the medulla. The CTZ is located in the floor of the fourth ventricle. Because this part of the brain has an incomplete blood-brain barrier, it is technically “peripheral.”
      • Wood GJ
      • Shega JW
      • Lynch B
      • Von Roenn JH
      Management of intractable nausea and vomiting in patients at the end of life: “I was feeling nauseous all of the time … nothing was working”.
      Nausea and vomiting were reduced in patients who were given PAMORAs in several trials that were not specifically designed to look at this effect. A recent meta-analysis of phase 3 clinical trials examining the use of alvimopan in patients with POI showed a significant reduction in postoperative nausea and vomiting.
      • Weese JL
      • Du W
      • Techner L
      Effect of alvimopan (ALV) on gastrointestinal (GI) recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity in patients (PTS) undergoing bowel resection (BR) for colon or rectal cancer (CRC) [abstract 4014].
      In one small study, MNTX markedly attenuated the nausea associated with parenteral morphine administration.
      • Weese JL
      • Du W
      • Techner L
      Effect of alvimopan (ALV) on gastrointestinal (GI) recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity in patients (PTS) undergoing bowel resection (BR) for colon or rectal cancer (CRC) [abstract 4014].
      In another small study, patients who received MNTX for reversal of opioid urinary effects had a decrease in vomiting compared with those who received placebo.
      • Weese JL
      • Du W
      • Techner L
      Effect of alvimopan (ALV) on gastrointestinal (GI) recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity in patients (PTS) undergoing bowel resection (BR) for colon or rectal cancer (CRC) [abstract 4014].
      This decrease in vomiting may have resulted from an action at the CTZ receptors or a modulation of afferent impulses from the enteric nervous system to the brain.
      • Yuan CS
      • Foss JF
      Gastric effects of methylnaltrexone on μ, β, and δ opioid agonists induced brainstem unitary responses.

      Urinary Retention

      Opioids cause urinary retention by inhibiting bladder detrusor (ie, smooth muscle) tone, by suppressing the micturition reflex, and by decreasing awareness of bladder distention. The clinical problem of urinary retention has not been as well studied as OBD, but some reports suggest a high incidence of urinary retention during the perioperative period.
      • O'Riordan JA
      • Hopkins PM
      • Ravenscroft A
      • Stevens JD
      Patient-controlled analgesia and urinary retention following lower limb joint replacement: prospective audit and logistic regression analysis.
      Certain patient populations are likely at greater risk of this problem. For example, one study reported an incidence of urinary retention of 18.1% in older patients who used patient-controlled analgesia with morphine after lower limb joint replacement.
      • O'Riordan JA
      • Hopkins PM
      • Ravenscroft A
      • Stevens JD
      Patient-controlled analgesia and urinary retention following lower limb joint replacement: prospective audit and logistic regression analysis.
      Complete urinary retention can be painful and distressing for the patient, and the usual treatment is immediate insertion of a bladder catheter to relieve symptoms.
      Opioid actions on the brain and spinal cord undoubtedly affect the bladder. Until recently, however, the involvement of peripheral opioid receptors had not been shown. In a recent study, the effects of placebo, naloxone, and MNTX were compared for reversal of bladder dysfunction induced by the opioid agonist remifentanil.
      • Rosow CE
      • Gomery P
      • Chen TY
      • Stefanovich P
      • Stambler N
      • Israel R
      Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.
      Detrusor pressure was measured by using bladder and rectal catheters in 13 male volunteers, and pupil constriction was measured by using infrared pupillometry. Remifentanil decreased detrusor pressure in 21 of 25 sessions and caused complete urinary retention in 18 of 25 sessions. Voiding was possible after administration of placebo, naloxone, and MNTX in 0%, 86%, and 42% of sessions, respectively (P=.0013; Figure 6).
      • Rosow CE
      • Gomery P
      • Chen TY
      • Stefanovich P
      • Stambler N
      • Israel R
      Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.
      Figure thumbnail gr6
      FIGURE 6Volume of urine voided by male volunteers during urodynamic testing. Measurements were made at baseline, during infusion of remifentanil (0.15 μg/kg per minute), and after injection of saline placebo, naloxone (0.01 mg/kg), or methylnaltrexone (MNTX, 0.3 mg/kg). Remifentanil greatly reduced or eliminated voiding in almost every case. The incidence of successful voiding was 0/6, 7/7, and 5/12 after saline, naloxone, and MNTX, respectively (P=.0013). Adapted from Clin Pharmacol Ther,
      • Rosow CE
      • Gomery P
      • Chen TY
      • Stefanovich P
      • Stambler N
      • Israel R
      Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.
      with permission.
      Pupil constriction was reversed only by naloxone, indicating once again that MNTX works peripherally. To our knowledge, this MNTX study
      • Rosow CE
      • Gomery P
      • Chen TY
      • Stefanovich P
      • Stambler N
      • Israel R
      Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.
      was the first demonstration of a peripheral opioid effect on bladder function. The results suggest that MNTX should be evaluated as a potential treatment for patients with opioid-induced urinary retention.

      The Cough Reflex

      Opioids are commonly used as cough suppressants, but cough suppression is undesirable in some clinical circumstances (eg, during the postoperative period). The receptor mechanisms of opioids in the cough reflex are different from those mediating analgesia and respiratory depression, because weak μ-opioids (eg, codeine) and nonanalgesic stereoisomers (eg, dextromethorphan) can have high activity as antitussives. Control of the cough reflex has long been thought to be a purely central effect involving a putative cough center in the medulla.
      • Adcock JJ
      • Schneider C
      • Smith TW
      Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig.
      However, no data have been published regarding whether PAMORAs prevent the antitussive effect of opiates in humans.
      A study of MNTX in guinea pigs suggests that a peripheral mechanism may be involved in the cough reflex. In that study,
      • Adcock JJ
      • Schneider C
      • Smith TW
      Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig.
      an intraperitoneal dose of MNTX (2 mg/kg) blocked morphine-induced cough suppression but did notaffect analgesia. The tertiary opioid antagonist naltrexone blocked both effects at a dose of only 0.16 mg/kg.
      Further studies are needed to determine whether MNTX blocks opioid-induced suppression of other (possibly related) airway reflexes. Opioids are frequently administered to patients with chronic obstructive pulmonary disease in order to attenuate the sensation of dyspnea. This is likely a central opioid effect, and some anecdotal reports suggest that it is not blocked by MNTX.
      • Rubinstein S
      Hospices are growing venue for drug trials.
      Understanding the effect of MNTX on dyspnea is important, because more than 10% of the patients in the phase 3 trials of MNTX for OBD had a primary diagnosis of chronic obstructive pulmonary disease or emphysema.
      • Thomas J
      • Lipman A
      • Slatkin N
      • et al.
      A phase III double-blind placebo-controlled trial of methylnaltrexone (MNTX) for opioid-induced constipation (OIC) in advanced medical illness (AMI) [abstract 8003].
      • Thomas J
      • Wang W
      • Yan N
      • et al.
      Analysis of response to methylnaltrexone by response to previous dose in advanced illness patients with opioid-induced constipation [abstract 9626].
      • Thomas J
      • Karver S
      • Cooney GA
      • et al.
      Methylnaltrexone for opioid-induced constipation in advanced illness.
      • Berde C
      • Nurko S
      Opioid side effects-mechanism-based therapy [editorial].

      Pruritus

      Opioids often cause itching, particularly around the face. Evidence suggests that itching is a dysesthesia that is mediated by opioid receptors in the CNS. Itching caused by certain opioids, particularly morphine, may also be related to the displacement of histamine from mast cells in peripheral tissues. Most itching, however, does not involve histamine release because itching can usually be reversed by naloxone and can be caused by opioids that do not release histamine (eg, fentanyl).
      • Yuan 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.
      • Gan TJ
      • Ginsberg B
      • Glass PS
      • Fortney J
      • Jhaveri R
      • Perno R
      Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate.
      In one small trial, oral MNTX decreased itching after morphine was administered intravenously.
      • Yuan CS
      • Foss JF
      • O'Connor M
      • Osinski J
      • Roizen MF
      • Moss J
      Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine.
      This result raises the intriguing possibility of a peripheral opioid receptor-mediated mechanism for itching, but such a mechanism needs to be confirmed in a larger trial.

      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 by both bacteria and viruses, including the human immunodeficiency virus (HIV).
      Many of these undesirable effects likely involve peripheral opioid receptors. In the laboratory, MNTX modulates opioid effects on the immune system, on angiogenesis, and on the production of lethality factors by bacteria. Such unexpected effects may have relevance for perioperative patients, as well as for patients with cancer or AIDS.

      Human Immunodeficiency Virus

      One area that is especially promising involves opioid upregulation of chemokine receptor 5 (CCR5), the main route by which HIV enters a cell. Approximately 90% of HIV is transmitted across CCR5, and several new therapies are based on the ability to block this receptor.
      • Keele BF
      • Giorgi EE
      • Salazar-Gonzalez JF
      • et al.
      Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection.
      • Gottlieb GS
      • Heath L
      • Nickle DC
      • et al.
      HIV-1 variation before seroconversion in men who have sex with men: analysis of acute/early HIV infection in the multicenter AIDS cohort study.
      Opioid abuse is an important risk factor for exposure to HIV. Indeed, research suggests that opioids may facilitate HIV infection of human macrophages by modulating β cytokines and CCR5. Methadone increases replication of the CCR5 binding site in monocyte-derived macrophages and glialcells.
      • Li Y
      • Wang X
      • Tian S
      • Guo CJ
      • Douglas SD
      • Ho WZ
      Methadone enhances human immunodeficiency virus infection of human immune cells.
      In this model system, concentrations of MNTX as low as 10 pM block the effect of methadone on viral replication and entry.
      • Ho WZ
      • Guo CJ
      • Yuan CS
      • Douglas SD
      • Moss J
      Methylnaltrexone antagonizes opioid-mediated enhancement of HIV infection of human blood mononuclear phagocytes.
      This result suggests that MNTX may possibly reduce HIV infectivity in patients who take large doses of opioids to manage pain or addiction.
      Other viral infections may be modified by opioids as well. One study recently demonstrated an enhanced and sustained viral suppression in addicted patients with hepatitis C who were treated with implanted naltrexone.
      • Jeffrey GP
      • MacQuillan G
      • Chua F
      • et al.
      Hepatitis C virus eradication in intravenous drug users maintained with subcutaneous naltrexone implants.

      Angiogenesis

      The role of opioids and other anesthetic drugs in promoting tumor recurrence is an area of current research interest. A recent retrospective study demonstrated a 2-fold to 4-fold difference in the recurrence rate of breast cancer, depending on whether patients received general or regional anesthesia for their primary breast surgery.
      • Exadaktylos AK
      • Buggy DJ
      • Moriarty DC
      • Mascha E
      • Sessler DI
      Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis?.
      In another retrospective study of patients who had undergone retropubic prostatectomy, the rate of tumor recurrence was 61% greater in patients who received general anesthesia with opioids than in those who received epidural anesthesia.
      • Biki B
      • Mascha E
      • Moriarty DC
      • Fitzpatrick JM
      • Sessler DI
      • Buggy DJ
      Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospectivwe analysis.
      Follow-up studies are being performed to determine whether such differences in recurrence rate are caused by the primary or secondary effects of regional anesthesia or by the use of opioids.
      • Sessler DI
      • Ben-Eliyahu S
      • Mascha EJ
      • Parat MO
      • Buggy DJ
      Can regional analgesia reduce the risk of recurrence after breast cancer? methodology of a multicenter randomized trial.
      One reason to postulate an effect of opioids on tumor growth is the ability of these drugs to promote tumor angiogenesis in cellular models. Gupta et al
      • Gupta K
      • Kshirsagar S
      • Chang L
      • et al.
      Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth.
      showed that clinically relevant concentrations of morphine induced new blood vessel growth in human breast tissue xenografts in mice.
      We initiated laboratory studies of the effects of opioids and MNTX in angiogenesis because a few of our patients with cancer who had received MNTX under a compassionate use protocol appeared to have slower disease progression. Furthermore, we recognized that MNTX would be given to many patients with cancer after FDA approval. Our first studies showed that clinically relevant concentrations of morphine in vitro—similar to those achieved in surgery and palliative care—increased the migration and proliferation of endothelial cells from dermal and pulmonary vessels in humans (Figure 7).
      • Singleton PA
      • Lingen MW
      • Fekete MJ
      • Garcia JGN
      • Moss J
      Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation.
      These effects were antagonized by both naloxone and MNTX, showing that opioids promote angiogenesis by direct action at the μ-opioid receptor.
      Figure thumbnail gr7
      FIGURE 7Rates of human endothelial cell migration into media containing bovine serum albumin (BSA), as a result of increasing concentrations of morphine, naloxone, methylnaltrexone (MNTX), or MNTX plus morphine. HPF = high-power field; VEGF = vascular endothelial growth factor. The line marked BSA represents background migration, and the line marked VEGF is a positive control. Increasing amounts of morphine increased cell migration, whereas naloxone and MNTX did not. Methylnaltrexone produced a concentration-dependent block of the morphine effect. From Microvasc Res,
      • Singleton PA
      • Lingen MW
      • Fekete MJ
      • Garcia JGN
      • Moss J
      Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation.
      with permission.
      This opioid effect is mediated by the angiogenic signaling pathway for vascular endothelial growth factor (VEGF). We showed that μ-opioids enhance the efficacy of VEGF receptor binding through a process called reciprocal transactivation. Activation of the VEGF receptor is blocked by both naloxone and MNTX, thereby preventing angiogenesis.
      Surprisingly, our cellular studies also showed that MNTX, even in the absence of opioids, potentiates the effects of 2 chemotherapeutic agents—5-fluorouracil and bevacizumab—on endothelial cell migration and proliferation.
      • Singleton PA
      • Garcia JGN
      • Moss J
      Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor-induced angiogenesis.

      Vascular Permeability

      Increased vascular permeability (ie, decreased endothelial barrier function) occurs in tumor angiogenesis, as well as in such inflammatory states as sepsis and in various types of lung injury. Singleton et al
      • Singleton PA
      • Moreno-Vinasco L
      • Sammani S
      • Wanderling SL
      • Moss J
      • Garcia JG
      Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation.
      explored the effect of MNTX in a laboratory model of pulmonary endothelial barrier disruption caused by a variety of agents, including morphine, thrombin, and lipopolysaccharide. They found that morphine and other μ-opioid agonists disrupt barrier function at clinically relevant concentrations; this effect is blocked by MNTX and naloxone. Methylnaltrexone can block barrier disruption by both opioid-specific and nonspecific mechanisms.
      • Singleton PA
      • Moreno-Vinasco L
      • Sammani S
      • Wanderling SL
      • Moss J
      • Garcia JG
      Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation.
      If confirmed clinically, these data suggest that MNTX may provide protective effects for patients with a variety of syndromes in which vascular permeability is increased.

      Bacterial Opioid Receptors

      Pseudomonas infection is a major problem in susceptible patients, including those in the ICU and those receiving palliative care. Opioids are now recognized as a cofactor in the development of sepsis in patients in the ICU.
      • Schwacha MG
      • McGwin G
      • Hutchinson CB
      • et al.
      The contribution of opiate analgesics to the development of infectious complications in burn patients.
      Of the estimated 2 million nocosomial infections occurring each year in the United States, 10% are attributable to Pseudomonas aeroginosa—the second most common cause of pneumonia in the ICU.
      • Todar K
      Todar's Online Textbook of Bacteriology [serial online] 2008.
      Recent in vitro studies have determined that Pseudomonas species have μ-opioid receptors that mediate the production of the lethality factors procyanin and PA-I lectin.
      • Zaborina O
      • Wu L
      • Turner J
      • et al.
      Morphine directly activates the virulence of Pseudomonas aeruginosa and enhances its barrier dysregulating effect against the epithelium [abstract A8].
      PA-I lectin increases epithelial permeability, allowing the bacteria to penetrate the gut wall. Opioid-induced production of these lethality factors is blocked by MNTX, suggesting that the risk of bacterial sepsis might be reduced by PAMORAs in susceptible patients receiving opioids.
      • Zaborina O
      • Wu L
      • Turner J
      • et al.
      Morphine directly activates the virulence of Pseudomonas aeruginosa and enhances its barrier dysregulating effect against the epithelium [abstract A8].

      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 injectable formulation will eventually become available.
      Although orally administered antagonists are relatively slow in onset of action, they may be more convenient for outpatients to use. Injectable antagonists are not only faster in onset, but they also act on the whole gut simultaneously. Injectables may be most useful when oral administration is problematic, as with patients in the ICU or patients who are nauseated. Parenteral formulations are most likely to be useful in hospital and hospice settings; however, many patients with advanced illness will probably inject MNTX at home. Thus, there are compelling reasons for development of both parenteral and oral peripheral opioid antagonists for clinical practice.
      Not a great deal of information exists about the use of PAMORAs in particular risk groups. However, it is clear that neither MNTX nor alvimopan should be given to a patient who has mechanical bowel obstruction. Renal clearance is important for permanently charged, hydrophilic molecules, and more studies are needed to establish whether MNTX dosing should be altered for patients with renal failure. Patients with cardiovascular disease may benefit from administration of alvimopan, but caution will be required until more is known about the cardiovascular toxicity of this drug.

      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 care, when response to laxative therapy has been insufficient. Alvimopan, which is orally administered, is approved for patients in the United States to accelerate gut function after bowel resection and primary anastomosis.
      Methylnaltrexone has been used in clinical trials to discriminate between the central and peripheral effects of opioids. We have presented data suggesting that PAMORAs may eventually prove useful for managing cases of opioid-induced nausea and vomiting, enteral feeding, pruritus, and urinary retention. However, these data are very preliminary.
      Finally, the development of PAMORAs has led to intriguing insights into the cellular effects of opioids. In laboratory studies, MNTX blocked the deleterious effects of opioids on tumor angiogenesis, vascular permeability, and bacterial virulence. If these laboratory effects prove to be clinically relevant, PAMORAs may eventually become useful therapeutic agents for physicians specializing in fields as varied as addiction, intensive care, oncology, and pain management.

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      Linked Article

      • Mutations in a Molecule: The Virtues of Antagonism
        Mayo Clinic ProceedingsVol. 83Issue 10
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          Drug development has evolved through eras of natural product use (willow bark, which contains aspirin), serendipitous discovery (penicillin from bread mold), more rational drug design that involves the testing of diverse synthetic analogues and structural refinement after identification of endogenous ligands (leading to development of β-adrenergic blockers), and fortuitous drug discovery (sulfanilamide that evolved to the sulfonylurea antibiotics and to loop diuretics).1 High (and progressively higher)-throughput screening (a practical method using miniaturized assays to evaluate large numbers of structurally diverse compounds for pharmacological activity) evolved to screen large collections of natural products.
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