JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bates, J. J.
Right arrow Articles by Murphy, D. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bates, J. J.
Right arrow Articles by Murphy, D. B.

Anesth Analg 2004;98:116-122
© 2004 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Are Peripheral Opioid Antagonists the Solution to Opioid Side Effects?

John J. Bates, MRCPI, FCARCSI*, Joseph F. Foss, MD{dagger}, and Damian B. Murphy, MD, FFARCSI*

*Department of Anaesthesia and Intensive Care Medicine, Cork University Hospital, Ireland; and {dagger}Clinical Research, Adolor Inc, Exton, Pennsylvania

Address correspondence and reprint requests to John J. Bates, Department of Intensive Care Medicine, Alfred Hospital, Commercial Rd, Prahran, Victoria 3181, Australia. Address e-mail to jbates{at}esatclear.ie


   Abstract
Top
 Abstract
Introduction
 Conclusion
 References
 
Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role.

IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.


   Introduction
Top
 Abstract
 Introduction
Conclusion
 References
 
Opioids are the mainstay of treatment of moderate to severe acute and chronic pain. Recognition of the undertreatment of pain and efforts to improve pain control has led to increased use of opioids in recent years. Unfortunately, their use is frequently associated with an array of troublesome side effects such as nausea, vomiting, constipation, pruritus, sedation, tolerance, dependence, and respiratory depression. Some of these side effects are mediated in whole or in part via peripheral receptors, whereas many of the desirable actions are central in origin.

Novel peripheral opioid antagonists have been recently introduced. These drugs can block the peripheral actions of opioids without affecting centrally-mediated analgesia. Although a peripherally-mediated analgesic effect of opioids has been demonstrated (1), peripherally-restricted opioid antagonists have no measurable effect on total analgesia. In this paper, we review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role.

We searched in Medline (from 1966), Embase (from 1974), and Cinahl (from 1982) using the words "opioid," "opiate," "peripheral," and drug names "methylnaltrexone," "alvimopan," and "ADL 8-2698." All clinical and experimental studies, case series, and review articles were considered for information relevant to the review. Reference lists in all selected articles were reviewed to identify other relevant articles. Clinical studies are listed in Table 1. Only opioid antagonists that have been evaluated in clinical trials were considered for further review.


View this table:
[in this window]
[in a new window]
  		Table 1. Randomized, Placebo Controlled clinical studies of peripheral opioid antagonists
 
Current Treatment of Opioid Side Effects
Many drugs have been used to treat side effects of opioids with variable success. Frequently, non-opioid pharmacological strategies are used: bulking agents and laxatives for constipation, dopaminergic or 5-hydroxytryptamine (HT)3 receptor antagonists for postoperative nausea and vomiting (PONV), and antihistamines for treatment of pruritus. Each of these drugs has adverse effects, and the resultant polypharmacy is undesirable. Laxatives can cause abdominal cramps, and their efficacy in opioid-induced constipation has not been established (2). When used to treat PONV, 5-HT3 antagonists are of limited efficacy and are associated with headache and increased liver enzymes in a proportion of patients (3). Centrally acting opioid antagonists often reverse the analgesic effects of opioid agonists in postoperative patients (4–6) and produce withdrawal effects in patients on long-term opioid therapy, even at small doses (7–9). They are unsuitable for acute postoperative patients and chronic opioid users. Peripheral opioid antagonists offer two distinct advantages in the prevention of opioid side effects: (a) They do not reverse centrally-mediated analgesia, and (b) a single drug may be used to prevent multiple adverse side effects. Therefore, these drugs represent a potential advance in medical therapy.

In view of evidence from published trials of the efficacy of peripheral opioid antagonists, it is timely to review the literature pertaining to these drugs and to assess their potential impact on daily clinical practice.

Basic Pharmacology of Peripheral Opioid Antagonists
Two peripheral opioid antagonists are in development for clinical use. Methylnaltrexone (MNTX), the first peripheral opioid antagonist to be developed for clinical use, is the quaternary derivative of the opioid antagonist naltrexone. The addition of the methyl group at the amine ring forms a more polar, less lipid-soluble molecule that crosses the blood-brain barrier (BBB) less readily (10). This peripheral selectivity has been demonstrated by the lack of central antagonism of opioids by MNTX when given peripherally in animal (11–13) and human studies (14–17). Antagonism does occur at low doses when given intrathecally in animals (12). Although MNTX is demethylated to naltrexone to some extent in rats and mice, demethylation does not seem to be significant with acute dosing in dogs or humans (18). The compound probably undergoes hepatic metabolism with subsequent renal elimination, although some is also excreted unchanged in the urine (10). MNTX is absorbed orally (19).

Alvimopan, a µ-selective opioid receptor antagonist, is a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine. Its moderately large, zwitterionic form and polarity prevent penetration of the BBB (20). It has minimal systemic bioavailability (0.03% in the dog) with a short plasma half-life (10 min when given IV in dogs) (21). Plasma concentrations of alvimopan are undetectable at the usual oral doses (21), and its molecular structure means that it is unlikely to be metabolized to an active compound (20).

Opioid Side Effects
Gastrointestinal Motility.
A single dose of an opioid can produce immediate effects on the motility of the gastrointestinal tract, and with continued administration, opioid agonists will produce both acute and chronic effects. Opioids alter the fluid dynamics of the gut, inhibit gastric emptying (22) and propulsive motor activity of the intestine, reduce transit time, and cause constipation (23). This is the most common side effect of opioid therapy. Almost all patients on long-term opioids suffer from constipation and require laxative therapy (24). The treatment results in polypharmacy, is often ineffective, and may require dose reduction (25). Tolerance to this side effect does not develop (10). Constipation may contribute to nausea and vomiting in these patients as well as causing other side effects such as pseudo-obstruction, pain, reduced absorption of medications, and fecal impaction (25).

Postoperative ileus (POI) is a multifactorial phenomenon that can delay return of bowel function after surgery. The inability to maintain hydration and nutrition prolongs hospitalization. Opioids contribute to POI, and restricting their use is a common approach to minimizing their effect on the gut. Unfortunately, withdrawal of opioid analgesics and inadequate pain relief are too often observed.

A peripheral mechanism has been demonstrated for the increase in intestinal transit time, which causes opioid-induced constipation in animals (11) and in humans (15,16,21,26,27). The peripheral opioid agonist loperamide is useful in the treatment of diarrhea for this reason. Centrally-acting opioid antagonists can be used to reverse this side effect, but effective doses may also reverse the analgesic effect of the drug in an unpredictable way. Sykes (7) evaluated the use of oral naloxone for the treatment of constipation in 27 opioid-dependent cancer patients. The dose was determined by matching a percentage of the patient’s daily opioid dose with naloxone in an upward titration. The study was unable to demonstrate a decrease in small bowel transit time at 10% replacement of the opioid dose with naloxone. At larger doses, opioid withdrawal, including a recurrence of pain, was observed in some patients (7). Similarly, Latasch et al. (8) found that naloxone, even at small dosage (2%–15% replacement of the morphine dosage with naloxone), produced withdrawal effects in patients using opioids chronically.

MNTX blocked opioid-induced reductions in gastrointestinal motility in rodents and dogs, with little effect on centrally-mediated analgesia (11,28). In humans, both oral and IV preparations of MNTX reduced oral-cecal transit time and reversed chronic opioid-induced constipation in a dose-dependent manner (15,16). This effect was observed in patients receiving long-term oral methadone therapy. The same effects of MNTX on gastrointestinal motility have been observed in healthy volunteers given IV morphine (26,27,29). The dose of MNTX required for this effect seems to be less in patients receiving long-term opioids (0.05–0.15 mg/kg) than in opioid naïve individuals (0.45 mg/kg) (15). Central nervous system (CNS) symptoms of opioid withdrawal have not been observed with the doses used in these studies.

Alvimopan prevented the increase in gastrointestinal transit time induced by IV morphine in 14 healthy volunteers (0.05 mg/kg morphine) and did not affect the analgesia produced by 0.15 mg/kg morphine in 45 acute postoperative patients (similar pain scores were observed in alvimopan and placebo groups) (21). Alvimopan 6 mg, administered orally before surgery and twice daily starting on the first postoperative day for up to 7 days also speeded recovery of bowel function after major abdominal surgery, as assessed by time to first passage of flatus, first bowel movement, first oral fluids, and first solids (30). This translated into a 1-day earlier discharge from the hospital compared with patients receiving placebo, a significant clinical benefit. There were no differences in analgesia or opioid use between the groups.

Alvimopan has been studied in patients receiving opioid therapy for chronic pain (n = 67) or methadone for opioid addiction (n = 34) (data on file, Adolor Corporation). All patients were on stable doses of a wide variety of oral opioid preparations or transdermal fentanyl. Doses of oral alvimopan 0.5, 1.5, 3.0, and 4.5 mg produced dose-related increases in the incidence of effective bowel movements and stool weight. Doses of 3.0 and 4.5 mg were associated with loose stools, cramps, and diarrhea indicative of the increased sensitivity of these opioid-dependent patients to antagonists. No patients demonstrated CNS signs of opioid withdrawal or reversal of analgesia.

Nausea and Vomiting
Opioid receptors play an important role in the control of emesis. Opioid receptors in the chemoreceptor trigger zone (CTZ) induce emesis, and central receptors inhibit emesis (31). The CTZ is physiologically located outside the BBB and the cerebrospinal fluid-brain barrier. The effects of opioids on gut motility may also contribute to nausea and activate the emetic reflex (32). In addition, opioids enhance the release of 5-HT from the small intestine (33). Peripheral opioid antagonists have the potential to affect all of these mechanisms. MNTX blocked morphine-induced emesis completely in dogs (34), and the combination of MNTX and morphine sulfate inhibited the emetogenic response to apomorphine and cisplatin in dogs (35).

In a double-blinded, randomized, placebo-controlled trial in 10 healthy volunteers, MNTX reduced nausea in a concentration-dependent manner after IV morphine (19). Moerman et al. (14) have evaluated MNTX in preventing PONV. In 120 patients undergoing laparoscopic gynecological procedures, less PONV was observed in the group receiving IV MNTX, but the difference was nonsignificant. The study was powered to detect a 50% reduction in the incidence of nausea. Vomiting episodes were reduced by 45% in the MNTX group. Patients in the study received comparatively small doses of opioids during the 6-h observation period (mean of 5.9 mg morphine in the MNTX group).

In contrast, Taguchi et al. (30) studied 79 patients undergoing either total abdominal hysterectomy or partial colectomy. These patients were not given nonsteroidal antiinflammatory analgesics and received larger doses of opioids than those in the Moerman (14) study. The cumulative dose of morphine was 71 mg in the postoperative period. Oral administration of alvimopan 6 mg significantly reduced the incidence of PONV compared with placebo (the incidence of vomiting was 0% in the alvimopan group versus 23% in the placebo group). This reduction in PONV was unlikely to be due to a direct effect on the CTZ because the drug is poorly absorbed orally (although this has not been established for postsurgical patients or those with diseased bowel, and systemic alvimopan concentrations were not measured in the study). The effect of alvimopan on PONV compares favorably with that of ondansetron. In a systematic review, ondansetron prevented vomiting in only 20% of patients at very high risk of PONV, and the effects on nausea were less pronounced (3).

Pruritus
The pathophysiology of opioid-induced pruritus remains unclear. Opioid µ receptor-dependent processes in the CNS regulate the intensity and quality of itch, but opioid peptides may also have a peripheral action, potentiating itch because of other drugs (36). Pruritus is a common and troublesome side effect of opioids, especially when given neuraxially. Opioid antagonists have been shown to reduce the sensation of pruritus in patients with uremia (37) and cholestatic jaundice (38,39). They have also been effective in treating pruritus after IV (40,41), epidural (42–44), and spinal opioids (45). Predictably, analgesia was adversely affected. Evidence of reversal of analgesia was seen with both naloxone (42–44) and nalbuphine (42). Peripheral opioid antagonists may have a role in elucidating the relative contributions of central and peripheral mechanisms to opioid-induced itch. Preliminary data suggest that there may be a therapeutic role for these drugs. Yuan et al. (19) demonstrated that oral MNTX reduced the sensation of skin itch in healthy volunteers given IV morphine. The effect of peripheral opioid antagonists on neuraxial opioid-induced itch is not known and warrants further study.

Cough Suppression
There is limited evidence that the effect of morphine on cough suppression may be in part peripherally mediated (46). MNTX blocks cough suppression induced by morphine, while having no effect on nociception in guinea pigs (47). MNTX may, therefore, maintain the cough reflex in those taking opioids. This awaits formal evaluation.

Biliary Spasm
Studies using endoscopic retrograde cholangiopancreatography have demonstrated that the sphincter of oddi is exquisitely sensitive to all opioid agonists (48), and morphine increases biliary pressure after biliary tract surgery (49). Naloxone has been successfully used to treat biliary spasm (50,51). Peripheral opioid antagonists may help advance our understanding of the mechanism of this phenomenon and could have a therapeutic role.

Urinary Retention
Urinary retention after neuraxial opioids is a troublesome complication. Studies on healthy volunteers have demonstrated that epidural, but not IM or IV morphine, causes detrusor relaxation for an average of 14–16 h but that this effect is promptly reversed by IV naloxone (52). The mechanism of urinary retention after epidural morphine is not fully understood, but an effect at a spinal level is postulated, as is a direct effect on the bladder sphincter (53). Peripheral opioid antagonists may play a role in elucidating the mechanism responsible for the urodynamic effects of opioids. There are no studies of the effect of peripheral opioid antagonists on urodynamics.

Respiratory Depression
Opioids cause a dose-dependent respiratory depression that is of major clinical importance. This is characterized by a reduction in tidal volume, minute volume, respiratory rate, and the response to hypoxia and hypercapnia. These effects are mediated via the respiratory center in the brainstem, although the ventilatory response to hypoxia is mediated via chemoreceptors in the carotid and aortic bodies (54). Amin et al. (55) compared MNTX (0.3 mg/kg) and naloxone (5 µg/kg) for the reversal of morphine-induced respiratory depression during hypoxia in healthy volunteers. As expected, naloxone was more effective in reversing opioid-induced respiratory depression than MNTX. However, there was a delayed, slight increase in the ventilatory response to hypoxia after MNTX compared with placebo. The authors postulated an effect of MNTX on peripheral chemoreceptors, or a leak of MNTX across the BBB, at the respiratory center. It is unlikely that peripheral opioid antagonists will have a clinically relevant effect on opioid-induced respiratory depression.

Therapeutic Role of Peripheral Opioid Antagonists and Future Directions
The areas in which peripheral opioid antagonists are of potential benefit are explained below. Acute postoperative pain: Taguchi et al. (30) have recently demonstrated that oral alvimopan can improve bowel function, reduce gastrointestinal symptoms, and shorten hospital stay in patients undergoing major abdominal surgery. The oral route is well tolerated, even in patients immediately after abdominal surgery. It delivers the compound to the target organ and minimizes exposure of nontarget organs.

MNTX is also well tolerated in postoperative patients but its therapeutic impact has not been demonstrated. It is suggested by preclinical models that systemically administered or orally absorbed opioid antagonists could have an impact on nongastrointestinal side effects. This will require additional research to establish efficacy in patients receiving opioids.

Opioid antagonists may have a role to play in reducing patient-controlled analgesia (PCA) delivered opioid-related side effects. Co-administration via the PCA may be an effective mode of delivery of these drugs if the pharmacokinetic profile of the selected drugs is demonstrated to be compatible.

Animal experiments have shown that epidurally administered MNTX does not cross the dura (56). The site of the analgesic and side effects of epidural opioids is still unclear. Possibilities include the epidural nerve roots, the substantia gelatinosa, or IV absorption with recirculation. Epidural MNTX might help elucidate the mechanism of action of epidurally administered opioids, and peripheral opioid antagonists may play a role in preventing side effects related to epidural opioids. We do not know which route of administration, if any, would be most effective.

Chronic Pain and Hospice Care
Studies suggest that in the short term, oral MNTX is effective in reversing opioid-related constipation. Long-term administration has the potential to improve quality of life in chronic opioid users, but this has not yet been evaluated in a clinical trial. MNTX, unlike alvimopan, is absorbed orally. Although both drugs are bulky molecules, research into novel routes of administration, such as transdermal or transnasal routes, may provide options for patients unable to tolerate oral medications.

Critical Illness
Prolonged ileus in the critically ill can be a troublesome side effect of opioid sedation that negatively impacts enteral feeding and is being studied as a factor in gut bacterial transmigration (57). Peripheral opioid antagonists can restore gut function without affecting the analgesic and sedative effects of opioids.

Dissection of Peripheral from Central Mechanisms of Opioid Side Effects
We know little of the site of many opioid side effects such as urinary retention and pruritus. The prevention of these side effects by peripherally restricted opioid antagonists would suggest a peripheral opioid–receptor-mediated site of action.

Adverse Effects of Peripheral Opioid Antagonists
The only serious adverse effects of MNTX and alvimopan observed have been abdominal cramping in patients on long-term opioids (15,58). This affect has not been problematic at smaller doses (16,17,58).


   Conclusion
Top
 Abstract
 Introduction
 Conclusion
References
 
MNTX and alvimopan are effective in treating opioid-induced constipation, and alvimopan shortens the duration of POI and reduces PONV after laparotomy. These drugs do not affect opioid-induced analgesia and are easy to administer. Their potential efficacy in treating other opioid side effects remains unproven. The grail of opioid research has been to develop agonists with selective analgesic effects and decreased side effects, but the opioid compounds in clinical use have not been able to achieve success in this area. Pending the availability of as yet undiscovered µ-opioids or clinical availability of compounds, such as peripherally selective kappa-opioids, that may be effective analgesics and lack the side effects of the currently available opioid drugs, there is a role for the further development of peripheral opioid antagonists in improving patient care.


   References
Top
 Abstract
 Introduction
 Conclusion
 References
 

  1. Machelska H, Stein C. Immune mechanisms in pain control. Anesth Analg 2002; 95: 1002–81.[Free Full Text]
  2. Jones MP, Talley NJ, Nuyts G, Dubois D. Lack of objective evidence of efficacy of laxatives in chronic constipation. Dig Dis Sci 2002; 47: 2222–30.[ISI][Medline]
  3. Tramer MR, Reynolds JM, Moore RA, McQuay HJ. Efficacy, dose-response, and safety of Ondansetron in prevention of postoperative nausea and vomiting. Anesthesiology 1997; 87: 1277–89.[ISI][Medline]
  4. Gairola RL, Gupta PK, Pandley K. Antagonists of morphine-induced respiratory depression: a study in postoperative patients. Anaesthesia 1980; 35: 17–21.[ISI][Medline]
  5. Lehmann KA, Reichling U, Wirtz R. Influence of naloxone on the postoperative analgesic and respiratory effects of buprenorphine. Eur J Clin Pharmacol 1988; 34: 343–52.[ISI][Medline]
  6. Abou-madi MN, Chin SP, Yaboub JM, Keszler H. Effects of naloxone on postoperative analgesia. Anesth Analg (Paris) 1976; 33: 757–62.[Medline]
  7. Sykes NP. An investigation of the ability of oral naloxone to correct opioid-constipation in patients with advanced cancer. Palliat Med 1996; 10: 135–44.[Abstract/Free Full Text]
  8. Latasch L, Zimmermann M, Eberhardt B, Jurna I. Treatment of morphine-induced constipation with oral naloxone. Anaesthesist 1997; 46: 191–4.[ISI][Medline]
  9. Choi YS, Billings JA. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage 2002; 24: 71–90.[ISI][Medline]
  10. Yuan CS, Foss JF. Antagonism of gastrointestinal opioid side effects. Reg Anesth Pain Med 2000; 6: 639–42.
  11. Russell J, Bass P, Goldberg LI, et al. Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists. Eur J Pharmacol 1982; 78: 255–61.[ISI][Medline]
  12. Brown DR, Robertson MJ, Goldberg LI. Reversal of morphine-induced catalepsy in the rat by narcotic antagonists and their quaternary derivatives. Neuropharmacology 1983; 22: 317–21.[ISI][Medline]
  13. Ramabadran K. Effects of N-methylnaloxone and N-methyl-naltrexone on nociception and precipitated abstinence in mice. Life Sci 1982; 31: 1253–6.[ISI][Medline]
  14. Moerman I, Franck P, Camu F. Evaluation of methylnaltrexone for the reduction of postoperative vomiting and nausea incidences. Acta Anaesthesiol Belg 1995; 46: 127–32.[Medline]
  15. Yuan CS, Foss JF, O’Connor M, et al. Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study. Pain 1999; 83: 631–5.[ISI][Medline]
  16. Yuan CS, Foss JF. Oral methylnaltrexone for opioid-induced constipation. JAMA 2000; 284: 1383–4.[Free Full Text]
  17. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use. JAMA 2000; 283: 367–72.[Abstract/Free Full Text]
  18. Kotake AN, Kuwahara SK, Burton E, et al. Variations in demethylation of N-methylnaltrexone in mice, rats, dogs and humans. Xenobiotica 1989; 19: 1247–54.[ISI][Medline]
  19. Yuan CS, Foss JF, O’Connor M, et al. Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine. Drug Alcohol Depend 1998; 52: 161–5.[ISI][Medline]
  20. Zimmerman DM, Gidda JS, Cantrell BE, et al. Discovery of a potent, peripherally selective trans-3, 4-dimethyl-4-(3-hydroxyphenyl) piperidine opioid antagonist for the treatment of gastrointestinal motility disorders. J Med Chem 1994; 37: 2262–5.[ISI][Medline]
  21. Liu SS, Hodgson PS, Carpenter RL, Fricke JR. ADL 8-2698, a trans-3, 4- dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther 2000; 68: 66–71.
  22. Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997; 87: 765–70.[ISI][Medline]
  23. De Luca A, Coupar IM. Insights into opioid action in the intestinal tract. Pharmacol Ther 1996; 69: 103–15.[ISI][Medline]
  24. Levy MH. Pharmacological treatment of cancer pain. N Engl J Med 1996; 335: 1124–32.[Free Full Text]
  25. Glare P, Lickiss JN. Unrecognised constipation in patients with advanced cancer: a recipe for therapeutic disaster. J Pain Symptom Manage 1992; 7: 369–71.[ISI][Medline]
  26. Yuan CS, Foss JF, Osinski J, et al. The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time. Clin Pharmacol Ther 1997; 61: 467–75.[ISI][Medline]
  27. Yuan CS, Foss JF, O’Connor M, et al. Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time. Clin Pharmcol Ther 2000; 67: 398–404.[ISI][Medline]
  28. Bianchi G, Fiocchi R, Tavani A, Manara L. Quaternary narcotic antagonists relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity. Life Sci 1982; 30: 1875–83.[ISI][Medline]
  29. Yuan CS, Wei G, Foss JF, et al. Effects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial. J Pharmacol Exp Ther 2002; 300: 118–23.[Abstract/Free Full Text]
  30. Taguchi A, Sharma N, Rao MS, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001; 345: 935–40.[Abstract/Free Full Text]
  31. Costello DJ, Borison HL. Naloxone antagonizes narcotic self blockade of emesis in the cat. J Pharmacol Exp Ther 1977; 203: 222–30.[Abstract/Free Full Text]
  32. Andrews PLR. Physiology of nausea and vomiting. Br J Anaesth 1992; 69: 2S–19
  33. Racke K, Schworer H. Regulation of serotonin release from the intestinal mucosa. Pharmacol Res 1991; 23: 13–25.[ISI][Medline]
  34. Foss JF, Bass AS, Goldberg LI. Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs. J Clin Pharmacol 1993; 33: 747–51.[Abstract]
  35. Foss JF, Yuan CS, Roizen MF, Goldberg LI. Prevention of apomorphine or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine. Cancer Chemother Pharmacol 1998; 42: 287–91.[ISI][Medline]
  36. Greaves MW, Wall PD. Pathophysiology of itching. Lancet 1996; 348: 938–40.[ISI][Medline]
  37. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348: 1552–4.[ISI][Medline]
  38. Bergasa NV, Alling DW, Talbot TL, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomized, controlled trial. Ann Intern Med 1995; 123: 161–7.[Abstract/Free Full Text]
  39. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997; 113: 1264–9.[ISI][Medline]
  40. Gan TJ, Ginsberg B, Glass PS, et al. Opioid sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulphate. Anesthesiology 1997; 87: 1075–81.[ISI][Medline]
  41. Joshi GP, Duffy L, Chehade J, et al. Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia. Anesthesiology 1999; 90: 1007–11.[ISI][Medline]
  42. Kendrick WD, Woods AM, Daly MY, et al. Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus. Anesth Analg 1996; 82: 641–7.[Abstract]
  43. Wang JJ, Ho ST, Tzeng JI. Comparison of intravenous nalbuphine infusion versus naloxone in the prevention of epidural morphine-related side effects. Reg Anesth Pain Med 1998; 23: 479–84.[ISI][Medline]
  44. Saiah M, Borgeat A, Wilder-Smith OH, et al. Epidural-morphine-induced pruritus: propofol versus naloxone. Anesth Analg 1994; 78: 1110–3.[Abstract/Free Full Text]
  45. Abbound TK, Lee K, Zhu J, et al. Prophylactic oral naltrexone with intrathecal morphine for cesarean section: effects on adverse reactions and analgesia. Anesth Analg 1990; 71: 367–70.[Abstract/Free Full Text]
  46. 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. Br J Pharmacol 1988; 93: 93–100.[ISI][Medline]
  47. Foss JF, Orelind E, Goldberg LI. Effects of methylnaltrexone on morphine-induced cough suppression in guinea pigs. Life Sci 1996; 59:P L235–8.
  48. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol 2001; 96: 1266–72.[ISI][Medline]
  49. Krimmer H, Bullingham RE, Lloyd J, Bruch HP. Effects on biliary tract pressure in humans of intravenous ketorolac tromethamine compared with morphine and placebo. Anesth Analg 1992; 75: 204–7.[Abstract/Free Full Text]
  50. Bird KJ. Narcotic-induced choledochoduodenal sphincter spasm reversed by naloxone: a case report and review. Anaesthesia 1986; 41: 1120–3.[ISI][Medline]
  51. Butler KC, Selden B, Pollack CV Jr. Relief by naloxone of morphine-induced spasm of the sphincter of Oddi in a post-cholecystectomy patient. J Emerg Med 2001; 21: 129–31.[ISI][Medline]
  52. Rawal N, Mollefors K, Axelsson K, et al. An experimental study of urodynamic effects of epidural morphine and of naloxone reversal. Anesth Analg 1983; 62: 641–7.[Abstract/Free Full Text]
  53. Malinovsky JM, Le Normand L, Lepage JY, et al. The urodynamic effects of intravenous opioids and ketoprofen in humans. Anesth Analg 1998; 87: 456–61.[Abstract/Free Full Text]
  54. West JB. Control of ventilation. In: West JB, ed. Respiratory physiology: the essentials. 5th ed. Williams and Wilkins: Baltimore, 1995: 117–32.
  55. Amin HM, Sopchak AM, Foss JF, et al. Efficacy of methylnaltrexone versus naloxone for reversal of morphine-induced depression of hypoxic ventilatory response. Anesth Analg 1994; 78: 701–5.[Abstract/Free Full Text]
  56. Murphy DB, El Behiery H, Chan VW, Foss JF. Pharmacokinetic profile of epidurally administered methylnaltrexone, a novel peripheral opioid antagonist in a rabbit model. Br J Anaesth 2001; 86: 120–2.[Abstract/Free Full Text]
  57. Kueppers PM, Miller TA, Chen CY, et al. Effect of total parenteral nutrition plus morphine on bacterial translocation in rats. Ann Surg 1993; 217: 286–92.[ISI][Medline]
  58. Schmidt WK. Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg 2001; 182: 27S–38.[ISI][Medline]
Accepted for publication July 23, 2003.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bates, J. J.
Right arrow Articles by Murphy, D. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bates, J. J.
Right arrow Articles by Murphy, D. B.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press