title: Peripheral opioid receptor blockade increases postoperative morphine demands--a randomized, double-blind, placebo-controlled trial.
abstract: Experimental studies suggest that a large proportion of opioid analgesia can be mediated by peripheral opioid receptors. This trial examined the contribution of such receptors to clinical analgesia induced by intravenous morphine. We hypothesized that the selective blockade of peripheral opioid receptors by methylnaltrexone (MNX) would increase the patients' demand for morphine to achieve satisfactory postoperative pain relief. In a double-blind, placebo-controlled, sequential 2-center trial, 50 patients undergoing knee replacement surgery were randomized (1:1) to receive either subcutaneous MNX (0.9 mg/kg) (hospital I: n=14; hospital II: n=11) or saline (hospital I: n=13; hospital II: n=12) at the end of surgery. The primary endpoint was the cumulative amount of intravenous morphine administered during the first 8 hours. Secondary endpoints were pain scores at rest and during movement (by numerical rating scale and McGill Questionnaire), vital signs, adverse side effects, and withdrawal symptoms. After MNX, demands for morphine were strongly (by about 40%) increased (hospital I: 35.31 ± 12.99 mg vs 25.51 ± 7.92 mg, P=0.03; hospital II: 35.42 ± 11.73 mg vs 24.80 ± 7.84 mg, P=0.02; pooled data: P<.001; means ± SD). Secondary endpoints were similar in all groups (P>.05). Thus, a significant proportion of analgesia produced by systemically administered morphine is mediated by peripheral opioid receptors. Drugs that selectively activate such receptors should have the potential to produce powerful clinical pain relief.
authors.affiliation: Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité, Campus Benjamin Franklin, Freie Universität Berlin, Berlin, Germany; Helmholtz Virtual Institute Multifunctional Biomaterials for Medicine, Teltow, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Jagla
authors.affiliation: Institut für Klinische Epidemiologie und Angewandte Biometrie, Universität Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Martus
authors.affiliation: Klinik für Anaesthesiologie und Operative Intensivmedizin, Charité, Campus Benjamin Franklin, Freie Universität Berlin, Berlin, Germany; Helmholtz Virtual Institute Multifunctional Biomaterials for Medicine, Teltow, Germany. Electronic address: christoph.stein@charite.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016058:Analgesia, Patient-Controlled; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000627:therapeutic use*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010147:Pain Measurement; D010149:Postoperative Pain / Q000188:drug therapy* / Q000209:etiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009271:Naltrexone; D009020:Morphine
keywords: Analgesia; Methylnaltrexone; Morphine; Opioid receptor; Opioids; Peripheral