Drug and Alcohol Dependence 52 (1998) 161–165 Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine Chun-Su Yuan *, Joseph F. Foss, Michael O’Connor, Joachim Osinski, Michael F. Roizen, Jonathan Moss Committee on Clinical Pharmacology and the Department of Anesthesia and Critical Care, The Pritzer School of Medicine, The Uniersity of Chicago, Chicago, IL 60637, USA Received 15 January 1998; accepted 2 April 1998 Abstract Opioid compounds are commonly used analgesics. After opioid administration, troublesome subjective effects, such as dysphoria, dizziness, nausea, and pruritus, have been reported. While some if not all of these are believed to occur due to central nervous system effects of opioids, the anecdotal reports heard from volunteers in our other studies suggest that a peripheral opioid antagonist reduced some of these effects. In this double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone, a selective peripheral opioid receptor antagonist, to decrease subjective effects after administering morphine to normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on ‘nauseous’, ‘skin itch’, ‘stimulated’, and ‘flushing’. Oral methylnaltrexone 19.2 mg/kg significantly decreased these four ratings. Plasma methylnaltrexone concentrations at two different oral doses were also measured to correlate between pharmacological effects of the compound and its plasma levels. Our results suggested that methylnaltrexone has a potential therapeutic value in decreasing some undesirable subjective effects associated with opioid medications. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Opioids; Morphine; Methylnaltrexone; Subjective effects; Dysphoria 1. Introduction Opioid compounds are widely used analgesics. However, their administration is associated with a number of side effects, including constipation, emesis, and troublesome subjective effects, such as dysphoria, dizziness, nausea, and pruritus (Lasagna et al., 1955; Smith and Beecher, 1962). In the last two decades, significant progress has been achieved in our under- standing of the mechanisms of action of opioids, but these advances have yielded few new approaches to the management of opioid side effects. Methylnaltrexone is a novel quaternary methylated opioid antagonist that does not cross the blood brain barrier (Brown and Goldberg, 1985). This compound has the potential to antagonize the peripherally medi- ated side-effects of opioid medication without inter- fering with analgesia. Using an isolated gut smooth muscle strip preparation, we observed that methylnal- trexone reversed morphine-induced inhibition of con- traction in both guinea-pig ileum and human small intestine (Yuan et al., 1995), indicating that periph- eral opioid gut effect can be blocked by this com- pound. Results from our previous human volunteer study demonstrated that intravenous methylnaltrexone prevented morphine-induced changes in gastrointesti- nal motility and transit without affecting analgesia (Yuan et al., 1996), suggesting that methylnaltrexone may have a clinical value in the prevention and treat- ment of opioid-induced peripherally mediated side ef- fects. * Corresponding author. Tel.: +1 773 7021916; fax: +1 773 8340601; e-mail: cyuan@midway.uchicago.edu 0376-8716/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(98)00087-8