ArticleMethadone maintenance patients are cross-tolerant to the antinociceptive effects of morphineDoverty, Marka,*; Somogyi, Andrew A.a,c; White, Jason M.a,b; Bochner, Felixa,c; Beare, Christopher H.c; Menelaou, Andrewa; Ling, WalterdAuthor Information aDepartment of Clinical and Experimental Pharmacology, Adelaide University, Adelaide, SA 5005, Australia bDrug and Alcohol Services Council of South Australia, 161 Greenhill Road, Parkside, SA 5063, Australia cDepartment of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia dIntegrated Substance Abuse Programs, University of California, 11075 Santa Monica Boulevard #200, Los Angeles, CA 90025, USA *Corresponding author. Tel.:+61-8-8303-5188; fax: +61-8-8224-0685 E-mail: [email protected] Received 14 November 2000; received in revised form 15 February 2001; accepted 20 February 2001. Pain: August 2001 - Volume 93 - Issue 2 - p 155-163 doi: 10.1016/S0304-3959(01)00306-2 Buy Metrics Abstract We have previously shown that methadone maintenance patients are hyperalgesic. Very little is known about the antinociceptive effects of additional opioids in these patients. This study (1) compared the intensity and duration of antinociceptive responses, at two pseudo-steady-state plasma morphine concentrations (CSS1 and CSS2), between four patients on stable, once daily, doses of methadone and four matched control subjects; and (2) determined, in methadone patients, whether the antinociceptive effects of morphine are affected by changes in plasma R(−)-methadone concentration that occur during an inter-dosing interval. Two types of nociceptive stimuli were used: (1) a cold pressor test (CP), (2) electrical stimulation (ES). Morphine was administered intravenously to achieve the two consecutive plasma concentrations. Blood samples were collected, concurrently with nociceptive responses, to determine plasma morphine concentrations. Methadone patients achieved mean CSS1 and CSS2 of 16 and 55 ng/ml respectively; those of controls were 11 and 33 ng/ml. Methadone patients were hyperalgesic to pain induced by CP but not ES. Despite significantly greater plasma morphine concentrations, methadone patients experienced minimal antinociception in comparison with controls. Furthermore in methadone patients, the antinociception ceased when the infusion ended. In comparison, the duration of effect in control subjects was 3 h. The fluctuations that occurred in plasma R(−)-methadone concentration during an inter-dosing interval had little effect on patients’ responses to morphine. Our findings suggest that methadone patients are cross-tolerant to the antinociceptive effects of morphine, and conventional doses of morphine are likely to be ineffective in managing episodes of acute pain amongst this patient group. Further research is needed to determine whether other drugs are more effective than morphine in managing acute pain in this patient population. © 2001 Lippincott Williams & Wilkins, Inc.