Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine.
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 (C(SS1) and C(SS2)), 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 C(SS1) and C(SS2) 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.
Doverty
Mark
M
Department of Clinical and Experimental Pharmacology, Adelaide University, Adelaide, SA 5005, Australia Drug and Alcohol Services Council of South Australia, 161 Greenhill Road, Parkside, SA 5063, Australia Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia Integrated Substance Abuse Programs, University of California, 11075 Santa Monica Boulevard #200, Los Angeles, CA 90025, USA.
Somogyi
Andrew A
AA
White
Jason M
JM
Bochner
Felix
F
Beare
Christopher H
CH
Menelaou
Andrew
A
Ling
Walter
W
D000208:Acute Disease; D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000097:blood; D003080:Cold Temperature; D004347:Drug Interactions; D004361:Drug Tolerance; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy; D007275:Injections, Intravenous; D008297:Male; D008691:Methadone / Q000009:adverse effects* / Q000097:blood; D009020:Morphine / Q000008:administration & dosage* / Q000097:blood; D009619:Nociceptors / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects
D000701:Analgesics, Opioid; D009020:Morphine; D008691:Methadone