TY - JOUR
T1 - Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine
AU - Doverty, Mark
AU - Somogyi, Andrew A.
AU - White, Jason M.
AU - Bochner, Felix
AU - Beare, Christopher H.
AU - Menelaou, Andrew
AU - Ling, Walter
N1 - Funding Information:
This investigation was partially supported by NIDA grant P50 DA 09260, and by the National Health and Medical Research Council of Australia. The authors would like to thank Yvonne Lungershausen and the staff of CMAX Pty Ltd (Drug Studies Unit), Royal Adelaide Hospital, Virginia Sharley and the production team of the Pharmacy Department, Royal Adelaide Hospital, for preparation of all drugs used in this study. Parts of this study have been presented at the 62nd Annual Scientific meeting of the College on Problems of Drug Dependence (CPDD), June 2000, San Juan, Puerto Rico. M.D. is the recipient of a Postgraduate Research scholarship awarded by the Drug and Alcohol Services Council of South Australia, and also a travel fellowship awarded by the Research Committee, Faculty of Health Sciences, Adelaide University.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Antinociception
KW - Cold pressor test
KW - Cross-tolerance
KW - Hyperalgesia
KW - Methadone maintenance treatment
KW - Plasma morphine
UR - https://www.scopus.com/pages/publications/0034972499
U2 - 10.1016/S0304-3959(01)00306-2
DO - 10.1016/S0304-3959(01)00306-2
M3 - Article
C2 - 11427327
AN - SCOPUS:0034972499
SN - 0304-3959
VL - 93
SP - 155
EP - 163
JO - Pain
JF - Pain
IS - 2
ER -