Hyperalgesic responses in methadone maintenance patients

Copyright © 2001 International Association for the Study of Pain. Published by Elsevier Science B.V.Opioid substitution treatment for dependence may alter sensitivity to pain. Previous studies on pain sensitivity in methadone maintenance patients have yielded contradictory results. This study compared nociceptive responses between 16 patients on stable, once daily, doses of methadone and 16 matched control subjects. Two types of nociceptive stimuli were used: (1) electrical stimulation; and (2) a cold pressor test. Two parameters were measured: detection for onset of pain, and pain tolerance. Methadone patients were tested over an inter-dosing period: at the time of trough plasma methadone concentration (0 h), and 3 h after their daily dose. Control subjects were tested twice 3 h apart. Blood samples were collected to determine plasma methadone concentration. In methadone patients, trough to peak increases in mean R-(−)- and S-(+)-methadone concentrations (118 and 138 ng/ml to 185 and 259 ng/ml, respectively) resulted in significant increases in pain detection and tolerance values for both nociceptive stimuli. Using electrical stimulation, methadone patients' pain tolerance values were lower than controls at 0 h, but higher than controls at 3 h; no significant differences in pain detection values were found. For the cold pressor test, methadone patients detected pain significantly earlier than controls at 0 h, and were also substantially less pain tolerant than controls at both 0 and 3 h. There were no significant differences in pain detection values between the two groups at 3 h. Pain tolerance to pain detection ratios for methadone patients were significantly lower than controls for the cold pressor test at 0 and 3 h, and for electrical stimulation at 0 h only. In summary, the relative pain sensitivity of methadone maintenance patients is determined by the nature of the nociceptive stimulus (e.g. cold pressor test versus electrical stimulation), the plasma methadone concentration (trough versus peak plasma concentration), and whether thresholds are determined for detection of pain or pain tolerance. Although responding to changes in plasma methadone concentration, maintenance patients are markedly hyperalgesic to pain induced by the cold pressor test.Mark Doverty, Jason M. White, Andrew A. Somogyi, Felix Bochner, Robert Ali and Walter Linghttp://www.elsevier.com/wps/find/journaldescription.cws_home/506083/description#descriptio

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 (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.Mark Doverty, Andrew A. Somogyi, Jason M. White, Felix Bochner, Christopher H. Beare, Andrew Menelaou and Walter Lin