A history of substance abuse is considered by many to be a contraindication to chronic opioid therapy for nonmalignant pain. Twenty patients with a history of chronic nonmalignant pain and substance abuse treated with chronic opioid therapy for a period of more than 1 year were retrospectively evaluated to determine the factors associated with prescription abuse. The prevalence of six aberrant behavioral patterns was assessed to see if these correlated with a history of prescription abuse, as reported by the patient's pain clinic physician. Those who did not abuse opioid therapy were more likely to have a history of alcohol abuse alone or a remote history of polysubstance abuse. They were also more likely to be active members of Alcoholics Anonymous and to have a stable family or other similar support system. In contrast, those who abused opioid therapy showed characteristic aberrant patterns of behavior in their management, which indicated a clear pattern of prescription abuse early in the course of therapy. Those patients were more likely to be recent polysubstance abusers, or have a prior history of oxycodone abuse. None of them were active members of Alcoholics Anonymous. Signing an "opioids contract" was not in and of itself a predictor of successful outcome.

Chronic spinal MK801 attenuates tolerance to, and withdrawal from spinal morphine in a dose-dependent fashion, supporting the hypothesis that N-methyl-D-aspartate receptor activity plays a role in the reorganization of spinal function produced by chronic opioid receptor activation. Chronic intrathecal MK801 appears to sensitize the spinal cord to intrathecal morphine.

The magnitude of tolerance and dependence is defined in part by agonist concentration and duration of receptor exposure. Therefore, in the face of continued exposure to an opioid agonist, periodic reduction in opiate receptor occupancy should reduce tolerance. Alternately, we have shown that reversal of opiate agonist action yields increased glutamate release and NMDA-antagonist studies indicated that this release may lead to an exacerbation of tolerance. To address this issue, we observed the effect of transient daily antagonism by naloxone of otherwise continuous opioid receptor exposure on morphine tolerance development. Rats with intrathecal (i.t.) catheters and osmotic minipumps were assigned to one of the following 7-day infusion/treatment groups: group A: i.t. morphine (20 nmol/h) with daily subcutaneous (s.c.) injection of naloxone 0.6 mg/kg, group B: i.t. morphine (20 nmol/h) with daily s.c. saline, group C: i.t. saline (1 microl/h) with daily s.c. injection of naloxone 0.6 mg/kg, or, group D: i.t. saline (1 microl/h) with daily s.c. saline. Hot plate response latency was measured daily before and after the s.c. injection. The infusion was discontinued on day 7 and on day 8 the response of the rat to a probe dose of i.t. morphine (60 nmol) given as a bolus was observed. Elevated hot plate latencies were observed for groups A and B on day 1 of infusion and this declined over the following 3-4-day interval. Group B approached baseline, but by day 5 group A showed a mild hyperalgesia prior to each naloxone injection. Groups C and D showed no change in baseline latency. On day 8, 24 h after termination of morphine infusion, the magnitude of the analgesic response to the probe i.t. morphine was: group D = group C > group B > group A (P < 0.05, 1-way ANOVA). Thus, in contrast to the expectation that tolerance would be reduced by periodic blockade of opiate receptor occupancy, rats that had daily transient receptor antagonism showed a greater tolerance than rats with simple continuous receptor occupancy. These results are, however, consistent with work showing that (i) naloxone will evoke spinal glutamate release in spinal morphine tolerant rats and (ii) spinal NMDA receptor antagonism ameliorates loss of opiate effect in this spinal infusion model.

Because of remifentanil's unique pharmacokinetics, its systemic administration may be suitable for clinical settings where a potent, fast-acting, systemic mu-opioid with a rapid recovery is required, e.g., short painful intervention in the emergency room or the intensive care unit, or procedures in the day surgery or endoscopy suite. Total intravenous anesthesia for longer lasting procedures may become more promising because of the predictability of the offset of remifentanil even after long infusions. Its closest competitor, alfentanil, depends on its small volume of distribution for rapid termination of its effect, but still possesses the potential to accumulate because of its relatively long terminal elimination half-life. Remifentanil might be the first potent mu-opioid that does not accumulate in this fashion, and therefore it opens promising new clinical perspectives (52). However, as mentioned above, the relative short-lasting analgesic effect after cessation of the remifentanil infusion might require new, sophisticated techniques from the anesthetist to prevent immediate onset of postoperative pain.