Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study

Abstract

Hyperalgesia has been demonstrated to be a cardinal sign of physical withdrawal from opioids in preclinical models for more than 30 years, although few empirical data exist to support its occurrence in humans. In this preliminary study we used the acute opioid physical dependence (APD) model to test for the presence of hyperalgesia to experimental cold-pressor pain in 4 healthy non-opioid-dependent men via 3 different pretreatment opioid administration protocols previously demonstrated to induce APD (morphine 18 mg/70 kg intramuscular, morphine 10 mg/70 kg intravenous, hydromorphone 2 mg/70 kg intravenous), repeated on 2 separate occasions, and placebo. Cold-pressor pain threshold and tolerance were examined before opioid administration and 5 and 15 minutes after precipitated withdrawal with naloxone 10 mg/70 kg intravenous. Paired t tests comparing change scores between the opioid pretreatments and placebo showed that pain threshold and tolerance to the cold-pressor uniformly decreased across all APD induction methods, and the effect size was large (approximately 70% of baseline) and reproducible. These findings provide initial support for the existence of opioid-induced hyperalgesia, which has been conceptualized as a coexisting opponent process to opioid-induced analgesia and proposed to be an alternative explanation for the development of analgesic tolerance to opioids.