Intravenous Remifentanil Produces Withdrawal Hyperalgesia in Volunteers with Capsaicin-Induced Hyperalgesia

Abstract

In Brief Opioids administered during surgery may be beneficial by preempting postoperative pain or detrimental by causing acute tolerance. We used a stable model of hyperalgesia in volunteers to test whether acute opioid exposure also results in such pain sensitization over a period of hours in humans. Ten healthy volunteers were studied. Areas of mechanical hyperalgesia and allodynia were induced by topical capsaicin application plus intermittent heating. Computer-controlled IV remifentanil infusion was titrated to a targeted plasma concentration that reduced pain report to noxious heat by 70% and was maintained at this level for 60–100 min. Areas of hyperalgesia and allodynia were measured during and after remifentanil infusion. Remifentanil (targeted concentration of 3.1 ± 1.2 ng/mL) reduced areas of hyperalgesia and allodynia by 33% ± 31% and 65% ± 28%, respectively, during infusion (P < 0.05). Areas of hyperalgesia and allodynia continuously enlarged 4 h after remifentanil was stopped, to 180% ± 47% and 180% ± 86%, respectively. This study demonstrates that acute opioid exposure enhances hypersensitivity for hours after exposure. If applicable to the surgical setting, this could increase the dose of opioid required for postoperative analgesia and enhance, rather than inhibit, postoperative pain. IMPLICATIONS: Remifentanil infusion in normal volunteers acutely reduces hypersensitivity induced by capsaicin, but after cessation of remifentanil infusion, hypersensitivity increases beyond baseline, consistent with growing animal and human literature suggesting that acute exposure to opioids, such as during surgery, can exacerbate subsequent pain.