Enhanced Buprenorphine Analgesia with the Addition of Ultra‐low‐dose Naloxone in Healthy Subjects

Animal studies have demonstrated that co-administration of an ultra-low-dose opioid antagonist with an opioid agonistmay result in enhanced analgesia. Investigation of this effect in humans has been limited and produced inconsistentfindings, with previous reports suggesting that dose ratio may be critical to analgesic potentiation. The aim of thecurrent investigation was to determine whether buprenorphine analgesia could be enhanced with the addition of ultra-low-dose naloxone among healthy volunteers, using a range of dose ratios. Tolerance to cold pressor pain wassignificantly greater with the combination of buprenorphine and naloxone compared to buprenorphine alone, andthis effect was dose ratio dependent. Importantly, this enhanced analgesia occurred without an increase in adverseeffects; indeed at some ratios, respiratory depression was attenuated. These findings demonstrate that the additionof ultra-low-dose naloxone can enhance the analgesic effect of buprenorphine in humans without a concurrent increasein side effects.While opioids are the most widely used class of drugs for thetreatment of moderate to severe pain, their use is compro-mised by unpleasant and potentially dangerous adverseeffects, the development of tolerance and physical depen-dence, as well as concerns regarding abuse liability. No viablealternatives to opioids have been developed, nor have anyopioids been found that are effective analgesics but withoutthese problems. One strategy to minimize the problemsassociated with opioid use is to co-administer a second drugthat may enhance the analgesic effects of the opioid and/orminimize its adverse effects.Early studies reported a reduction in opioid side effectswith the addition of low-dose opioid antagonist to opioidagonist administration.