Animal studies have demonstrated that co-administration of an ultra-low-dose opioid antagonist with an opioid agonist may result in enhanced analgesia. Investigation of this effect in humans has been limited and produced inconsistent findings, with previous reports suggesting that dose ratio may be critical to analgesic potentiation. The aim of the current 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 was significantly greater with the combination of buprenorphine and naloxone compared to buprenorphine alone, and this effect was dose ratio dependent. Importantly, this enhanced analgesia occurred without an increase in adverse effects; indeed at some ratios, respiratory depression was attenuated. These findings demonstrate that the addition of ultra-low-dose naloxone can enhance the analgesic effect of buprenorphine in humans without a concurrent increase in side effects.