Peripheral opioid analgesia in experimental human pain models

This placebo‐controlled, double‐blind crossover study assessed whether exclusive activation of peripheral opioid receptors results in significant pain reduction. To achieve opioid activity restricted to the periphery, we used a short‐term (2 h) low dose infusion of morphine‐6‐β‐glucuronide (M6G) because M6G does not pass the blood–brain barrier during this time in amounts sufficient to induce CNS effects. The lack of central opioid effects of M6G was confirmed by a lack of change of the pupil size and absence of other opioid‐related CNS effects. As a positive control, morphine was infused at a dosage that definitely produced CNS effects. This was evident by a rapid decrease of the pupil size and by other typical opioid‐related side effects including nausea, vomiting, itchiness, hiccup and sedation. Three different pain models were employed to evaluate the analgesic effects: (i) cutaneous inflammatory hyperalgesia induced by briefly freezing a small skin area to –30°C (‘freeze lesion’); (ii) muscle hyperalgesia induced by a series of concentric and eccentric muscle contractions (DOMS model; delayed onset of muscle soreness); and (iii) pain induced by electrical current (5 Hz sinus stimuli of 0–10 mA). M6G significantly reduced cutaneous hyperalgesia in the ‘freeze lesion’ model as assessed with von Frey hairs. It also reduced muscle hyperalgesia in the DOMS model. Electrical pain, however, was not affected by M6G. Morphine was significantly more active in the ‘freeze lesion’ and DOMS model, and also significantly increased the electrical pain threshold and tolerance. Subcutaneous tissue concentrations of M6G and morphine as assessed with microdialysis were about half those of the respective plasma concentrations. The results of the study indicate that M6G has antihyperalgesic effects in inflammatory pain through activation of peripheral opioid receptors. Since this occurs at concentrations that do not cause central opioid effects, M6G might be useful as a peripheral opioid analgesic.