Morphine- and buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain model: a double-blind, randomized, placebo-controlled, five-arm crossover study

Pernille Ravn,¹ Erik L Secher,² Ulrik Skram,³ Trine Therkildsen,¹ Lona L Christrup,¹ Mads U Werner<sup>4

1</sup>Department of Drug Design and Pharmacology, University of Copenhagen, ²Department of Anesthesiology, Juliane Marie Center, Rigshospitalet, Copenhagen University Hospitals, ³Department of Intensive Care, Gentofte Hospital, Copenhagen University Hospitals, ⁴Multidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark

Purpose: Opioid therapy is associated with the development of tolerance and paradoxically increased sensitivity to pain. It has been suggested that buprenorphine is associated with a higher antihyperalgesia/analgesia ratio than µ-opioid receptor agonists. The primary outcome of this study was therefore to investigate relative differences in antihyperalgesia and analgesia effects between morphine and buprenorphine in an inflammatory pain model in volunteers. The secondary outcome was to examine the relationship between pain sensitivity and opioid-induced effects on analgesia, antihyperalgesia, and descending pain modulation.
Subjects and methods: Twenty-eight healthy subjects were included. The study was a double-blind, randomized, placebo-controlled, five-arm crossover study with a multimodal (electrical, mechanical, and thermal stimuli) testing technique. After baseline assessments, intravenous infusions of morphine (10/20 mg), buprenorphine (0.3/0.6 mg), or placebo (normal saline) were administered over a 210-minute period, during which a cold pressor test, heat injury (47°C, 7 minutes, 12.5 cm²), and the first postburn assessment were done. After completion of the drug infusions, two additional postburn assessments were done. The subjects were monitored during each 8-hour session by an anesthesiologist.
Results: For nearly all tested variables, significant dose-dependent analgesic effects were demonstrated. The median antihyperalgesia/analgesia ratio (secondary hyperalgesia/heat injury relative to placebo) for low-dose morphine was 0.01 (interquartile range: −6.2; 9.9), 0.00 (−2.4; 2.1) for high-dose morphine, 0.03 (−1.8; 2.1) for low-dose buprenorphine, and 0.00 (−3.2; 1.1) for high-dose buprenorphine (P > 0.466). There were no significant differences in opioid responses between high and low pain-sensitive subjects (P > 0.286). High-dose buprenorphine, compared to placebo, was associated with a significantly enhanced action of the descending inhibitory pain control system (P = 0.004).
Conclusion: The present study, using multimodal testing technique, could not demonstrate any significant differences between morphine and buprenorphine in the profiles of antihyperalgesia and analgesia. Only high-dose buprenorphine was associated with a significant effect on the descending inhibitory pain control system.

Keywords: analgesia, antihyperalgesia, experimental pain, opioid, pain sensitivity, randomized trial