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

Abstract

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 cm(2)), 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.

Figures

Figure 1

Study algorithm (the order of the tests in the baseline assessments are as listed in the table). Abbreviations: CDT, cool detection threshold; EDT, electrical detection threshold; EPT, electrical pain threshold; EPTo, electrical pain tolerance; HPT, heat pain threshold; WDT, warmth detection threshold.

Figure 2

Participant flow-diagram. Notes: Participant flow-diagram of the study illustrating patient enrollment, inclusion, the two study days and analysis. The intention-to-treat (ITT) and per-protocol (PP) groups were 33/33 (females/males) and 13/14, respectively.

Figure 3

CPM-efficiency. Notes: The conditioned pain modulation (CPM) efficiency with repeated phasic heat stimuli (47°C, 4 s [1,3,4,5]) in relation to submersion of the non-dominant hand (2) in the cold pressor test (CPT [0.3°C–0.5°C, 30 s]). During the phasic heat stimuli, the subjects rated their maximal pain on a visual analog scale (VAS [0–10]).

Figure 4

Drug effect and drug like. Note: Drug effect and drug like scores for placebo, morphine and buprenorphine (low- and high-doses). *P < 0.005, **P < 0.001, ***P < 0.0001. Abbreviations: DE, drug effect; DL, drug like.

Figure 5

Electrical pain threshold and electrical pain tolerance. Notes: Electrical pain threshold and electrical pain tolerance for baseline, postburn 1–3 assessments and mean postburn assessments. The asterisks on baseline values indicates differences between baseline and its respective mean postburn value, while asterisks on mean postburn values indicate differences between the five sessions mean postburn assessments. Abbreviations: EPT, Electrical pain threshold; EPTo, electrical pain tolerance; Mean PB, mean of PB1, PB2 and PB3; PB1, 1 hour postburn; PB2, 2 hours postburn; PB3, 3 hours postburn.

Figure 6

Cool detection threshold and heat pain threshold. Notes: Cool Detection Threshold (CDT) and Heat Pain Threshold (HPT) for baseline, postburn 1–3 (PB1-3) and mean postburn (mean PB) assessments. The asterisks on baseline values indicate differences between baseline and its respective mean postburn value while asterisks on mean postburn values indicate differences between the five sessions mean postburn assessments. Abbreviations: CDT, cool detection threshold; HPT, heat pain threshold; Mean PB, mean of PB1, PB2 and PB3; PB1, 1 hour postburn; PB2, 2 hours postburn; PB3, 3 hours postburn.

Figure 7

Accumulated visual analog scale scores during heat injury. Notes: Accumulated VAS scores [0–10] during the heat injury. *P < 0.005, **P < 0.001, ***P < 0.0001. Abbreviation: VAS, visual analog scale.

Figure 8

Pressure algometry. Notes: Pressure pain tolerance before and after the cold pressor test, and delta pressure pain tolerance. *P < 0.005, **P < 0.001, ***P < 0.0001. Abbreviations: PTo1, pressure pain tolerance before CPT; PTo2, pressure pain tolerance after CPT; ΔPTo = PTo2 – PTo1.

Figure 9

Cold pressor test. Notes: Cold pressor test with registration of cold pressor pain and cold pressor tolerance. *P < 0.005, **P < 0.001, ***P < 0.0001. Abbreviations: CPP, cold pressor pain; CPT, cold pressor test; CPTo, cold pressor tolerance.

Figure 10

Conditioned pain modulation. Notes: Visual analog scale scores (0–10) during the test for CPM-efficiency. (Statistics only performed on ΔCPM). *P < 0.005, **P < 0.001, ***P < 0.0001. Abbreviations: CPM1, conditioned pain modulation rating before the cold pressor test; CPM2, conditioned pain modulation rating during the cold pressor test; CPM3, conditioned pain modulation rating 12 seconds after the cold pressor test; CPM4, conditioned pain modulation rating 24 seconds after the cold pressor test; ΔCPM, conditioned pain modulation efficiency; VAS, visual analog scale.

Figure 11

Secondary hyperalgesia areas. Note: Secondary hyperalgesia areas, in the three postburn assessments (PB1-3) and mean postburn values. Abbreviations: Mean PB, mean of PB1, PB2 and PB3; PB1, 1 hour postburn; PB2, 2 hours postburn; PB3, 3 hours postburn.

Figure 12

Anti-hyperalgesia and analgesia. Notes: Placebo-corrected differences for the active treatments in secondary hyperalgesia areas (Δ2HA[%], upper panel), pain-ratings during the heat injury (ΔPHI[%], middle panel), and electrical pain thresholds (ΔEPTo[%], lower panel). Columns are median (IQR). The anti-hyperalgesia/analgesia ratios (Δ2HA/ΔPHI and Δ2HA/ΔEPTo) for the four opioids relative to placebo. Abbreviations: Δ2HA(%), secondary hyperalgesia area relative to placebo; ΔPHI(%), heat injury relative to placebo; ΔEPTo(%), electrical pain tolerance relative to placebo; 2HA/PHI, ratio (secondary hyperalgesia/heat injury) relative to placebo; 2HA/EPTo, ratio (secondary hyperalgesia/electrical pain tolerance) relative to placebo; IQR, inter-quartile range