Pain response to cannabidiol in opioid-induced hyperalgesia, acute nociceptive pain, and allodynia using a model mimicking acute pain in healthy adults in a randomized trial (CANAB II)

Markus Dieterle, Laura Zurbriggen, Eckhard Mauermann, Katja Mercer-Chalmers-Bender, Priska Frei, Wilhelm Ruppen, Tobias Schneider, Markus Dieterle, Laura Zurbriggen, Eckhard Mauermann, Katja Mercer-Chalmers-Bender, Priska Frei, Wilhelm Ruppen, Tobias Schneider

Abstract

Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm 2 [8.1-28.7] vs 25.3 cm 2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 μg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations.

Trial registration: ClinicalTrials.gov NCT04059978.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Copyright © 2022 International Association for the Study of Pain.

Figures

Figure 1.
Figure 1.
Participant randomization scheme CBD, cannabidiol.
Figure 2.
Figure 2.
Schematic illustration of experimental setup. CBD, cannabidiol;NRS, numeric rating scale.
Figure 3.
Figure 3.
Outcome variable of intradermal electrical stimulation over time. All values are represented as box-plots (whiskers display minimum and maximum values). CBD, cannabidiol; NRS, numeric rating scale.
Figure 4.
Figure 4.
The left panel shows the relationship between the measured CBD concentration at the time point 200 minutes with the average pain score (NRS), area of hyperalgesia, and allodynia over time. The right panel shows the relationship between the measured CBD concentration at the time point 200 minutes with the pain score (NRS), area of hyperalgesia, and area of allodynia at the same time point (200 min). CBD, cannabidiol; conc, concentration; NRS, numeric rating scale; r, Pearson correlation coefficient.

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