Background & Aims
As awareness of insufficient pain management from long-term pharmacological treatment increases, interest in non-pharmacological approaches to treat chronic pain is also on the rise. Whereas meditation and breathing-related pain management strategies have been reported to rely on non-opioid brain mechanisms, hypoalgesic effects from treatment with placebo, acupuncture and repeated transcranial magnetic stimulation (rTMS) are believed to result from opioidergic neurotransmission [1–4]. Here, we used a set of meta-regressions to test the conditions associated with endogenous opioid analgesia, as revealed by increased pain ratings or decreased pain threshold/tolerance after antagonist treatment, taking into account the sources of heterogeneity (e.g., non-drug interventions, pain modality).
Methods
We conducted a systematic review and meta-analysis of experimental pain studies using an opioid antagonist in healthy humans, searching Web of Science, Scopus, PubMed and EMBASE. Eligible studies were at least double-blind, randomized, and placebo-controlled, used physiological pain interventions, and administered a centrally active ?-opioid receptor antagonist. Quality assessment and funnel plots were used to evaluate risk of bias. To compare drug effects on pain, we calculated Hedges’ g for individual outcomes and estimated the summary effect with a three-level random effects meta-regression. The primary analysis focused on the effect of opioid blockade on pain ratings (intensity, tolerance, unpleasantness, threshold). A secondary set of meta-regressions was conducted to test under which conditions full mu-opioid blockade affects pain perception, considering pain modality, pain location, duration and non-drug interventions.
Results
A total of 60 studies (n = 2011) were included. Opioid antagonism significantly increased all pain measures (intensity, unpleasantness, pain threshold and tolerance) but the main effect was small (g=0.15-0.21) and with considerable heterogeneity (I2 = 77.2%). Estimated effects of medium or large size (g?0.5) were only found for the placebo (g [95% CI]=0.7[0.5-0.9]), acupuncture (g=0.5[0.1-0.9] and rTMS (g=1.1[0.8-1.4]) categories. The evidence indicated little or no contribution of endogenous opioids to meditation/relaxation strategies (g=0[-0.3-0.2], nor to conditioned pain modulation (g=0.1[-0.1-0.3]). Neither pain modality, location or duration added explanatory variance to the models (all R2=0% with Hedge’s g < 0.5).
Conclusions
The overall effect of opioid antagonism on pain perception was in the hypothesized direction but small and with a large amount of heterogeneity. The small increase in pain sensitivity during experimental pain in healthy humans after full endogenous opioid blockade is therefore more consistent with endogenous opioid fine-tuning rather than full regulation of the subjective experience of pain. Our results support previous literature indicating that hypoalgesic effects from placebo, acupuncture and rTMS are relying on endogenous opioid transmission, suggesting an underlying mechanism for these non-pharmacological treatments of acute and chronic pain. Other modalities such as pain location, duration or type did not add explanatory variance to our models.
References
[1] de Andrade DC, Mhalla A, Adam F, Texeira MJ, Bouhassira D. Neuropharmacological basis of rTMS-induced analgesia: The role of endogenous opioids. Pain 2011;152:320–326.
[2] Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, Büchel C. Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia. Neuron 2009;63:533–543.
[3] Sirucek L, Price RC, Gandhi W, Hoeppli M-E, Fahey E, Qu A, Becker S, Schweinhardt P. Endogenous opioids contribute to the feeling of pain relief in humans. Pain 2021;162:2821–2831.
[4] Zhang R, Lao L, Ren K, Berman BM. Mechanisms of Acupuncture–Electroacupuncture on Persistent Pain. Anesthesiology 2014;120:482–503.
Presenting Author
Isabell M. Meier
Poster Authors
Topics
- Systematic Reviews/Meta-Analysis