Background & Aims

Endogenous opioids are thought to downregulate pain and stress and to underpin positive mood, pleasure and social bonding across species (1,2,3). However, when endogenous opioid function is blocked systemically via antagonist treatment (naloxone, naltrexone), pain measures are not consistently increased in either humans or rodents (4). Certain conditions must be met before pharmacological blockade unveils a role of endogenous opioids for pain. One possible explanation is that systemic drugs bind indiscriminately to opioid receptors, which are arranged in microcircuits shown in preclinical studies to regulate not just pain, but circuits that shape reward-related behaviours such as feeding or social bond formation (2,3). Here, we use meta-analysis to compare effects of systemic opioid antagonism on ratings of pain versus social connectedness.

Methods

We conducted two pre-registered meta-analyses on the effects of a centrally active mu-opioid antagonist and placebo on pain and on social connection in an experimental setting in healthy humans. We searched for studies in Web of Science, Scopus, PubMed and EMBASE. Eligible studies were at least double-blind, randomized, and placebo-controlled, and administered a centrally active antagonist (unspecific or ?-opioid receptor specific). Quality assessment and funnel plots were used to evaluate risk of bias. To compare drug effects on pain or social connectedness, we calculated Hedges’ g for individual outcomes and estimated the summary effect with a three-level random effects meta-analysis.

Results

A total of 60 studies (n = 2011) were included from the pain literature, 6 studies (N=379) were included to investigate changes in social connectedness. Overall, experimental pain responses were significantly higher with full mu-opioid blockade compared to placebo (Hedges’ g [95% CI] = 0.18 [0.10, 0.26]), but the main effect was small and with considerable heterogeneity (I2 = 77.2%). Similarly, full mu-opioid blockade resulted in a slight but significant reduction in social connectedness (Hedges’ g [95% CI] = -0.24 [-0.36, -0.11].

Conclusions

The estimated effects of systemic opioid antagonism were in line with the hypotheses, yet of modest size for both pain and feelings of social connection in healthy humans. The small increase in pain sensitivity during experimental pain and the slight reduction in subjective social connectedness in healthy humans after full endogenous opioid blockade is consistent with endogenous opioid fine-tuning rather than full regulation of the subjective experience of pain and feeling connected to others (5). An alternative hypothesis is that systemic pharmacological manipulation could yield small or noisy effects due to the simultaneous activation/deactivation of multiple opioid-regulated microcircuits. An overall take-home message is that the endogenous opioid system’s role in regulating social relationships may be as important as opioid regulation of pain in humans.

References

1. Akil, H., Watson, S. J., Young, E., Lewis, M. E., Khachaturian, H., & Walker, J. M. (1984). Endogenous Opioids: Biology and Function. Annual Review of Neuroscience, 7(1), 223–255.

2. Le Merrer, J., Becker, J. A., Befort, K., & Kieffer, B. L. (2009). Reward processing by the opioid system in the brain. Physiological reviews.

3. Lutz, P. E., & Kieffer, B. L. (2013). The multiple facets of opioid receptor function: implications for addiction. Current opinion in neurobiology, 23(4), 473-479.

4. Werner, M. U., Pereira, M. P., Andersen, L. P. H., & Dahl, J. B. (2015). Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review. PLOS ONE, 10(6), e0125887.

5. Eikemo, M., Løseth, G. E., & Leknes, S. (2021). Do endogenous opioids mediate or fine-tune human pain relief? Pain, 162(12), 2789-2791

Presenting Author

Guro Løseth

Poster Authors

Guro Løseth

Cand.Psychol.

University of Oslo

Lead Author

Isabell M. Meier*

PhD,

Oslo University Hospital

Lead Author

Martin Trøstheim

MSc

University of Oslo

Lead Author

Siri Leknes

University of Oslo

Lead Author

Topics

  • Treatment/Management: Pharmacology: Opioid