Researchers have shown that dopamine does not directly cause the development of positive treatment expectations or placebo analgesia in pain management.
The study used a double-blind, placebo-controlled trial with medications that alter dopamine levels, finding no significant influence of dopamine on the effectiveness of placebo treatments. These findings suggest the need for a more nuanced understanding of the neurobiological basis of placebo effects and could guide future research toward optimizing medical treatments.
New findings argue against a direct causal role for dopamine during the experience of a treatment effect in the establishment of positive treatment expectations and placebo analgesia in healthy volunteers. This is according to a research study published September 24th in the open-access journal PLOS Biology by Ulrike Bingel from University Hospital Essen, Germany, and colleagues.
Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of the brain messenger molecule dopamine in their generation and maintenance is still unclear. To fill this knowledge gap, Bingel and colleagues examined the causal role of dopamine in expecting positive treatment effects, as well as the magnitude and duration of their effects on pain.
To this end, they used an established placebo pain relief paradigm in combination with two opposing medications to change dopamine levels in the brain, i.e., the dopamine antagonist sulpiride, the dopamine precursor L-dopa, and an inactive pill with no medication as control, which were applied in an experimental, double-blind, randomized, placebo-controlled trial involving 168 healthy volunteers.
The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to the hypothesis, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested one day later. Placebo analgesia was no longer detectable on day eight after conditioning. Overall, the data provided strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects.
Implications for Dopamine in Pain Management
The results suggest that, while dopamine is evidently not necessary for establishing placebo analgesia, certain dopamine-dependent dimensions of reward processing which are more linked to active agency and motivational aspects may still interact with the pain experience. In addition, the results contribute to a more nuanced understanding of the neurobiology underpinning placebo analgesia, which aids the characterization of the intricate interplay between cognition, neurochemistry, and treatment outcome.
According to the authors, further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. In particular, future efforts to advance the understanding of dopaminergic mechanisms for modulating treatment response in pain must consider the undoubtedly complex involvement of dopaminergic neurotransmission in pain and its modulation.
The authors add, “Our research is driven by the motivation to target the underlying mechanisms of placebo effects to make active medical treatments more effective. The results of our study help to redirect the search for novel treatment targets to achieve this goal.”
Reference: “Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans” by Kunkel A, Asan L, Krüger I, Erfurt C, Ruhnau L, Caliskan EB, et al., 24 September 2024, PLOS Biology.
DOI: 10.1371/journal.pbio.3002772
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; Project-ID 422744262 – TRR 289, to UB; and Project ID-FU 356/12 – UMEA, to LA) and the Medical Faculty Essen and Stiftung Universitätsmedizin Essen (Project ELAN, to IK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.