Investigating the Placebo Effect: Does Dopamine Modulation Impact Analgesia?

Researchers investigated the direct causal role of dopamine on the placebo effect in response to pain relief. The study, published in PLoS Biology, questions current beliefs.

Dopamine is implicated in placebo analgesia

The placebo effect is a powerful phenomenon that can impact an individual's response to treatments that are physically and pharmacologically inert. This effect is thought to arise from complex interactions between cognitive expectations, learning processes and neurobiological mechanisms. In the context of pain relief, placebo analgesia refers to a reduction in perceived pain when an individual is given an inactive treatment.

The phenomenon is believed to activate the brain’s natural pain-relief mechanisms, involving the release of endorphins and other neurochemicals, mimicking the effects of actual painkillers. One neurotransmitter implicated in this process is dopamine, which is involved in various physiological and behavioral functions. Recent research has linked dopamine-based reward mechanisms to the placebo effect, suggesting that expectation and anticipation of pain relief play key roles in shaping the brain's response to treatment.

A study using positron emission tomography (PET) imaging discovered dopamine signaling increased during the anticipation of analgesia following the administration of a placebo treatment. Although there is clear evidence of the involvement of dopamine in the placebo effect, its exact functional role remains poorly understood.

Dopamine modulation does not impact placebo analgesia

To investigate dopamine's role in the placebo effect and its influence on pain relief, 168 healthy volunteers participated in a double-blind, randomized, placebo-controlled trial. The participants underwent a well-established placebo pain relief protocol and were given one of three treatments during a conditioning procedure:

1. L-dopa, a precursor to dopamine which increases dopamine levels.
2. Sulpiride, a dopamine antagonist that blocks dopamine receptors, reducing dopamine activity.
3. A placebo, to act as a control.

On day one, participants were introduced to two skin creams: a placebo cream, falsely described as containing the analgesic lidocaine, and a control cream, described as inactive. Heat pain stimuli were applied to the participant’s skin, with the temperature at the placebo site set lower to simulate a pain-relieving effect, while a higher temperature was used at the control site. This manipulation led participants to believe the placebo cream was reducing pain. The process was repeated across multiple trials, with participants rating their pain levels after each stimulus, reinforcing the placebo effect through conditioning. to test the durability of the conditioned placebo analgesia over time.

The researchers assessed the participant's pain relief after conditioning, on days two and eight, to see whether altering dopamine levels would affect the formation of positive treatment expectations and the subsequent placebo analgesia.

Although dopamine levels were successfully altered, neither L-dopa nor sulpiride influenced the participant's ability to develop positive expectations of pain relief. Neither medication had an effect on the strength or duration of placebo analgesia compared to the control group. The initial placebo pain relief observed was no longer detectable by day eight after the conditioning, regardless of dopamine modulation.

Dopamine may interact with pain experience

The results provided evidence against the researcher's original hypothesis that dopamine plays a direct causal role in the generation or maintenance of placebo analgesia.

Although the results suggest dopamine is not necessary for establishing the placebo effect, the authors argue a more nuanced role of the neurotransmitter: “Certain dopamine-dependent dimensions of reward processing, including active agency and motivational aspects, may interact with pain experience and contribute to placebo analgesia”.

Future research aimed at understanding how dopamine-related mechanisms influence treatment responses in pain should still consider the complex role of dopaminergic neurotransmission in both pain perception and its modulation.

“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,” the authors add.

Reference: Kunkel A, Asan L, Krüger I, et al. Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans. Seymour B, ed. PLoS Biol. 2024;22(9):e3002772. doi: 10.1371/journal.pbio.3002772

This article is a rework of a press release issued by PLOS. Material has been edited for length and content.