Placebo Effect on Pain-Related Autonomic Responses in a State of Experimentally-Induced Sensitization

Pain-related autonomic responses are increased after experimentally-induced secondary mechanical hyperalgesia (SMH), as well as in a variety of chronic pain cohorts. In this state of sensitization, negative expectations further amplify these enhanced responses. Whether these pain-related autonomic responses can also be modulated by positive expectations, i.e., placebo, was investigated in this experimental study.

Forty healthy participants (20 females) were recruited and assigned to either a PLACEBO or a CONTROL group. Pain ratings and skin conductance responses (SCR) were recorded in response to five pinprick stimuli applied to the volar forearm at three timepoints: before and after experimental heat pain, and after an inert cream was applied to the volar forearm with instructions to enhance expectation for pain relief and conditioning (i.e., PLACEBO) or neutral instructions and no conditioning (i.e., CONTROL).

Pain ratings and SCR increased in both the PLACEBO and CONTROL groups after the application of the heat pain model, signalling the induction of secondary mechanical hyperalgesia (all p's < 0.05). Both outcomes decreased after PLACEBO, returning to near baseline levels (both p's < 0.05). In contrast, SCR and pain ratings remained elevated in the CONTROL group. The decrease in pain ratings and SCR observed in the PLACBO group were, however, not correlated (p = 0.35).

Our results show that positive expectations shape both psychophysical and physiological pain-related responses in a state of central sensitization. The lack of correlation between the placebo effect on pain ratings and on SCR implies different expectation-related modulatory processes on the two pain responses.

Our findings provide evidence that pain-related autonomic responses are modulated by expectations, even in a state of heightened sympathetic arousal, such as after experimentally-induced sensitization in healthy participants. In the context of clinical assessments, this implies that caution is warranted when interpreting unprocessed pain-related autonomic signals, such as SCR amplitudes, as surrogate markers of central sensitization.