Effects of sex on placebo effects in chronic pain participants: a cross-sectional study

Abstract

Sex-related differences can influence outcomes of randomized clinical trials and may jeopardize the effectiveness of pain management and other therapeutics. Thus, it is essential to understand the mechanistic and translational aspects of sex differences in placebo outcomes. Recently, studies in healthy participants have shed light on how sex-related placebo effects might influence outcomes, yet no research has been conducted in a patient population. Herein, we used a tripartite approach to evaluate the interaction of prior therapeutic experience (eg, conditioning), expectations, and placebo effects in 280 chronic (orofacial) pain patients (215 women). In this cross-sectional study, we assessed sex differences in placebo effects, conditioning as a proxy of prior therapeutic effects, and expectations evaluated before and after the exposure to positive outcomes, taking into account participant–experimenter sex concordance and hormonal levels (estradiol and progesterone assessed in premenopausal women). We used mediation analysis to determine how conditioning strength and expectations impacted sex differences in placebo outcomes. Independent of gonadal hormone levels, women showed stronger placebo effects than men. We also found significant statistical sex differences in the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related placebo effects. In addition, the participant–experimenter sex concordance influenced conditioning strength, reinforced expectations, and placebo effects in women but not in men. Our findings suggest that women experience larger conditioning effects, expectations, and placebo effects emphasizing the need to consider sex as a biological variable when placebo components of any outcomes are part of drug development trials and in pain management.

Quantitative Sensory Testing Across Chronic Pain Conditions and Use in Special Populations

“…Alongside the promise of QST in improving the characterization of pain, and in turn, the prescription of individualized treatment interventions, limitations of this methodology must also be addressed. As highlighted in our descriptions of QST in TMD and placebo research, sex and racial effects regarding pain sensitivity, and racial effects regarding placebo efficiency have been observed, and thus need be accounted for when analyzing results ( 57 , 58 ). In addition, effects of age must be considered when incorporating QST, as loss of sensory function has been observed in older adults for cold, warmth, mechanical, and vibratory detection thresholds ( 90 ).…”

“…We found that Afro-American Blacks had lower pain tolerance in both TMD participants and healthy control participants ( 57 ). Additionally, we found women in the TMD cohort to have lower levels of both thermal heat pain threshold and thermal heat pain tolerance than men ( 58 ). Both results are in line with the literature on racial and sex effects with regard to pain sensitivity, as in experimental pain studies, women tend to be more sensitive to pain than men in measures of heat, cold, and pressure pain tolerance ( 55 , 59 , 60 ).…”

Placebo and nocebo effects: from observation to harnessing and clinical application

“…Sex and race matter for placebo effects. Females and white populations seem to experience larger placebo effects [ 114 , 115 ]. Another set of important predictors of placebo effects is psychological factors, e.g., expectation, trait optimism, desire for control [ 116 ], emotional distress, and maladaptive cognitive appraisals of pain [ 117 ].…”

Placebo Effects on Stress, but Not on Pain Reports. A Multi-Experiment Study

“…Recently, Enck and Klosterhalfen (2019) showed that males are more responsive to verbally generated placebo treatments, while females are more responsive to placebo treatments generated by classical conditioning. However, the inconsistent findings (e.g., females also have been shown to be more responsive to verbally produced placebo effects; Olson et al, 2021 ), and the interaction of participant and experimenter/clinician sex (e.g., Mogil, 2012 ), have made it difficult to understand the effects of sex/gender on placebo effects.…”