Abstract
Objective: Predicting who will be a placebo responder is a prerequisite to maximize placebo effects in pain treatment and to minimize them in clinical trials. First evidence exists that genetics could affect placebo effects. However, a classical twin study to estimate the relative contribution of genetic influences compared to common and individual environmental influences in explaining interindividual differences in placebo responsiveness has yet not been performed. Methods: In a first explorative twin study, 25 monozygotic (MZ) and 14 dizygotic (DZ) healthy twin pairs (27.5 ± 7.7 years; 73% female) were conditioned to the efficacy of a placebo analgesic ointment with an established heat pain paradigm on their non-dominant arm. Placebo analgesia was then tested on their dominant arm. Furthermore, warmth detection thresholds (WDTs) and heat pain thresholds (HPTs) were assessed, and participants filled in questionnaires for the assessment of psychological traits such as depression, anxiety, optimism, pain catastrophizing, and sensitivity to reward and punishment. Their expectations were determined with a visual analog scale. Results: There was a small but significant placebo analgesic effect in both MZ and DZ twins. Estimates of heritability were moderate for WDT only but negligible for HPT, the conditioning response, and placebo analgesia. Common environment did not explain any variance, and the individual environment explained the largest parts. Therefore, the placebo analgesia response can be seen as influenced by individual learning experiences during the conditioning procedure, whereas other variables assessed were not associated. Conclusions: Compared to the individual learning experience, genetic influences seem to play a minor role in explaining variation in placebo analgesia in this experimental paradigm. However, our results are restricted to placebo effects through conditioning on pain in healthy volunteers and should be replicated in larger samples and in patients. Furthermore, potential gene–environment interactions should be further investigated.
Highlights
Placebo effects are part of every medical intervention and should be used to maximize treatment effects in daily routine, but need to be minimized in randomized controlled clinical trials (RCTs) to estimate the “pure” drug effect [1, 2] that should exceed the placebo effect
Pecina and colleagues report that AA homozygotes compared to G carriers of the Mu-opioid receptor polymorphism (OPRM1 A118G) [15], as well as Pro/Pro homozygotes compared to Thr carriers of the fatty acid amide hydrolase (FAAH Pro129Thr) [16], showed higher placebo effects through verbal suggestions on pain induced through hypertonic saline
When placebo effects were induced through conditioning on thermal pain, Yu and colleagues found an association between Met allele carriers of the catechol-O-methyltransferase polymorphism (COMT Val158Met) and placebo analgesia [17]
Summary
Placebo effects are part of every medical intervention and should be used to maximize treatment effects in daily routine, but need to be minimized in randomized controlled clinical trials (RCTs) to estimate the “pure” drug effect [1, 2] that should exceed the placebo effect. Placebo effects and responses are influenced by situational factors [5, 6], interact with personal factors [3] and prior experiences [7, 8], and are affected by the environment through explicit social (observational) learning of interventional effects [9, 10] and by an implicit social learning phenomenon called “placebo by proxy” [11, 12] Neither of these approaches has been able to allow the precise identification of placebo responders [1, 2]. Results seem to be partly inconclusive, but influencing factors such as the type of pain stimuli and placebo procedure have only seldom been considered
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