Effects of Oxytocin on Placebo and Nocebo Effects in a Pain Conditioning Paradigm: A Randomized Controlled Trial

Skvortsova, Aleksandrina; Veldhuijzen, Dieuwke S.; Middendorp, Henriët van; Colloca, Luana; Evers, Andrea W M

doi:10.1016/j.jpain.2019.08.010

Cited by 21 publications

(14 citation statements)

References 47 publications

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“…Some studies have reported that intranasal oxytocin can enhance placebo analgesia [4] and even generate both placebo and nocebo effects in working memory performance [5] in men. However, several other recent studies on men [6] and women [7,8] found no evidence for effects of oxytocin. In an attempt to resolve these conflicting results Liu et al [9] have systematically re-evaluated the effects of intranasal oxytocin on placebo analgesia across sexes, dosages, and placebo effect induction paradigms in a large sample of subjects.…”

mentioning

confidence: 78%

Reply to the Letter to the Editor: “Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia”

Becker

Zhao

Kendrick

2020

Psychother Psychosom

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in the placebo analgesia paradigms experimenters are involved in causing actual physical pain to subjects, this may even have contributed to a reduced trust in them. Interestingly, in a clinical context, patients who report greater similarities with and trust in their clinician tend to report greater reduction in pain after treatment [11]. Further studies therefore need to assess the extent to which trust in an expert may influence the ability of oxytocin to facilitate placebo effects.An important difference between the placebo analgesia studies and that reporting altered performance following oxytocin combined with verbal suggestion in working memory tasks is that in the latter, there was no placebo effect in the absence of oxytocin [5]. This raises the possibility that oxytocin may be more effective in enhancing the power of verbal suggestion in influencing complex cognitive behaviors that do not show pronounced placebo effects and are based on objective task performance rather than subjective ratings.During the last decade, the placebo effect has gained considerable attention in clinical and basic research. Although traditionally considered an unspecific confounder in treatment evaluation trials requiring strictly controlled designs [1], more recently potential enhancement of the placebo effect as a strategy to facilitate treatment responses in clinical samples has been considered [2]. A number of studies have considered whether the neuropeptide oxytocin, which increases attention to social cues and conformity to the opinions of trusted individuals [3], might enhance placebo effects. Some studies have reported that intranasal oxytocin can enhance placebo analgesia [4] and even generate both placebo and nocebo effects in working memory performance [5] in men. However, several other recent studies on men [6] and women [7,8] found no evidence for effects of oxytocin. In an attempt to resolve these conflicting results Liu et al. [9] have systematically re-evaluated the effects of intranasal oxytocin on placebo analgesia across sexes, dosages, and placebo effect induction paradigms in a large sample of subjects. They report no evidence for oxytocin enhancing either placebo or nocebo effects on analgesia.The study by Liu et al. [9] and other previous studies were powered sufficiently to detect effects of oxytocin on placebo analgesia, and while there are methodological differences between them, a parsimonious conclusion at this point is that oxytocin has no influence. However, an important consideration in this respect is that oxytocin rather than simply increasing trust in others may instead act to increase conformity to the opinions of only the most trusted experts [3,10]. Unfortunately, none of the studies conducted so far has quantified levels of trust by subjects in the experimenter(s), although interestingly in both studies reporting positive effects of oxytocin, experimenters in white coats identified as physicians/ medical experts gave the verbal suggestions. Thus, while subjects across the different analge...

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confidence: 78%

Reply to the Letter to the Editor: “Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia”

Becker

Zhao

Kendrick

2020

Psychother Psychosom

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“…In a more recent study, it was found that 24 IU of oxytocin did not enhance placebo analgesia in females [7]. Most recently, Skvortsova et al [8] found that 40 IU of oxytocin did not influence placebo analgesia and nocebo hyperalgesia responses in males. The links between oxytocin and placebo/nocebo remain to be established.…”

Section: Karger@kargercommentioning

confidence: 94%

Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia

Liu

Huang

Chen

et al. 2019

Psychother Psychosom

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cues associated with either a high or low electrical pain for 20 times each. In the testing stage, the high cue, low cue, and a new cue were all paired with identical moderate pain for 20 times each. In study 2, a verbal suggestion plus conditioning paradigm was used. Three identical inert ointments were applied to 3 sites on each participant's forearm, with the sites randomized across participants. A female experimenter described ointments as creams that increase pain (nocebo), reduce pain (placebo), and have no effect on pain (control), respectively. After 10 min, the 3 sites were stimulated for 10 times with high, moderate, and low shocks, corresponding to their instructed functions, to strengthen the effect of verbal suggestions. In the subsequent testing stage, all 3 sites were paired with moderate shocks for 20 times each.Participants rated how much pain they felt after each shock, using the same 9-point numeric rating scale. The placebo and nocebo effects were assessed as participants rated the low-cue (study 1) or placebo site (study 2)-associated shock as less painful and high-cue/nocebo site-associated shock as more painful compared to the new-cue/control site-associated shock during the test stage.Data from 12 participants were excluded because of poor pain discrimination during calibration or doubt of ointments' effects, leaving 306 participants for analysis (age, 18-26 years). A 2 (group: oxytocin/saline) × 2 (dosage: 24/40 IU) factorial ANOVA on placebo effect revealed no main effects and interaction effect in both studies (study 1: group, F(1, 156) = 0.16, p = 0.692; dosage, F(1, 156) = 0.06, p = 0.814; group × dosage, F(1, 156) = 0.30, p = 0.588; study 2: group, F(1, 142) = 0.17, p = 0.682; dosage, F(1, 142) = 0.03, p = 0.860; group × dosage, F(1, 142) = 0.09, p = 0.764). A similar ANOVA on nocebo effect also revealed no main effects and interaction effect (study 1: group, F(1, 156) = 0.29, p = 0.589; dosage, F(1, 156) = 0.65, p = 0.420; group × dosage, F(1, 156) = 1.12, p = 0.292; study 2: group, F(1, 142) < 0.001, p = 0.99; dosage, F(1, 142) = 0.57, p = 0.452; group × dosage, F(1, 142) = 0.98, p = 0.324).To further examine whether sex modulates the effect of oxytocin on placebo and nocebo effects, we conducted a 2 (group: oxytocin/ saline) × 2 (dosage: 24/40 IU) × 2 (sex: female/male) factorial ANOVA on placebo and nocebo responses, respectively. Results showed no sex-related effects (p values > 0.1), possibly due to the small number of participants in each subgroup for each gender. In addition, we examined pain ratings in the conditioning stage and found no significant differences across 4 arms in both studies (p values > 0.1), suggesting that the strength of conditioning was well-balanced across groups.In summary, using a randomized, double-blind design, we found no evidence for oxytocin effects on placebo and nocebo across paradigms and dosages in a large sample. Our findings challenge previous findings that placebo responses can be enhanced by the application of intranasal oxytocin and furth...

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“…The evidence from such studies is presently equivocal. For men, two studies indicate that intranasal oxytocin administration enhances placebo effects induced by verbal description (for analgesia [ 127 ] and working memory [ 128 ]), while three studies indicate that it does not (for analgesia induced by verbal description combined with conditioning [ 129 – 131 ]). For women, the results are less ambiguous, with three studies indicating that intranasal oxytocin administration does not enhance placebo analgesia, induced by verbal description [ 132 ], or verbal description combined with conditioning ([ 130 , 131 ]; [ 131 ] controlled for menstrual phase).…”

Section: Oxytocin Biology and The Identification Of Placebo Effectsmentioning

confidence: 99%

Oxytocin and the social facilitation of placebo effects

et al. 2022

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Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of this “improvement” reflects experimental design limitations (e.g., reliance on subjective outcomes, unbalanced groups, reporting biases), some of it reflects genuine improvement corroborated by physiological change. Converging evidence across diverse medical conditions suggests that clinically-relevant benefits from placebo treatment are associated with the activation of brain reward circuits. In parallel, evidence has accumulated showing that such benefits are facilitated by clinicians that demonstrate warmth and proficiency during interactions with patients. Here, we integrate research on these neural and social aspects of placebo effects with evidence linking oxytocin and social reward to advance a neurobiological account for the social facilitation of placebo effects. This account frames oxytocin as a key mediator of treatment success across a wide-spectrum of interventions that increase social connectedness, thereby providing a biological basis for assessing this fundamental non-specific element of medical care.

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Effects of Oxytocin on Placebo and Nocebo Effects in a Pain Conditioning Paradigm: A Randomized Controlled Trial

Abstract: Highlights Placebo analgesia and nocebo hyperalgesia can be induced by classical conditioning. Oxytocin does not enhance placebo effect or decrease nocebo effect. Oxytocin does not influence extinction of placebo and nocebo responses.

Cited by 21 publications

References 47 publications

Reply to the Letter to the Editor: “Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia”

Reply to the Letter to the Editor: “Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia”

Lack of Evidence for the Effect of Oxytocin on Placebo Analgesia and Nocebo Hyperalgesia

Oxytocin and the social facilitation of placebo effects

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