Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide

Università degli Studi di Torino, Torino, Piedmont, Italy
Pain (Impact Factor: 5.21). 07/1997; 71(2):135-40. DOI: 10.1016/S0304-3959(97)03346-0
Source: PubMed


In patients who reported mild postoperative pain, we evoked a nocebo response, a phenomenon equal but opposite to placebo. Patients who gave informed consent to increase their pain for 30 min received a substance known to be non-hyperalgesic (saline solution) and were told that it produced a pain increase. A nocebo effect was observed when saline was administered. However, if a dose of 0.5 or 5 mg of the cholecystokinin antagonist proglumide was added to the saline solution, the nocebo effect was abolished. A dose of 0.05 mg of proglumide was ineffective. The blockade of the nocebo hyperalgesic response was not reversed by 10 mg of naloxone. These results suggest that cholecystokinin mediates pain increase in the nocebo response and that proglumide blocks nocebo through mechanisms not involving opioids. Since the nocebo procedure represents an anxiogenic stimulus and previous studies showed a role for cholecystokinin in anxiety, we suggest that nocebo hyperalgesia may be due to a cholecystokinin-dependent increase of anxiety.

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    • "However, while both placebo analgesia and nocebo hyperalgesia are considered to result from the same general learning mechanisms, i.e. instruction and conditioning, some asymmetries exist. For example, nocebo hyperalgesia is more readily induced via instruction than placebo analgesia is [16] and while endogenous opioids have been shown to underlie instruction-induced placebo analgesia [3] [8] [30] [31], instruction-induced nocebo hyperalgesia appears to be mediated by cholecystokinin [5] [6]. "
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    ABSTRACT: Many studies have found evidence of conditioning-induced nocebo hyperalgesia. However, these studies have exclusively involved continuous reinforcement schedules. Thus, it is currently unknown whether nocebo hyperalgesia can result following partial reinforcement. We tested this using electrodermal pain stimulation in healthy volunteers. Undergraduates (n=135) received nocebo treatment under the guise of a hyperalgesic. Participants were randomly allocated to continuous reinforcement (CRF), partial reinforcement (PRF), or control (no conditioning). Conditioning involved surreptitiously increasing pain stimulation on nocebo trials relative to control trials. During training, the CRF group always had the nocebo paired with the surreptitious pain increase, whereas the PRF group only experienced the increase on 62.5% of nocebo trials. In the test phase, pain stimulation was equivalent across nocebo and control trials. Partial reinforcement was sufficient to induce nocebo hyperalgesia, however, this was weaker than continuous reinforcement. Interestingly, nocebo hyperalgesia failed to extinguish irrespective of the training schedule. Additional assessment of expectancies indicated strong concordance between these and nocebo hyperalgesia. Overall, these findings suggest that once established, nocebo hyperalgesia may be difficult to disrupt. As such, partial reinforcement may be one method of reducing the intensity of nocebo hyperalgesia in the clinic, which may be particularly important given its persistence. This study provides novel evidence that partial reinforcement results in weaker nocebo hyperalgesia than continuous reinforcement and that nocebo hyperalgesia fails to extinguish, irrespective of the training schedule. As a result, partial reinforcement may serve as a method for reducing the intensity of nocebo hyperalgesia in the clinic. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · The journal of pain: official journal of the American Pain Society
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    • "Six articles were excluded based on the second selection criterion, as they did not administer an inert nocebo treatment/intervention. Ten articles were examined in detail and included in the meta-analysis, as they met all of the selection criteria [8] [9] [11] [20] [21] [26] [39] [45] [62] [66]. No additional articles were identified by checking the references of the included articles . "
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    ABSTRACT: The investigation of nocebo effects is evolving and a few literature reviews have emerged, however, so far without quantifying such effects. This quantitative systematic review investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term "nocebo". Only studies that investigated nocebo effects as the effects that follow the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen's d and Hedges' g. The overall magnitude of the nocebo effect was moderate to large (lowest g = 0.62 (0.24-1.01) and highest g = 1.03 (0.63-1.43)) and highly variable (range of g = -0.43-4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic studies. In studies where nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g = 0.76 (0.39-1.14) and highest g = 1.17 (0.52-1.81)) than in studies where nocebo effects were induced by verbal suggestions alone (lowest g = 0.64 (-0.25-1.53) and highest g = 0.87 (0.40-1.34)). These findings are similar to those in the placebo literature. Since the magnitude of the nocebo effect is variable and sometimes large, this systematic review demonstrates the importance of minimizing nocebo effects in clinical practice.
    Full-text · Article · Apr 2014 · Pain
    • "The present findings, together with reports in other pain models, provide a sound experimental basis for much-needed patient-oriented research. Clearly, the challenge of transferring knowledge from experimental placebo and nocebo research into clinical practice is to move beyond primarily descriptive approaches to resolving how, in real clinical encounters, positive and negative expectations are shaped [8,19], as has recently been accomplished in the context of neuraxial analgesia delivered with either gentle or harsh wording [47] as well as in patients with postoperative [3] and neuropathic pain [37]. Ultimately, the goal is to address the fundamental question, ''How can placebo effects be maximized and nocebo effects be minimized to the benefit of the patient?'' "
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    ABSTRACT: In order to elucidate placebo and nocebo effects in visceral pain, we conducted a functional magnetic resonance imaging (fMRI) study to analyze effects of positive and negative treatment expectations in a rectal pain model. In N=36 healthy volunteers, painful rectal distensions were delivered following intravenous application of an inert substance combined with either positive instructions of pain relief (placebo group) or negative instructions of pain increase (nocebo group), each compared to neutral instructions. Neural activation during cued-pain anticipation and pain was analyzed along with expected and perceived pain intensity. Expected and perceived pain intensity were significantly increased in the nocebo group and significantly decreased in the placebo group. Within the placebo group, positive expectations significantly reduced activation of the somatosensory cortex during anticipation and of the insula, somatosensory cortex and amygdala during pain delivery when compared to neutral expectations. Within the nocebo group, negative expectations led to significantly increased insula activation during painful stimulation. Direct group contrasts during expectation modulation revealed significantly increased distension-induced activation within the somatosensory cortex in the nocebo group. In conclusion, the experience and neural processing of visceral pain can be increased or decreased by drug-specific expectations. This first brain imaging study on nocebo effects in visceral pain has implications for the pathophysiology and treatment of patients with chronic abdominal complaints such as irritable bowel syndrome.
    No preview · Article · Jul 2013 · Pain
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