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.
    The journal of pain: official journal of the American Pain Society 07/2015; 16(10). DOI:10.1016/j.jpain.2015.06.012 · 4.01 Impact Factor
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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.
    Pain 04/2014; 155(8). DOI:10.1016/j.pain.2014.04.016 · 5.21 Impact Factor
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    • "This can be defined as the increase in pain experienced by an individual led by environmental clues to expect a negative outcome, in the absence of an effective cause of symptom worsening [34]. By antagonizing the pronociceptive effect of CCK, proglumide produces the inhibition of the nocebo response [35] "
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    ABSTRACT: The concept of placebo response has evolved in the past few years from the clinical trial setting and medical practice to a psychobiological model that gives us important information on how the patient's brain is modified by the psychosocial context around the therapy. In this review, some examples will be given where physiological or pathological conditions are altered following the administration of an inert substance along with verbal instructions tailored to induce expectation of a change, and explanations will be presented with details on neurotransmitter changes and neural pathways activated. Although nothing is known about the biological underpinnings of the placebo response in the respiratory system, this review may help extending the neurobiological investigation of placebos from conditions such as pain and Parkinson's disease to respiratory disorders and symptoms such as cough.
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