The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect

Abstract

Despite the increasing research on placebos in recent times, little is known about the nocebo effect, a phenomenon that is opposite to the placebo effect and whereby expectations of symptom worsening play a crucial role. By studying experimental ischemic arm pain in healthy volunteers and by using a neuropharmacological approach, we found that verbally induced nocebo hyperalgesia was associated to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of adrenocorticotropic hormone and cortisol plasma concentrations. Both nocebo hyperalgesia and HPA hyperactivity were antagonized by the benzodiazepine diazepam, suggesting that anxiety played a major role in these effects. The administration of the mixed cholecystokinin (CCK) type-A/B receptor antagonist proglumide blocked nocebo hyperalgesia completely but had no effect on HPA hyperactivity, which suggests a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect. Importantly, both diazepam and proglumide did not show analgesic properties on basal pain, because they acted only on the nocebo-induced pain increase. These data indicate a close relationship between anxiety and nocebo hyperalgesia, in which the CCKergic systems play a key role in anxiety-induced hyperalgesia. These results, together with previous findings showing that placebo analgesia is mediated by endogenous opioids, suggest that the analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.

Figure 1.

A, Proglumide is a nonselective CCK antagonist that binds to both CCK-A (or CCK-1) and CCK-B (or CCK-2) receptors. Note the similar binding affinity, expressed as the concentration required to inhibit by 50% the specific binding of ¹²⁵I-Bolton-Hunter CCK-8 (IC₅₀), for CCK-A and CCK-B receptors. B, Experimental design used in the present study. Each group was tested twice with tourniquet, and the interval between tests 1 and 2 was 4 d. C, Each tourniquet test lasted 10 min, and the subjects had to rate their pain every minute while a blood sample was taken just before and at 5 and 10 min during the tourniquet.

Figure 2.

The natural history of pain (A), ACTH (B), and cortisol (C) in test 1 (black symbols) is compared with the natural history of test 2 (white symbols). Note that no difference was present between tests 1 and 2, indicating stable conditions of our experimental setup.

Figure 3.

The natural history of pain (A), ACTH (B), and cortisol (C) in test 1 (black symbols) is compared with the nocebo condition of test 2 (white symbols), in which verbal suggestions of pain worsening were given. Note that, in the nocebo condition, there was a significant increase of both pain perception and ACTH and cortisol plasma concentrations. **p < 0.01; ***p < 0.001.

Figure 4.

The effect of diazepam on basal pain increase (A), basal ACTH increase (B), and basal cortisol increase (C) in test 1 (black symbols) is compared with diazepam in the nocebo condition of test 2 (white symbols). Note that diazepam suppressed both nocebo hyperalgesia and nocebo increase of ACTH and cortisol plasma concentrations. In fact, no difference was present between tests 1 and 2.

Figure 5.

The effect of proglumide on basal pain increase (A), basal ACTH increase (B), and basal cortisol increase (C) in test 1 (black symbols) is compared with proglumide in the nocebo condition of test 2 (white symbols). Note that, whereas proglumide suppressed nocebo hyperalgesia, it was ineffective in suppressing the nocebo increase of ACTH and cortisol plasma concentrations. **p < 0.01; ***p < 0.001.

Figure 6.

Model to explain the findings of the present study. Nocebo-induced anxiety affects both the HPA axis and pain mechanisms. The link between anxiety and pain is represented by CCK, which has a facilitating effect on pain. Benzodiazepines, like diazepam, can block anxiety, thus preventing both HPA hyperactivity and hyperalgesia. CCK antagonists, such as proglumide, only block the CCKergic anxiety–pain link. Therefore, CCK antagonists do not inhibit pain per se but rather the anxiety–pain link.

Figure 7.

The structural formula of the anxiolytic drug diazepam, one of the most used benzodiazepines, is similar to L-365,260, a benzodiazepine-based CCK antagonist, thus suggesting similar mechanisms of action of benzodiazepines and CCK antagonists. Note the higher binding affinity of L-365,260 for CCK-B receptors compared with CCK-A receptors, expressed as the concentration required to inhibit by 50% the specific binding of ¹²⁵I-Bolton-Hunter CCK-8 (IC₅₀).