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.

Locked out and still knocking: predictors of excessive demands for postoperative intravenous patient-controlled analgesia

“…47,48 Administration of proglumide, a mixed CCK-A and B receptor antagonist reduces anxiety-induced facilitation of pain (i.e., nocebo hyperalgesia). 47,49 These data suggest two alternative possibilities. It is possible, as described above, that with time after surgery, the PCA button or tone becomes a safety signal that is associated with a CCK-mediated increase in pain and lockout interval demands.…”

Nocebo hyperalgesia and the startle response

“…Previous studies have shown that nocebo hyperalgesic manipulations heighten HPA activity (Benedetti et al 2006, Johansen et al 2003, cortical activity in pain-related regions (Kong et al 2008;Bingel et al 2011;Schmid et al 2015), pain-related activity in the spinal 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 cord (Geuter & Buchel 2013), blood pressure and reported negative emotions combined with increased pain reports. The findings from the present study further add that successful induction of nocebo expectations increase negative emotions significantly enough to engage physiological and motivational defense systems (Grillon et al 1991), that enhance cortical alertness measured by startle responses.…”

“…Hence, expecting a negative event, such as increased pain induced by nocebo suggestions should increase the startle response. A previous study (Benedetti et al 2006) demonstrated that nocebo suggestions increase hypothalamic-pituitary-adrenal (HPA) activity, showing that endocrine stress responses are core features of nocebo responses. Thus, information that pain will be increased may activate physiological defense systems that in turn can be measured as increased startle responses.…”

Nocebo phenomenon

“…Conversely, the CCK antagonist, proglumide, has been found to prevent nocebo hyperalgesia but not the hypothalamuspituitary-adrenal hyperactivity, which suggests two independent biochemical pathways activated by nocebo suggestions and anxiety (Benedetti, Amanzio, Vighetti & Asteggiano, 2006).…”