Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses

Abstract

The placebo and nocebo effect is believed to be mediated by both cognitive and conditioning mechanisms, although little is known about their role in different circumstances. In this study, we first analyzed the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients and found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. We also measured the effects of opposing verbal suggestions on hormonal secretion and found that verbally induced expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones. However, if a preconditioning was performed with sumatriptan, a 5-HT(1B/1D) agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given. These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo responses are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.

Classical conditioning of analgesic and hyperalgesic pain responses without conscious awareness

“…Although this study did not include placebos stricto sensu, we believe that our data map well onto that literature, as we used visual cues as conditional stimuli, standing in for placebos. Our data thus challenge the current notion that placebo and nocebo responses can be dichotomized and explained either as the result of an automatic nonconscious conditioning process or by the formation of conscious expectancies by, for example, verbal suggestions (10). Previous studies have reported that conditioning procedures for physiological functions that can be consciously perceived (e.g., pain reduction) are mediated by expectancy compared with responses that are not consciously perceptible (e.g., hormone release) (7,10).…”

“…On one hand, associative learning with subliminally presented stimuli has been demonstrated [e.g., by Degonda and colleagues (5)]; on the other hand, a sizeable literature indicates that pain conditioning is mediated by conscious expectations (6)(7)(8)(9)(10). Studies of fear learning in humans suggest that emotional contingencies can be acquired nonconsciously, as demonstrated by conditioned changes in autonomic and motor responses (11)(12)(13)(14).…”

The self-regulating brain and neurofeedback: Experimental science and clinical promise

“…And yet, EEG-nf may harbor a sizeable placebo component because it costs money, requires dozens of sessions, involves medical-like instrumentation, and carries the allure of brain science (Ali, Lifshitz, & Raz, 2014). Add to that an emphasis on cognitive demands that often aims to improve psychological rather than physiological conditions (Benedetti et al, 2003;Moseley et al, 2002;Waber, Shiv, Carmon, & Ariely, 2008) and the multi-faceted nature of neurofeedback becomes evident: whereas EEG-nf alters both brain patterns and behavioral measures, current findings hardly support a direct link between the specific feedback and these observed alterations.…”

Neurophysiologic Correlates of Side Effects in Normal Subjects Randomized to Venlafaxine or Placebo

“…Experimentally-induced expectations have been shown to produce a wide range of adverse effects including asthmatic symptoms (McFadden et al, 1969), allergic reactions (Jewett et al, 1990), vomiting (Kissel and Barrucand 1964), and hyperalgesia (Benedetti et al, 2003) after receiving an inert treatment. Even when expectations of adverse effects are not explicitly induced, healthy subjects often report side effects.…”