How the number of learning trials affects placebo and nocebo responses

Abstract

Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.

Nocebo hyperalgesia and the startle response

“…Previous studies have shown that a single learning trial is sufficient to induce both nocebo and placebo responses, but as learning trials increase, the more persistent the effects of the manipulation become (Colloca et al 2010). Thus, the present results are consistent with previous studies suggesting that verbal suggestions efficiently induce nocebo responses Aslaksen & Lyby 2015), while placebo responses might require a more robust pain relief experience (Schenk et al 2014).…”

“…The few studies that do exist suggest that nocebo hyperalgesia is caused by expectations of pain increase that induce negative emotions, which in turn increase pain. Furthermore, only a few studies have compared nocebo hyperalgesia and placebo analgesia in the same design (Colloca et al 2010;Reicherts et al 2016). Nocebo hyperalgesia can be reversed by anxiolytic drugs (Benedetti et al 2007).…”

Facilitation of Pain in the Human Spinal Cord by Nocebo Treatment

“…For example, pain can be reduced by distraction (Valet et al, 2004;Buhle and Wager, 2010;Sprenger et al, 2012), expectation (Koyama et al, 2005;Atlas et al, 2010), or in general by placebo interventions (Levine et al, 1978;Montgomery and Kirsch, 1996;Amanzio and Benedetti, 1999;Benedetti, 2008). On the other hand, pain can be increased by negative expectations, for example in nocebo hyperalgesia (Lorenz et al, 2005;Colloca et al, 2008). In some studies, negative expectations even equalized the effects of analgesic drugs (Dworkin et al, 1983;Bingel et al, 2011).…”

“…However, it has been suggested that placebo and nocebo responses rely on different neurobiological mechanisms (Colloca et al, 2008;Enck et al, 2008;Petrovic, 2008), which could mean that only placebo analgesia affects spinal pain transmission. To test the hypothesis of a spinal cord involvement in nocebo hyperalgesia, we used novel functional magnetic resonance imaging (fMRI) acquisition techniques, allowing for the investigation of pain transmission in the human spinal cord (Eippert et al, 2009b;Cahill and Stroman, 2011;.…”

Behavioural conditioning as the mediator of placebo responses in the immune system

“…However, the results of clinical and experimental studies have clearly shown that placebos can indeed affect symptomatology, as demonstrated, for example in patients with depression [1,2], Parkinson's disease [3 -6], pain [7,8] and asthma [9]. How is it that substances without any defined active component affect not only psychological but more importantly physiological functions?…”