Placebo, nocebo, and neuropathic pain

Abstract

Over the last decade, the apparent increase in placebo responses in randomized controlled trials (RCTs) of neuropathic pain have complicated and potentially limited development and availability of new effective pain medication. Placebo analgesia and nocebo hyperalgesia effects are well described in nociceptive and idiopathic pain conditions, but less is known about the magnitude and mechanisms of placebo and nocebo effects in neuropathic pain. In neuropathic pain, placebo treatments have primarily been used as control conditions for active agents under investigation in RCTs and these placebo responses are typically not controlled for the natural history of pain and other confounding factors. Recently, mechanistic studies that control for the natural history of pain have investigated placebo and nocebo effects in neuropathic pain in their own right. Large placebo analgesia but no nocebo hyperalgesic effects have been found, and the underlying mechanisms are beginning to be elucidated. Here we review placebo and nocebo effects and the underlying mechanisms in neuropathic pain and compare them with those of nociceptive and idiopathic pain. This allows for a novel discussion on how knowledge of psychological, neurobiological, and genetic factors underlying well-controlled placebo effects may help improve the information that can be obtained from and potentially restore the utility of RCTs.

Neuropathic pain

“…60, 61 tested expectancy-induced analgesia in patients who developed neuropathic pain after thoracotomy. Patients received lidocaine in an open (that is, patients were told: “The agent you have just been given is known to powerfully reduce pain in some patients”) or hidden (“This is a control condition for the active medication”) manner in accordance with a previously described protocol 62 ; the results showed a large reduction of ongoing pain, maximum wind-up-like pain and an area of hyperalgesia in those in the open group, recapitulating previous reports 59,60 . These findings point to a clinically relevant endogenous pain inhibitory mechanism with implications for phenotyping patients with neuropathic pain in clinical trial designs and practices.…”

“…In laboratory settings, expectancy-induced analgesia influences clinical pain in irritable bowel syndrome 56–58 , idiopathic and neuropathic pain 59 . For example, Petersen et al .…”

Effects of 8 weeks of masticatory muscles focused endurance exercises on women with oro‐facial pain and temporomandibular disorders: A placebo randomised controlled trial

“…Lower values of VAS on the placebo group were expected, as this effect is derived from the participants' perception and experience of receiving a pain-reducing treatment as well as the integration of this sensory information with memories of previous experiences and current expectations. 30,31 Placebo effects are also associated with the expected pain levels and emotional feelings, such as reduced anxiety and the previous experience of relief. 31,32 The current study used a simulated low intensity laser therapy with the equipment emitting beep sounds, but without the actual laser application.…”

“…30,31 Placebo effects are also associated with the expected pain levels and emotional feelings, such as reduced anxiety and the previous experience of relief. 31,32 The current study used a simulated low intensity laser therapy with the equipment emitting beep sounds, but without the actual laser application. The equipment is widely used by physical therapists to treat pain and inflammatory musculoskeletal conditions.…”

The placebo response in myasthenia gravis assessed by quantitative myasthenia gravis score: A meta‐analysis

“…The placebo effect in neuromuscular disorders has received little attention; knowledge comes mostly from neuropathic pain and pain in general . However, the placebo response is not the primary objective of these studies, as placebo treatments have been used primarily as control conditions in RCTs of neuromuscular disorders.…”