The hypothesis put forth is that expectations of treatment effects reduce negative emotions and thereby reduce symptoms, e.g. pain. Negative emotions increase pain, and it is hypothesized that placebos reduce pain by reducing negative emotions, i.e. feelings of nervousness, fear and anxiety. Placebo analgesia has been shown to be mediated via opioid activity, and relaxation increases opioid activity. The placebo acquires its relaxing effect due to verbal information that pain will be reduced, or due to associations between the placebo and the reduction in pain after effective treatment. Thus, the placebo signals that unpleasantness will be less after administration of the placebo. This involves negative reinforcement which is due to activation of a dopaminergic system that has been found to be activated during placebo analgesia and is involved in positive emotions. The nocebo effect of increased pain is, consistent with this model, because of increased fear and anxiety. The new aspect of the presented model is the hypothesis that expectations reduce negative emotions, and that negative reinforcement that involves the dopaminergic reinforcement system should be a contributor to placebo responses.

ObjectiveChronic pain is believed to be related to a dysfunction of descending pain modulatory mechanisms. Functioning of descending pain modulation can be assessed by various methods, including conditioned pain modulation (CPM). CPM refers to the inhibition of one source of pain by a second noxious stimulus, termed the conditioning stimulus. This procedure can activate an endogenous pain inhibitory mechanism that inhibits early nociceptive processing. Chronic pain and anxiety disorders are more prevalent among females and it has been hypothesized that females react with more negative emotions towards unpleasant stimuli and this might be part of the explanation of greater pain sensitivity in females. The present study investigated whether expectations modulate the effect of conditioning stimulation on pain, subjective stress, and heart rate. In addition, we investigated whether the modulation of CPM by expectations differed between males and females.MethodsSeventy-two subjects (including 36 women) received six noxious heat stimuli to the forearm. During three of these stimuli, a conditioning stimulus (cold-water bath) was applied to the contralateral arm in order to activate CPM. One third of the subjects were told that this would reduce pain (analgesia group), one-third that it would increase pain (hyperalgesia group), and one third received no information about its effect (no info group).ResultsInformation that conditioning stimulation decreased or enhanced pain had the corresponding effect in females, but not in males. Conditioning stimulation increased stress, but not heart rate in females in the hyperalgesia group. A higher expectation of analgesia and lower stress during conditioning stimulation was associated with larger inhibitory CPM.ConclusionThese results suggest that reduced inhibitory CPM can be due to contextually induced cognitive and emotional factors and not necessarily a dysfunction of descending inhibitory pathways.

Several studies have shown that psychological factors such as learning, expectation, and emotions can affect pharmacological treatment and shape both favorable and adverse effects of drugs. This study investigated whether nocebo information provided during administration of an analgesic cream could reverse topical analgesia to hyperalgesia. Furthermore, we tested whether nocebo effects were mediated by negative emotional activation. A total of 142 healthy volunteers (73 women) were randomized into 6 groups. A topical analgesic cream (Emla) was administered together with suggestions of analgesia in 1 group, whereas another group received Emla with suggestions of hyperalgesia. Two other groups received a placebo cream together with the same information as the groups receiving Emla. A fifth group received Emla with no specific information about the effect, and the sixth group received no treatment but the same pain induction as the other groups. Heat pain stimulation (48°C) was administered during a pretest and 2 posttests. Pain was continuously recorded during stimulation, and measures of subjective stress and blood pressure were obtained before the pretest, after the application of cream, and after the posttests. The results revealed that pain was significantly lower in the group receiving Emla with positive information and highest in the groups receiving suggestions of hyperalgesia, regardless of whether Emla or the placebo was administered. Mediation analyses showed that stress and blood pressure mediated hyperalgesia after nocebo suggestions. These results suggest that nocebo information can reverse topical analgesia and that emotional factors can explain a significant proportion of variance in nocebo hyperalgesia.

Inactive interventions can have significant effects on cognitive performance. Understanding the generation of these cognitive placebo/nocebo effects is crucial for evaluating the cognitive impacts of interventional methods, such as non-invasive brain stimulation (NIBS). We report both cognitive placebo and nocebo effects on reward-based learning performance induced using an active sham NIBS protocol, verbal suggestions and conditioning in 80 healthy participants. Whereas our placebo manipulation increased both expected and perceived cognitive performance, nocebo had a detrimental effect on both. Model-based analysis suggests manipulation-specific strategic adjustments in learning-rates: Participants in the placebo group showed stronger learning from losses and reduced behavioral noise, participants in the nocebo group showed stronger learning from gains and increased behavioral noise. We conclude that experimentally induced expectancy can impact cognitive functions of healthy adult participants. This has important implications for the use of double-blind study designs that can effectively maintain blinding in NIBS studies.

RationaleIn a randomised placebo-controlled clinical trial it is assumed that psychosocial effects of the treatment, regression to the mean and spontaneous remission are identical in the drug and placebo group. Consequently, any difference between the groups can be ascribed to the pharmacological effects. Previous studies suggest that side effects of drugs can enhance expectancies of treatment effects in the drug group compared to the placebo group, and thereby increase placebo responses in the drug group compared to the placebo group.ObjectivesThe hypothesis that side effects of drugs can enhance expectancies and placebo responses was tested.MethodPainful laser stimuli were delivered to 20 healthy subjects before and after administration of a drink with 0 or 4 mg/kg caffeine. The drink was administered either with information that it contained a painkiller or that it was a placebo. Laser-evoked potentials and reports of pain, expectancy, arousal and stress were measured.ResultsFour milligrammes per kilogramme of caffeine reduced pain. Information that a painkiller was administered increased the analgesic effect of caffeine compared to caffeine administered with no drug information. This effect was mediated by expectancies. Information and expectancies had no effect on pain intensity when 0 mg/kg was administered.ConclusionThe analgesic effect of caffeine was increased by information that a painkiller was administered. This was due to an interaction of the pharmacological action of the drug and expectancies. Hence, psychosocial effects accompanying a treatment can differ when an active drug is administered compared to a placebo.