Failure to Find a Conditioned Placebo Analgesic Response

Background: Associative learning has, in several studies, been modulated by the sex of the participant. Consistent with this, a recent review found that conditioned nocebo effects are stronger in females than in males.Purpose: It has been suggested that conditioned placebo responses are stronger in females, and this hypothesis was investigated in the present study. Cortisol and measures of negative emotions were taken to investigate if these processes could mediate any conditioned placebo effects.Methods: Cold pain was applied to the volar forearm. The Conditioned group received inert capsules prior to two presentations of less painful stimulations, to associate intake of the capsules with reduced pain. The pain control group received the same painful stimulation as the Conditioned group, but no capsules. The Capsule control group received the capsules in the same way as the Conditioned group, but no decrease in the painful stimulation. Participant sex was crossed across groups. It was hypothesized that in the Conditioned group, an expectation of reduced pain should be induced after administration of the capsules, and this should generate placebo analgesia, and mostly so in females.Results: The Conditioned group reported lower pain during conditioning, and rated the capsules as more effective painkillers than the capsule control group. However, placebo analgesia was not reliably observed in the Conditioned group.Conclusion: The placebo capsules were rated as effective painkillers, but this did not translate into a placebo analgesic effect. This could be due to violation of response expectancies, too few conditioning trials, and differences in pain ratings in the pre-test that could be due to previous experience with painkillers

Interaction between expectancies and drug effects: an experimental investigation of placebo analgesia with caffeine as an active placebo

In 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. The hypothesis that side effects of drugs can enhance expectancies and placebo responses was tested. Painful 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. Results Four 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. The 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

Active Placebo - The relation of treatment expectancies to active analgesic treatments

The placebo analgesic effect refers to the improvement in a group receiving an inert treatment compared to a group receiving no treatment. Conversely, nocebo hyperalgesia refers to the worsening in a group receiving an inert treatment compared to a no treatment control group. The hypothesis that active treatments, e.g. a drug, enhance the placebo effect has received some support but rarely been tested experimentally. In the present work this hypothesis was tested by administering caffeine or placebo to healthy subjects after induction of pain. Both caffeine and placebo were administered with information that they received a painkiller which would alleviate the pain or that they received a placebo with no effect. The effect of this manipulation was tested by comparing subjective and physiological responses to identical painful stimulation before and after treatment. It was predicted that the active drug would increase the placebo analgesic effect. The total treatment effect consists of the specific treatment response, e.g. the response to the pharmacological action of a drug, and the placebo response. Previous research indicate that the total treatment effect is modulated by placebo and nocebo responses, such that placebo responses increase the treatment effect and nocebo responses decrease it. The present work consists of two experiments that investigated the relation of placebo and nocebo responses to the treatment effect. In both experiments, pain was induced in healthy subjects before and after administering a known analgesic treatment with information that it was analgesic, hyperalgesic or with no specific information about its effect. We predicted that treatment effects would be enhanced by placebo information and reduced by nocebo information. The role of stress in placebo and nocebo responding was investigated by including subjective and physiological measures of stress. It was predicted that placebo responses was mediated by reductions in stress, while nocebo responses were mediated by increased stress. The results showed that a placebo response was only present when caffeine was administered. This supports the hypothesis that active drugs enhance placebo responses. It was further observed that the analgesic effect of a topical analgesic cream was reversed in the nocebo group and had a hyperalgesic effect. Placebo and nocebo responses were related to reduced and increased anticipatory stress, respectively, and anticipatory stress was a predictor of subsequent pain. The present work is relevant for both the design and interpretation of clinical trials and for clinical practice. Clinical trials assume that the only difference between drugs and placebos are the pharmacological action of the drug. However, if placebo responses are larger in the presence of the active drug the assumption might not always hold. The modulation of treatment effects by placebo and nocebo responses is relevant for maximizing treatment effects in clinical practice. Increasing positive expectations and decreasing stress is important to maximize placebo responses and minimize nocebo responses

Expectations of increased and decreased pain explain the effect of conditioned pain modulation in females

Chronic 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. Seventy-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). Information 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. These 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

Nocebo hyperalgesia and the startle response

Background: The literature on the effects of nocebo on pain is sparse. The present experimental study investigated whether suggestions of nocebo hyperalgesia modified the startle response and whether increased startle contributed to the nocebo hyperalgesic effect. Methods: A design with four groups was employed; the participants were randomized into either a placebo group, a natural history group, or into two nocebo groups. The participants in the placebo and nocebo groups received suggestions of pain decrease or pain increase, together with a placebo or nocebo cream applied to the lower arm, respectively. Heat pain was induced by a PC-controlled thermode before and after the treatment. White noise was used to elicit startle responses. Startle was assessed by measuring eye blink electromyographic responses recorded from the right orbicularis oculi muscle. Results: The results showed that nocebo suggestions increased reports of pain and startle responses. Increased startle was significantly associated with the nocebo hyperalgesic response. Conclusions: The results of the present study suggest that verbally induced expectations of increased pain engage cortical physiological defensive systems that in turn mediate the experience of increased pain

Evidence for Cognitive Placebo and Nocebo Effects in Healthy Individuals

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, whereas in the nocebo group 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

Evidence for Cognitive Placebo and Nocebo Effects in Healthy Individuals

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, whereas in the nocebo group 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

Evidence for Cognitive Placebo and Nocebo Effects in Healthy Individuals

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, whereas in the nocebo group 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