A Watson

Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

ABSTRACT The neural mechanisms whereby placebo conditioning leads to placebo analgesia remain unclear. In this study we aimed to identify the brain structures activated during placebo conditioning and subsequent placebo analgesia. We induced placebo analgesia by associating a sham treatment with pain reduction and used fMRI to measure brain activity associated with three stages of the placebo response: before, during and after the sham treatment, while participants anticipated and experienced brief laser pain. In the control session participants were explicitly told that the treatment was inactive. The sham treatment group reported a significant reduction in pain rating (p = 0.012). Anticipatory brain activity was modulated during placebo conditioning in a fronto‐cingulate network involving the left dorsolateral prefrontal cortex (DLPFC), medial frontal cortex and the anterior mid‐cingulate cortex (aMCC). Identical areas were modulated during anticipation in the placebo analgesia phase with the addition of the orbitofrontal cortex (OFC). However, during altered pain experience only aMCC, post‐central gyrus and posterior cingulate demonstrated altered activity. The common frontal cortical areas modulated during anticipation in both the placebo conditioning and placebo analgesia phases have previously been implicated in placebo analgesia. Our results suggest that the main effect of placebo arises from the reduction of anticipation of pain during placebo conditioning that is subsequently maintained during placebo analgesia.

Reproducibility of placebo analgesia: Effect of dispositional optimism

ABSTRACT Placebo has been shown to be a powerful analgesic with corresponding reduction in the activation of the pain matrix in the brain. However it is not clear whether the placebo response is reproducible within individuals and what role personality traits might play in predicting it. We induced placebo analgesia by conditioning subjects to expect pain reduction following a sham‐treatment in the guise of a local anaesthetic cream applied to one arm. Pain ratings were assessed before, during and after treatment. The procedure was repeated in a second session to assess the degree of reproducibility of the response. A high degree of correlation was found between the two sessions for the sham‐treatment group (R2 = 0.55; p < 0.001). Personality questionnaires were given during both experimental sessions to assess key traits such as optimism and state and trait anxiety. A regression model was used to statistically define a placebo responder in terms of personality scores. High dispositional optimism and low state anxiety were found to be significant predictors of placebo response. We suggest that repeated placebo responders are high in dispositional optimism and having a placebo response in the first session causes a drop in state anxiety at the beginning of the repeat session.

Harnessing expertise: involving peer interviewers in qualitative research with hard‐to‐reach populations

The use of peer interviewers with privileged access to a particular population group, which is difficult to reach via more conventional methods, has been acknowledged in recent research. This paper explores a number of key issues relating to the employment of peer interviewers by reflecting on a project designed to explore the views and experiences of parents who use illegal drugs. The project presented the research team with a number of challenges. These included the need to provide on‐going support for the interviewers, a sense of distance felt by the researchers from the raw data they collected, and the difficulties of gaining from the skills and experiences of peer interviewers without exploiting their labour. The paper also explores the advantages of involving peer interviewers closely in research work and reflects on the nature and boundaries of expert knowledge that can become evident in such collaborations. The need for a certain amount of flexibility over the roles and domains of control that lay experts and researchers traditionally inhabit is suggested. In conclusion, it is argued that the involvement of peer interviewers in research can be a valuable means of enhancing our knowledge and understanding of a variety of population groups who tend to live beyond the gaze of more orthodox researchers.

Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence

This study was designed to resolve whether experimental placebo responses are due to either increased compliance or habituation. We stimulated both forearms and recorded laser-evoked potentials from 18 healthy volunteers treated on one arm with a sham analgesic cream and an inactive cream on the other (treatment group), and 13 volunteers with an inactive cream on both arms (controls). The treatment group showed a significant reduction in the pain ratings and laser-evoked potentials with both the sham and inactive creams. The control group showed no evidence of habituation to the laser stimulus. The results indicate that the reduction in pain during experimental placebo response is unlikely to be due to sensory habituation or compliance with the experimental instructions.

Differential effects on the laser evoked potential of selectively attending to pain localisation versus pain unpleasantness.

OBJECTIVE To determine the effects on the laser evoked potential (LEP) of selectively attending to affective (unpleasantness) versus sensory-discriminative (localisation) components of pain. METHODS LEPs, elicited by painful CO2 laser stimulation of two areas of the right forearm, were recorded from 62 electrodes in 21 healthy volunteers, during three tasks that were matched for generalised attention: Localisation (report stimulus location), Unpleasantness (report stimulus unpleasantness), Control (report pain detection). LEP components are named by polarity, latency, and electrode. RESULTS N300-T7 peak amplitude was significantly greater during Localisation than Unpleasantness. The difference in N300-T7 amplitude between Localisation and Control approached significance, suggesting an increased amplitude in Localisation compared with Control, rather than a reduced amplitude in Unpleasantness. Peak amplitude, latency, and topography of N300-FCz, P450, P600-800 (early P3) and P800-1000 (late P3) did not differ significantly between tasks. CONCLUSIONS These results suggest that the N300-T7 LEP peak reflects the activity of cerebral generators involved in the localisation of pain. The topography of N300-T7 is consistent with a source in contralateral secondary somatosensory cortex/insula and maybe primary somatosensory cortex. SIGNIFICANCE This study confirms a role of the lateral pain system in the localisation of pain, and distinguishes it from stimulus novelty or attention.

Cognitive changes as a result of a single exposure to placebo.

Placebo has been shown to be a powerful analgesic with corresponding reduction in the activation of the pain matrix in the brain. However, the response to placebo treatment is highly variable. It is unclear how anticipatory and pain-evoked potentials are affected by the treatment and how reproducible the response is. Laser stimulation was used to induce moderate pain in healthy volunteers. We induced placebo analgesia by conditioning subjects to expect pain reduction by applying a sham anaesthetic cream on one arm in conjunction with a reduced laser stimulus. Pain ratings were assessed before, during and after treatment. Using lectroencephalography (EEG) we measured anticipatory neural responses and pain-evoked potentials to laser heat to determine how expectation of analgesia affected the response to a placebo manipulation. This was a reproducibility study and as such the experimental procedure was repeated after a minimum gap of 2 weeks. Significant reductions in pain-evoked potentials were shown after treatment. The anticipatory responses did not change after treatment for the control and sham-treatment groups in the first session but were significantly lower in the repeat session relative to the first session in the sham-treatment group only. A significant correlation was found between the reduction in state anxiety in the repeat session relative to the first and the reduction in the anticipatory response in the sham-treatment group. Receiving a placebo treatment appears to cause a lasting change in the cognitive processing of pain for at least 6 weeks. This cognitive change may be facilitated by a change in state anxiety.

Categories of placebo response in the absence of site-specific expectation of analgesia

&NA; Experimental placebo analgesia is induced by building an expectation of reduced pain in a specific body part, usually using an inert cream in the guise of a local anaesthetic in conjunction with conditioning. We investigated non‐site‐specific placebo analgesia by conditioning subjects to expect the anaesthetic cream on one arm, without specifying if they will definitely receive the cream, or to which arm it might be applied. Painful heat pulses (150 ms) from a CO2 laser were delivered randomly to both arms. A treatment group (n = 24) underwent three experimental blocks (pre‐cream, conditioning after cream, and post‐conditioning). During the conditioning block, the intensity of the stimulus was reduced on one arm only. In the post‐conditioning block it was returned to the painful level. We evaluated the change of intensity rating post‐conditioning compared to the pre‐cream block. In contrast to a control group (n = 16), the treatment group reported a significant reduction in intensity ratings (F1,38 = 12.1; p = 0.001). In the treatment group, we observed a range of placebo responses: unilateral responders (33.3%), subjects with a placebo response in the conditioned arm only; bilateral responders (33.3%), subjects reporting reduction in the intensity ratings in both arms, and non‐responders, whose intensity ratings were not influenced by conditioning. We discuss these responses in terms of different levels of expected analgesia, facilitated by the absence of a site‐specific focus for the treatment. We suggest this allowed the individuals suggestibility to influence their assessment of the pain experience by combining different levels of expectation with the information from the actual pain stimulus.

Acoustic noise in functional magnetic resonance imaging reduces pain unpleasantness ratings

Functional magnetic resonance imaging (fMRI) is increasingly used in cognitive studies. Unfortunately, the scanner produces acoustic noise during the image acquisition process. Interference from acoustic noise is known to affect auditory, visual and motor processing, raising the possibility that acoustic interference may also modulate processing of other sensory modalities such as pain. With the increasing use of fMRI in the investigation of the mechanisms of pain perception, particularly in relation to attention, this issue has become highly relevant. Pain is a complex experience, composed of sensory-discriminative, affective-motivational and cognitive-evaluative components. The aim of this experiment was to assess the effect of MRI scanner noise, compared to white noise, on the affective (unpleasantness) and the sensory-discriminative (localisation) components of pain. Painful radiant heat from a CO(2) laser was delivered to the skin of the right forearm in 24 healthy volunteers. The volunteers attended to either pain location or pain unpleasantness during three conditions: i) no noise, ii) exposure to MRI scanner noise (85 dB) or iii) exposure to white noise (85 dB). Both MRI scanner noise and white noise significantly reduced unpleasantness ratings (from 5.1 +/- 1.6 in the control condition to 4.7 +/- 1.5 (P = 0.002) and 4.6 +/- 1.6 (P < 0.001) with scanner and white noise respectively), whereas the ability to localise pain was not significantly affected (from 85.4 +/- 9.2% correct in the control condition to 83.1 +/- 10.3% (P = 0.06) and 83.9 +/- 9.5% (P = 0.27) with MRI scanner and white noise respectively). This phenomenon should be taken into account in the design of fMRI studies into human pain perception.

Role of Functional Brain Imaging in Understanding Rheumatic Pain

Rheumatic pain and, in particular, rheumatoid arthritis, osteoarthritis and fibromyalgia, are common and debilitating chronic pain syndromes. Recently, human functional neuroimaging, for example EEG, fMRI, and PET has begun to reveal some of the crucial central nervous system mechanisms underlying these diseases. The purpose of this review is to summarise current knowledge on the brain mechanisms of rheumatic pain revealed by functional neuroimaging techniques. The evidence suggests that two mechanisms may be largely responsible for the clinical pain associated with these rheumatic diseases: abnormalities in the medial pain system and/or central nervous system sensitisation and inhibition. If we can understand how functioning of the central nociceptive system becomes altered, even in the absence of peripheral nociceptive input, by using functional neuroimaging techniques, in the future we may be able to develop improved, more effective treatments for patients with chronic rheumatic pain.

Placebo analgesia: cognitive influences on therapeutic outcome

The therapeutic response to a drug treatment is a mixture of direct pharmacological action and placebo effect. Therefore, harnessing the positive aspects of the placebo effect and reducing the negative ones could potentially benefit the patient. This article is aimed at providing an overview for clinicians of the importance of contextual psychosocial variables in determining treatment response, and the specific focus is on determinants of the placebo response. A better understanding of the physiological, psychological, and social mechanisms of placebo may aid in predicting which contexts have the greatest potential for inducing positive treatment responses. We examine the evidence for the role of psychological traits, including optimism, pessimism, and the effect of patient expectations on therapeutic outcome. We discuss the importance of the patient-practitioner relationship and how this can be used to enhance the placebo effect, and we consider the ethical challenges of using placebos in clinical practice.