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Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up-like pain). There was a significant placebo effect on both ongoing (P=.009 to .019) and evoked neuropathic pain (P=.0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P⩽.001). Pain increases during nocebo were nonsignificant (P=.394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients' expectations coexist with emotional feelings about treatments., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The combined oral contraceptive pill (COCP) has been implicated in the development of a number of chronic pain conditions. Modern COCP formulations produce a low endogenous estradiol, low progesterone environment similar to the early follicular phase of the natural menstrual cycle, with a variable effect on serum androgen levels. We used behavioural measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli in healthy women, in both a natural and COCP-induced low endogenous estradiol state, to investigate whether alterations in central pain processing may underlie these observations in COCP users. Although COCP users overall did not require lower temperatures to obtain a fixed pain intensity, alterations in the brain response to these stimuli were observed. In a subgroup of COCP users with significantly reduced serum testosterone, however, lower temperatures were required. Region-of-interest analysis revealed that within key regions of the descending pain inhibitory system, activity in response to noxious stimulation varied with serum testosterone levels in both groups of women. Of particular interest, in COCP users, activity in the rostral ventromedial medulla increased with increasing testosterone and in those women with low testosterone, was significantly reduced compared to controls. These findings suggest that, in a low endogenous estradiol state, testosterone may be a key factor in modulating pain sensitivity via descending pathways. Specifically, failure to engage descending inhibition at the level of the rostral ventromedial medulla may be responsible for the reduction in temperature required by COCP users with low circulating testosterone., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Context can influence the experience of any event. For instance, the thought that "it could be worse" can improve feelings towards a present misfortune. In this study we measured hedonic feelings, skin conductance, and brain activation patterns in 16 healthy volunteers who experienced moderate pain in two different contexts. In the "relative relief context," moderate pain represented the best outcome, since the alternative outcome was intense pain. However, in the control context, moderate pain represented the worst outcome and elicited negative hedonic feelings. The context manipulation resulted in a "hedonic flip," such that moderate pain elicited positive hedonics in the relative relief context. Somewhat surprisingly, moderate pain was even rated as pleasant in this context, despite being reported as painful in the control context. This "hedonic flip" was corroborated by physiological and functional neuroimaging data. When moderate pain was perceived as pleasant, skin conductance and activity in insula and dorsal anterior cingulate were significantly attenuated relative to the control moderate stimulus. "Pleasant pain" also increased activity in reward and valuation circuitry, including the medial orbitofrontal and ventromedial prefrontal cortices. Furthermore, the change in outcome hedonics correlated with activity in the periacqueductal grey (PAG) of the descending pain modulatory system (DPMS). The context manipulation also significantly increased functional connectivity between reward circuitry and the PAG, consistent with a functional change of the DPMS due to the altered motivational state. The findings of this study point to a role for brainstem and reward circuitry in a context-induced "hedonic flip" of pain., (Copyright © 2012 International Association for the Study of Pain. All rights reserved.)

Cannabis is reported to be remarkably effective for the relief of otherwise intractable pain. However, the bases for pain relief afforded by this psychotropic agent are debatable. Nonetheless, the frontal-limbic distribution of cannabinoid receptors in the brain suggests that cannabis may target preferentially the affective qualities of pain. This central mechanism of action may be relevant to cannabinoid analgesia in humans, but has yet to be demonstrated. Here, we employed functional magnetic resonance imaging to investigate the effects of delta-9-tetrahydrocannabinol (THC), a naturally occurring cannabinoid, on brain activity related to cutaneous ongoing pain and hyperalgesia that were temporarily induced by capsaicin in healthy volunteers. On average, THC reduced the reported unpleasantness, but not the intensity of ongoing pain and hyperalgesia: the specific analgesic effect on hyperalgesia was substantiated by diminished activity in the anterior mid cingulate cortex. In individuals, the drug-induced reduction in the unpleasantness of hyperalgesia was positively correlated with right amygdala activity. THC also reduced functional connectivity between the amygdala and primary sensorimotor areas during the ongoing-pain state. Critically, the reduction in sensory-limbic functional connectivity was positively correlated with the difference in drug effects on the unpleasantness and the intensity of ongoing pain. Peripheral mechanisms alone cannot account for the dissociative effects of THC on the pain that was observed. Instead, the data reveal that amygdala activity contributes to interindividual response to cannabinoid analgesia, and suggest that dissociative effects of THC in the brain are relevant to pain relief in humans., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Na(v)1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Patients with chronic pain conditions demonstrate altered central processing of experimental noxious stimuli, dysfunction of the hypothalamic-pituitary-adrenal axis, and reduced quality of life. Dysmenorrhoea is not considered a chronic pain condition, but is associated with enhanced behavioural responses to experimental noxious stimuli. We used behavioural measures, functional magnetic resonance imaging, and serum steroid hormone levels to investigate the response to experimental thermal stimuli in otherwise healthy women, with and without dysmenorrhoea. Women with dysmenorrhoea reported increased pain to noxious stimulation of the arm and abdomen throughout the menstrual cycle; no menstrual cycle effect was observed in either group. During menstruation, deactivation of brain regions in response to noxious stimulation was observed in control women but not in women with dysmenorrhoea. Without background pain (ie, in nonmenstrual phases), activity in the entorhinal cortex appeared to mediate the increased responses in women with dysmenorrhoea. Mean cortisol was significantly lower in women with dysmenorrhoea and was negatively correlated with the duration of the symptom. Additionally, women with dysmenorrhoea reported significantly lower physical but not mental quality of life. Thus, many features of chronic pain conditions are also seen in women with dysmenorrhoea: specifically a reduction in quality of life, suppression of the hypothalamic-pituitary-adrenal axis, and alterations in the central processing of experimental noxious stimuli. These alterations persist when there is no background pain and occur in response to stimuli at a site distant from that of the clinical pain. These findings indicate the potential importance of early and adequate treatment of dysmenorrhoea., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

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.

Although religious belief is often claimed to help with physical ailments including pain, it is unclear what psychological and neural mechanisms underlie the influence of religious belief on pain. By analogy to other top-down processes of pain modulation we hypothesized that religious belief helps believers reinterpret the emotional significance of pain, leading to emotional detachment from it. Recent findings on emotion regulation support a role for the right ventrolateral prefrontal cortex (VLPFC), a region also important for driving top-down pain inhibitory circuits. Using functional magnetic resonance imaging in practicing Catholics and avowed atheists and agnostics during painful stimulation, here we show the existence of a context-dependent form of analgesia that was triggered by the presentation of an image with a religious content but not by the presentation of a non-religious image. As confirmed by behavioral data, contemplation of the religious image enabled the religious group to detach themselves from the experience of pain. Critically, this context-dependent modulation of pain specifically engaged the right VLPFC, whereas group-specific preferential liking of one of the pictures was associated with activation in the ventral midbrain. We suggest that religious belief might provide a framework that allows individuals to engage known pain-regulatory brain processes.

Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.

Neuroimaging methods have so far identified various structures in the brain involved in the processing of pain and its control. However, our understanding of their anatomical connectivities is relatively weak. Diffusion tensor imaging (DTI), a magnetic resonance imaging-based method, allows in vivo mapping of the anatomical connections in the human brain and was used to investigate the white matter connections originating from the periaquaductal grey (PAG) and nucleus cuneiformis (NCF). We performed DTI on 8 healthy right-handed male volunteers. Group analysis showed that tract paths could be defined and their likelihood quantified for connections between the PAG and separately for the NCF, to the prefrontal cortex, amygdala, thalamus, hypothalamus and rostroventral medial medulla bilaterally. The connections identified confirm the existence of an anatomical circuitry for the functionally characterised top-down influences on pain processing via brainstem structures in humans.