The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning

Research shows that placebo analgesia can be induced through social observational learning. Our aim was to replicate and extend this result by studying the effect of the sex of both the model and the subject on the magnitude of placebo analgesia induced by social observational learning. Four experimental (1 through 4) and 2 control (5 and 6) groups were observed: groups 1, 3, and 5 were female; groups 2, 4, and 6 were male. All subjects received pain stimuli of the same intensity preceded by green and red lights. Before receiving pain stimuli, groups 1 and 4 observed a female model and groups 2 and 3 a male model; both models simulated responses to pain stimuli preceded by green lights as less painful than those preceded by red lights. Groups 1 through 4 also rated pain stimuli preceded by green lights as less painful. Further investigation revealed that in fact subjects in experimental groups rated red-associated stimuli as more painful than subjects from control groups who did not observe a model before receiving the same pain stimuli, indicating that nocebo hyperalgesia rather than placebo analgesia was induced. Empathy traits predicted the magnitude of nocebo hyperalgesia. Regardless of the sex of the subject, nocebo hyperalgesia was greater after the male model was observed. The results show that social observational learning is a mechanism that produces placebo effects. They also indicate that the sex of the model plays an important role in this process.     

Successful Reversal of Hyperalgesia/Myoclonus Complex with Low‐Dose Ketamine Infusion

Abstract: We report the successful use of low‐dose ketamine infusion for treating a severe episode of painful myoclonus in the lower extremities, associated with opioid‐induced hyperalgesia (OIH), in a patient who was receiving long‐term, high dose intrathecal hydromorphone therapy. A low‐dose ketamine infusion immediately relieved the painful myoclonus. It also enabled a reduction in the intrathecal opioid dosage leading to a resolution of the acute symptoms attributed to OIH.     

The Influence of Placebo Analgesia Manipulations on Pain Report,the Nociceptive Flexion Reflex,and Autonomic Responses to Pain

Expectations for pain relief and experience/conditioning are psychological factors that contribute to placebo analgesia, yet few studies have studied the physiological mechanisms underlying their effects. This study randomized 133 participants to 4 groups: an expectation only (E-only) group, a conditioning only (C-only) group, an expectation plus conditioning (E+C) group, and a natural history (NH) control group. Painful electric stimulations were delivered before and after an inert cream was applied to the site of stimulation. Pain-related outcomes (pain ratings, nociceptive flexion reflex [NFR], skin conductance response, and heart rate acceleration) were recorded after each stimulation. NFR (a measure of spinal nociception) assessed if placebo analgesia inhibited spinal processing of pain. E+C was the only manipulation that significantly inhibited pain and skin conductance response. Surprisingly, NFR was facilitated in the E+C and E-only groups. No effects were noted for C-only. Mediation analysis suggested 2 descending processes were engaged during E+C that influenced spinal nociception: 1) descending facilitation and 2) descending inhibition that was also responsible for pain reduction. These results suggest that E+C manipulations produce the strongest analgesia and have a complex influence on spinal nociception involving both inhibitory and facilitatory processes.

Chronic Worry as Avoidance of Arousal

Previous research suggests that worry is primarily a verbal-linguistic activity that may serve as a method of cognitive avoidance of fearful imagery. The purpose of the present study was to examine cognitive avoidance in high worriers (N=22) and low worriers (N=24) using psychophysiological measures and a modified dichotic listening task. The task involved presenting neutral words into an unattending ear while worry or neutral scenarios were presented into the attending ear. Participants were given a surprise word recognition test of the words presented to provide evidence of cognitive avoidance beyond self-report. Contrary to the hypotheses, high worriers did not have less physiological reactivity than did low worriers. Low worriers recognized more words than did high worriers overall. High worriers remembered more words from the worry scenario than the neutral condition, as would be expected if they attempted to avoid the worry scenario. Implications for treatment of worry and the use of the dichotic listening task in researching worry are discussed.     

Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway

Nocebo and placebo effects have been found to modulate several neurochemical systems, such as cholecystokinin, endogenous opioids, and endocannabinoids. Here we show that also the cyclooxygenase-prostaglandins pathway can be modulated by both nocebos and placebos. In fact, we found that negative expectation, the crucial element of the nocebo effect, about headache pain led to the enhancement of the cyclooxygenase-prostaglandins pathway, which, in turn, induced pain worsening. As an experimental model, we studied hypobaric hypoxia headache at high altitude in 2 populations of subjects. Whereas the experimental nocebo group received negative information by a single individual who was informed about the risk of headache, the control group did not know about the possible occurrence of headache. We found a significant increase in headache and salivary prostaglandins and thromboxane in the nocebo group compared to the control group, suggesting that negative expectations enhance cyclooxygenase activity. In addition, placebo administration to headache sufferers at high altitude inhibited the nocebo-related component of pain and prostaglandins synthesis, which indicates that the cyclooxygenase pathway can be modulated by both nocebos and placebos. Our results show for the first time how nocebos and placebos affect the synthesis of prostaglandins, which represent an important target of analgesic drugs, thus emphasizing once again the notion that placebos and drugs may use common biochemical pathways.     

Resiniferatoxin (RTX) Causes a Uniquely Protracted Musculoskeletal Hyperalgesia in Mice by Activation of TRPV1 Receptors

Inactivation of transient receptor potential vanilloid-1 (TRPV1) receptors is one approach to analgesic drug development. However, TRPV1 receptors exert different effects on each modality of pain. Because muscle pain is clinically important, we compared the effect of TRPV1 ligands on musculoskeletal nociception to that on thermal and tactile nociception. Injected parenterally, capsaicin had no effect on von Frey fiber responses (tactile) but induced a transient hypothermia and hyperalgesia in both the tail flick (thermal) and grip force (musculoskeletal) assays, presumably by its agonistic action at TRPV1 sites. In contrast, resiniferatoxin (RTX) produced a chronic (>58 days) thermal antinociception, consistent with its reported ability to desensitize TRPV1 sites. In the same mice, RTX produced a transient hypothermia (7 hours) and a protracted (28-day) musculoskeletal hyperalgesia in spite of a 35.5% reduction in TRPV1 receptor immunoreactivity in muscle afferents. Once musculoskeletal hyperalgesia subsided, mice were tolerant to the hyperalgesic effects of either capsaicin or RTX whereas tolerance to hypothermia did not develop until after 3 injections. Musculoskeletal hyperalgesia was prevented but not reversed by SB-366791, a TRPV1 antagonist, indicating that TRPV1 receptors initiate but do not maintain hyperalgesia. Injected intrathecally, RTX produced only a brief musculoskeletal hyperalgesia (2 days), after which mice were tolerant to this effect.     

氯诺昔康防治瑞芬太尼所致痛觉过敏现象的临床观察

[目的]探讨氯诺昔康对瑞芬太尼痛觉过敏现象的防治作用.[方法]选择因甲状腺肿块行择期手术患者40例,随机分为A、B两组(n=20),A组在诱导前予以氯诺昔康16 mg,B组在诱导前予以生理盐水5 mL.观察比较两组在PACU的躁动情况及注药前(T1),清醒后30 min(T2),1 h(T3),2 h(T4),4 h(...     

Widespread Hyperalgesia in Adolescents With Symptoms of Irritable Bowel Syndrome: Results From a Large Population-Based Study

Widespread hyperalgesia is well documented among adult patients with irritable bowel syndrome (IBS), but little is known about pain sensitivity among adolescents with IBS. We examined pain sensitivity in 961 adolescents from the general population (mean age 16.1 years), including pain threshold and tolerance measurements of heat (forearm) and pressure pain (fingernail and shoulder) and cold pressor tolerance (hand). Adolescents with IBS symptoms (Rome III criteria) had lower heat pain thresholds compared to controls after adjustments for sex, comorbid pain, and psychological distress (mean difference = –.8°C; 95% confidence interval [CI] = ?1.6 to ?.04). Similar results were found for pressure pain threshold at the shoulder (mean difference = ?46 kPa; 95% CI = ?78 to ?13) and fingernail (mean difference = –62 kPa; 95% CI = ?109 to ?15), and for an aggregate of all 3 threshold measures (z-score difference = ?.4; 95% CI = ?.6 to ?.2), though pressure pain threshold differences were nonsignificant after the final adjustments for psychological distress. No difference of pain tolerance was found between the IBS cases and controls. Our results indicate that adolescents in the general population with IBS symptoms, like adults, have widespread hyperalgesia.PerspectiveThis is the first report of widespread hyperalgesia among adolescents with IBS symptoms in the general population, with lower pain thresholds found to be independent of sex and comorbid pain. Our results suggest that central pain sensitization mechanisms in IBS may contribute to triggering and maintaining chronic pain symptoms.     

Pain reduction of acupoint electrical stimulation for patients with spinal surgery: a placebo-controlled study

Background

Acupoint electrical stimulation (AES) is commonly used for pain management. However, its true or placebo effect to achieve pain relief needs to be verified.

Objective

This study aimed to examine the true effect of AES to reduce postoperative pain in patients with spinal surgery receiving patient-controlled analgesia (PCA).

Method

A placebo- and sham-controlled study was conducted. Participants were randomly assigned to intervention with AES at true acupoints (the AES group, n = 30), AES at sham acupoints (the sham group, n = 30), or no intervention with AES (the control group, n = 30). Outcomes were assessed according to the amount of pain experienced and analgesics used.

Results

There were significant differences among the three groups in pain relief across time, and the occurrence of PCA button pushed and amount of analgesics used. The beneficial effects of AES were discernible when compared to the sham and the control.

Conclusions

AES at the true acupoints effectively reduced postoperative pain and analgesic usage. AES has now been implemented into healthcare and it is recommended that nurses be provided with the opportunity to earn their AES skills. More studies evaluating the effects of AES over a longer period and on pain after different surgical procedures are suggested.     

Investigating dose-dependent effects of placebo analgesia: a psychophysiological approach

Investigating dose-dependent effects of placebo analgesia (PA) in laboratory subjects undergoing pain testing, we evaluated 2 hypotheses: (1) greater expectancy for relief produces greater PA, and (2) cued expectancy for relief triggered by a predictive cue leads to more enhanced analgesia than does passive expectancy (no predictive cue). We used conditioning procedures in which 84 subjects experienced reduced stimulation intensity following the application of purported analgesic creams to the 2 experimental fingers, while the control finger received the same levels of stimulation as in the baseline block. The dose of placebos was manipulated by creating 2 levels of expectations for relief. The form of expectation (cued vs uncued) was also manipulated by a predictive cue specifying the next finger to be stimulated. Subjective reports and psychophysiological responses served as critical indicators for evaluating impacts of the placebo manipulation on subsequent pain processing. The dose-dependent PA was unambiguously demonstrated by the predicted ordering of the 3 fingers (ie, manipulated expectation levels) in terms of both response sensitivity and average response magnitude, in mixed-effects analysis of 3 outcome indicators (evoked potential, skin conductance response, pain report). Greater expectation for relief led to both (1) greater reductions in the average dependent variable slope (response sensitivity) as a function of stimulus intensity, and (2) greater reductions in average response magnitude. Unexpectedly, uncued expectation led to a slightly larger PA than did cued expectation. The study provided clear evidence that PA can occur in a “dose”-dependent manner, mediated by the levels of expectancy for pain relief.     

Induced fear reduces the effectiveness of a placebo intervention on pain

Fear was induced by the anticipation of electric shock in order to investigate whether fear reduced the effectiveness of a placebo intervention on reported pain and the acoustic startle reflex. Thirty-three subjects participated in a 3 Condition (Natural History [NH], Placebo [P], Placebo+Fear [PF])×3 Test (Pretest, Posttest 1, Posttest 2) within-subject design, tested on 3 separate days. Measures of fear were fear of pain (FOP), measured by the Fear of Pain Questionnaire (FPQ-III); fear-potentiated startle; and a self-report measure that assessed the effectiveness of the fear induction procedure. In the pain intensity data, there was a trend towards a placebo effect. This trend was abolished by induced fear, and was most pronounced in subjects who were highest in measures of fear. The placebo manipulation also caused a reduction in startle reflex amplitude. This effect was abolished by induced fear, and was strongest amongst high FOP subjects. In conclusion, induced fear abolished placebo analgesia, and this effect was strongest in subjects who had high scores on measures of fear.     

White matter integrity of the descending pain modulatory system is associated with interindividual differences in placebo analgesia

The ability for endogenous pain control varies considerably among individuals. The mechanisms underlying this interindividual difference are incompletely understood. We used placebo analgesia as a classic model of endogenous pain modulation in combination with diffusion tensor magnetic resonance imaging to test the hypothesis of a structural predisposition for the individual capacity of endogenous pain control. Specifically we determined white matter integrity within and between regions of the descending pain modulatory system. Twenty-four healthy participants completed a placebo paradigm and underwent diffusion tensor magnetic resonance imaging. The individual placebo analgesic effect was correlated with white matter integrity indexed by fractional anisotropy. The individual placebo analgesic effect was positively correlated with FA in the right dorsolateral prefrontal cortex, left rostral anterior cingulate cortex, and the periaqueductal grey. Probabilistic tractography seeded in these regions showed that stronger placebo analgesic responses were associated with increased mean fractional anisotropy values within white matter tracts connecting the periaqueductal grey with pain control regions such as the rostral anterior cingulate cortex and the dorsolateral prefrontal cortex. Our findings provide the first evidence that the white matter integrity within and between regions of the descending pain modulatory network is critically linked with the individual ability for endogenous pain control.     

Analgesic Effects of Transcutaneous Ultrasound Nerve Stimulation in a Rat Model of Oxaliplatin-Induced Mechanical Hyperalgesia and Cold Allodynia

This study investigated the effects and underlying mechanisms of therapeutic ultrasound (TUS) in a rat model of oxaliplatin-induced peripheral neuropathy. Animals received a total of eight injections with oxaliplatin (4 mg/kg), administered at 3-d intervals. TUS intervention (1 MHz, 0.5 W/cm²) started on the fifth oxaliplatin administration and continued for 10 consecutive d. Sensory behavioral examinations, protein levels of transient receptor potential channels (TRPM8 and TRPV1) in dorsal root ganglia (DRG) and substance P (SP) in spinal dorsal horn were examined. Results indicated that TUS can reduce mechanical and cold hyper-responsive behaviors caused by repeated administration of oxaliplatin. Oxaliplatin-related increases in protein levels of TRPM8 in DRG and SP in the dorsal horn were also reduced after TUS. Taken together, the results revealed beneficial effects of TUS on oxaliplatin-induced mechanical hyperalgesia and cold allodynia and suggested involvement of TUS biochemicals in suppressing TRPM8 in DRG and SP in spinal cords.     

Cognitive manipulation targeted at decreasing the conditioning pain perception reduces the efficacy of conditioned pain modulation

Although painfulness of the conditioning stimulus (CS) is required for the activation of conditioned pain modulation (CPM), it is still unclear whether CPM expression depends on the objective physical intensity of the CS or the subjective perception of its pain. Accordingly, we cognitively manipulated the perceived CS pain, rendering the physical aspects of the CPM paradigm untouched. Baseline CPM was measured among 48 young healthy male subjects using the parallel paradigm with contact heat as test pain and hand immersion in hot water as CS. Subjects were then randomized into 4 groups, all of which were cognitively manipulated as to the CS-induced pain: group 1, placebo (CS less painful); group 2, nocebo (CS more painful); and groups 3 and 4, the informed control groups for groups 1 and 2, respectively. CPM was reassessed after the manipulation. Comparing the groups by MANCOVA (multivariate analysis of covariance) revealed that placebo exerted decreased CS pain and consequent attenuation of CPM magnitudes, while nocebo elicited increased CS pain, but without CPM elevation (P < .0001). Within the placebo group, the reduction in CS pain was associated with diminished CPM responses (r = 0.767; P = .001); however, no such relationship characterized the nocebo group. Pain inhibition under CPM seems to depend on the perceived level of the CS pain rather than solely its physical intensity. Cognitively decreasing the perceived CS pain attenuates CPM magnitude, although a ceiling effect may limit CPM enhancement after cognitively increased CS pain. These findings emphasize the relevance of cognitive mechanisms in determining endogenous analgesia processes in humans.     

Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: an fMRI study in healthy placebo responders and nonresponders

This functional magnetic resonance imaging study analysed the behavioural and neural responses during expectation-mediated placebo analgesia in a rectal pain model in healthy subjects. In N = 36 healthy subjects, the blood oxygen level-dependent (BOLD) response during cued anticipation and painful rectal stimulation was measured. Using a within-subject design, placebo analgesia was induced by changing expectations regarding the probability of receiving an analgesic drug to 0%, 50%, and 100%. Placebo responders were identified by median split based on pain reduction (0% to 100% conditions), and changes in neural activation correlating with pain reduction in the 0% and 100% conditions were assessed in a regions-of-interest analysis. Expectation of pain relief resulted in overall reductions in pain and urge to defecate, and this response was significantly more pronounced in responders. Within responders, pain reduction correlated with reduced activation of dorsolateral and ventrolateral prefrontal cortices, somatosensory cortex, and thalamus during cued anticipation (paired t tests on the contrast 0% > 100%); during painful stimulation, pain reduction correlated with reduced activation of the thalamus. Compared with nonresponders, responders demonstrated greater placebo-induced decreases in activation of dorsolateral prefrontal cortex during anticipation and in somatosensory cortex, posterior cingulate cortex, and thalamus during pain. In conclusion, the expectation of pain relief can substantially change perceived painfulness of visceral stimuli, which is associated with activity changes in the thalamus, prefrontal, and somatosensory cortices. Placebo analgesia constitutes a paradigm to elucidate psychological components of the pain response relevant to the pathophysiology and treatment of chronic abdominal pain.     

硬膜外分娩镇痛联合心理干预对产妇焦虑抑郁情绪的影响

【目的】探讨硬膜外分娩镇痛联合心理干预对产妇焦虑抑郁情绪的影响。【方法】160例无相关禁忌的初产妇,随机分成两组,每组80例。P组为硬膜外分娩镇痛联合心理干预（渐进性肌肉放松法和腹式呼吸法）、R组为硬膜外分娩镇痛。比较两组镇痛效果（VAS）、病人自控镇痛（PCA）用药量、焦虑自评量表（SAS）和抑郁自评量表（SDS）评分。【结果】第一产程潜伏期、活跃期和第二产程、第三产程VAS评分、PCA用药量、SAS和SDS评分均P组低于R组。【结论】硬膜外分娩镇痛联合心理干预用于分娩期,能显著改善产妇的心理状态,镇痛效果确切,有助于提高围生期质量。     

Intra-Articular Blockade of P2X7 Receptor Reduces the Articular Hyperalgesia and Inflammation in the Knee Joint Synovitis Especially in Female Rats

Synovitis is a key factor in joint disease pathophysiology, which affects a greater proportion of women than men. P2X7 receptor activation contributes to arthritis, but whether it plays a role in articular inflammatory pain in a sex-dependent manner is unknown. We investigated whether the P2X7 receptor blockade in the knee joint of male and female rats reduces the articular hyperalgesia and inflammation induced by a carrageenan knee joint synovitis model. Articular hyperalgesia was quantified using the rat knee joint incapacitation test and the knee joint inflammation, characterized by the concentration of cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cytokine-induced neutrophil chemoattractant-1, and by neutrophil migration, was quantified using enzyme-linked immunosorbent assay and by myeloperoxidase enzyme activity measurement, respectively. P2X7 receptor blockade by the articular coadministration of selective P2X7 receptor antagonist A740003 with carrageenan significantly reduced articular hyperalgesia, pro-inflammatory cytokine concentrations, and myeloperoxidase activity induced by carrageenan injection into the knee joint of male and estrus female rats. However, a lower dose of P2X7 receptor antagonist was sufficient to significantly induce the antihyperalgesic and anti-inflammatory effects in estrus female but not in male rats. These results suggest that P2X7 receptor activation by endogenous adenosine 5’-triphosphate is essential to articular hyperalgesia and inflammation development in the knee joint of male and female rats. However, female rats are more responsive than male rats to the antihyperalgesic and anti-inflammatory effects induced by P2X7 receptor blockade.

Enhancing the Placebo Response: Functional Magnetic Resonance Imaging Evidence of Memory and Semantic Processing in Placebo Analgesia

Two groups of patients with irritable bowel syndrome rated pain and underwent functional magnetic resonance imaging brain scanning during experimentally induced rectal distension (20 seconds, 7 stimuli). Group 1 was tested under baseline (natural history [NH]) and a verbally induced placebo condition, whereas Group 2 was tested under baseline and standard placebo (no verbal suggestion for pain reduction) and intrarectal lidocaine conditions. As hypothesized, intrarectal lidocaine reduced evoked pain and pain-related brain activity within Group 2. Between-group comparisons showed that adding a verbal suggestion to a placebo condition increased neural activity involved in memory and semantic processing, areas that process the placebo suggestions. These areas, in turn, are likely to influence brain areas involved in emotions and analgesia and consequently the placebo effect. These placebo suggestions also added significant decreases in activity of brain areas that process pain. The test stimulus itself seems to cue these effects and is consistent with previous explanations that somatic focus and sensory feedback reinforce expectations and other factors that mediate placebo analgesic effects.PerspectiveExpectations for pain can be verbally manipulated to produce placebo analgesia. Placebo analgesia is accompanied by decreased brain activity related to processing pain and increased brain activity that generates placebo analgesia, including semantic and memory regions. Placebo suggestions may enhance placebo analgesia by engaging a feedback mechanism triggered by the painful stimulus itself and related to brain mechanisms involved in memory and semantic processing.     

Variability in placebo analgesia and the role of fear of pain--an ERP study

Fear of pain (FOP) and its effect on placebo analgesia was investigated. It was hypothesized that FOP should interfere with placebo-mediated pain inhibition and result in weaker placebo responding in pain intensity, pain unpleasantness, stress, and event-related potentials to contact heat pain. Thirty-three subjects participated in a balanced 2 condition (natural history, placebo) × 3 test (pretest, posttest 1, posttest 2) within-subject design, tested on 2 separate days. FOP was measured by the Fear of Pain Questionnaire and subjective stress by the Short Adjective Check List. Placebo effects were found on reported pain unpleasantness and N2 and P2 amplitudes. FOP was related to reduced placebo responding in pain unpleasantness, but this was only evident for the subjects who received the placebo condition on day 1. Subjects who received the placebo condition on day 1 experienced more pretest stress than those who received the placebo condition on day 2 (ie, reversed condition order), and this explained the interaction effect on placebo responding. FOP was related to reduced placebo responding on P2 amplitude, whereas placebo responding on N2 amplitude was unaffected by FOP. Higher placebo responses on N2 and P2 amplitudes were both related to higher placebo analgesic magnitude in pain unpleasantness. In conclusion, increased FOP was found to reduce subjective and electrophysiological placebo analgesic responses.     

Differential effects of experimental central sensitization on the time-course and magnitude of offset analgesia

Pain perception is temporally altered during states of chronic pain and acute central sensitization; however, the mechanisms contributing to temporal processing of nociceptive information remain poorly understood. Offset analgesia is a phenomenon that reflects the presence of temporal contrast mechanisms for nociceptive information and can provide an end point to study temporal aspects of pain processing. In order to investigate whether offset analgesia is disrupted during sensitized states, 23 healthy volunteers provided real-time continuous visual analogue scale responses to noxious heat stimuli that evoke offset analgesia. Responses to these stimuli were evaluated during capsaicin-heat sensitization (45°C stimulus, capsaicin cream 0.1%) and heat-only sensitization (40°C stimulus, placebo cream). Capsaicin-heat sensitization produced significantly larger regions of secondary mechanical allodynia compared to heat-only sensitization. Although areas of mechanical allodynia were positively related to individual differences in heat pain sensitivity, this relationship was altered at later time points after capsaicin-heat sensitization. Heat hyperalgesia was observed in the secondary region following both capsaicin-heat and heat-only sensitization. Increased latencies to maximal offset analgesia and prolonged aftersensations were observed only in the primary regions directly treated by capsaicin-heat or heat alone. However, contrary to the hypothesis that offset analgesia would be reduced following capsaicin-heat sensitization, the magnitude of offset analgesia remained remarkably intact after both capsaicin-heat and heat-only sensitization in zones of both primary and secondary mechanical allodynia. These data indicate that offset analgesia is a robust phenomenon and engages mechanisms that interact minimally with those supporting acute central sensitization.