Melissa Chont

Validation of proposed diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome

&NA; Current IASP diagnostic criteria for CRPS have low specificity, potentially leading to overdiagnosis. This validation study compared current IASP diagnostic criteria for CRPS to proposed new diagnostic criteria (the “Budapest Criteria”) regarding diagnostic accuracy. Structured evaluations of CRPS‐related signs and symptoms were conducted in 113 CRPS‐I and 47 non‐CRPS neuropathic pain patients. Discriminating between diagnostic groups based on presence of signs or symptoms meeting IASP criteria showed high diagnostic sensitivity (1.00), but poor specificity (0.41), replicating prior work. In comparison, the Budapest clinical criteria retained the exceptional sensitivity of the IASP criteria (0.99), but greatly improved upon the specificity (0.68). As designed, the Budapest research criteria resulted in the highest specificity (0.79), again replicating prior work. Analyses indicated that inclusion of four distinct CRPS components in the Budapest Criteria contributed to enhanced specificity. Overall, results corroborate the validity of the Budapest Criteria and suggest they improve upon existing IASP diagnostic criteria for CRPS.

Development of a severity score for CRPS

&NA; The clinical diagnosis of Complex Regional Pain Syndrome (CRPS) is a dichotomous (yes/no) categorization necessary for clinical decision‐making. However, such dichotomous diagnostic categories do not convey an individuals subtle and temporal gradations in severity of the condition, and have poor statistical power when used as an outcome measure in research. This study evaluated the validity and potential utility of a continuous type score to index severity of CRPS. Psychometric and medical evaluations were conducted in 114 CRPS patients and 41 non‐CRPS neuropathic pain patients. Based on the presence/absence of 17 clinically‐assessed signs and symptoms of CRPS, an overall CRPS Severity Score (CSS) was derived. The CSS discriminated well between CRPS and non‐CRPS patients (p < .001), and displayed strong associations with dichotomous CRPS diagnoses using both IASP diagnostic criteria (Eta = 0.69) and proposed revised criteria (Eta = 0.77–0.88). Higher CSS was associated with significantly higher clinical pain intensity, distress, and functional impairments, as well as greater bilateral temperature asymmetry and thermal perception abnormalities (p’s < .05). In an archival prospective dataset, increases in anxiety and depression from pre‐surgical baseline to 4 weeks post‐knee arthroplasty were found to predict significantly higher CSS at 6‐ and 12‐month follow‐up (p’s < .05). Results indicate the CSS corresponds with and complements currently accepted dichotomous diagnostic criteria for CRPS, and support its validity as an index of CRPS severity. Its utility as an outcome measure in research studies is also suggested, with potential statistical advantages over dichotomous diagnostic criteria.

Pain-related effects of trait anger expression: neural substrates and the role of endogenous opioid mechanisms.

Literature is reviewed indicating that greater tendency to manage anger via direct verbal or physical expression (trait anger-out) is associated with increased acute and chronic pain responsiveness. Neuroimaging data are overviewed supporting overlapping neural circuits underlying regulation of both pain and anger, consisting of brain regions including the rostral anterior cingulate cortex, orbitofrontal cortex, anterior insula, amygdala, and periaqueductal gray. These circuits provide a potential neural basis for observed positive associations between anger-out and pain responsiveness. The role of endogenous opioids in modulating activity in these interlinked brain regions is explored, and implications for understanding pain-related effects of anger-out are described. An opioid dysfunction hypothesis is presented in which inadequate endogenous opioid inhibitory activity in these brain regions contributes to links between trait anger-out and pain. A series of studies is presented that supports the opioid dysfunction hypothesis, further suggesting that gender and genetic factors may moderate these effects. Finally, possible implications of interactions between trait anger-out and state behavioral anger expression on endogenous opioid analgesic activity are described.

Baroreflex sensitivity associated hypoalgesia in healthy states is altered by chronic pain

&NA; While experimental baroreceptor stimulation is known to elicit hypoalgesia in healthy individuals, the impact of spontaneous baroreflex sensitivity (BRS) on acute pain responses is not known. We tested for associations between BRS and pain responses in healthy individuals, whether these associations are altered in chronic low back pain (CLBP), and the role of alpha‐2 adrenergic (ADRA2) mechanisms in these effects. Twenty‐five healthy controls and 21 CLBP subjects completed three acute pain tasks after receiving placebo or an intravenous ADRA2 antagonist (yohimbine hydrochloride, 0.4 mg/kg) across two sessions in counterbalanced order. Resting pre‐drug spontaneous BRS was assessed using the sequence method. CLBP subjects displayed lower resting BRSDown than controls (p < .05). Drug × BRSDown interactions indicated that significant BRS‐related hypoalgesia on thermal pain threshold and tolerance was eliminated with yohimbine (p’s < .05). Subject Type × BRSUp interactions on finger pressure (MPQ‐Sensory) and ischemic tasks (MPQ‐Sensory, pain threshold, intra‐task numeric intensity ratings) indicated that inverse BRS/pain associations in controls (p’s < .05) were absent in CLBP subjects. Subject Type × Drug × BRSDown interactions on finger pressure MPQ‐Sensory and intra‐task numeric intensity ratings (p’s < .05) indicated that for controls, yohimbine attenuated the significant inverse BRS/pain sensitivity associations noted under placebo. In contrast, CLBP subjects displayed a nonsignificant positive BRS/pain association under placebo, with yohimbine producing an inverse association similar to controls (significant for MPQ‐Sensory). Results suggest presence of spontaneous BRS‐related hypoalgesia in healthy individuals that is partially mediated by ADRA2 mechanisms, and that CLBP blunts BRS‐related hypoalgesia. As a group, the CLBP subjects do not manifest baroreceptor‐induced antinociception.

Associations between daily chronic pain intensity, daily anger expression, and trait anger expressiveness: an ecological momentary assessment study.

Summary Within‐day associations between behavioral anger expression and momentary chronic pain intensity show significant lagged effects, with elevated behavioral anger expression linked to greater subsequent pain intensity. ABSTRACT Links between elevated trait anger expressiveness (anger‐out) and greater chronic pain intensity are well documented, but pain‐related effects of expressive behaviors actually used to regulate anger when it is experienced have been little explored. This study used ecological momentary assessment methods to explore prospective associations between daily behavioral anger expression and daily chronic pain intensity. Forty‐eight chronic low back pain (LBP) patients and 36 healthy controls completed electronic diary ratings of momentary pain and behavioral anger expression in response to random prompts 4 times daily for 7 days. Across groups, greater trait anger‐out was associated with greater daily behavioral anger expression (P < 0.001). LBP participants showed higher levels of daily anger expression than controls (P < 0.001). Generalized estimating equation analyses in the LBP group revealed a lagged main effect of greater behavioral anger expression on increased chronic pain intensity in the subsequent assessment period (P < 0.05). Examination of a trait × situation model for anger‐out revealed prospective associations between elevated chronic pain intensity and later increases in behavioral anger expression that were restricted largely to individuals low in trait anger‐out (P < 0.001). Trait × situation interactions for trait anger suppression (anger‐in) indicated similar influences of pain intensity on subsequent behavioral anger expression occurring among low anger‐in persons (P < 0.001). Overlap with trait and state negative affect did not account for study findings. This study for the first time documents lagged within‐day influences of behavioral anger expression on subsequent chronic pain intensity. Trait anger regulation style may moderate associations between behavioral anger expression and chronic pain intensity.

Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes.

Summary Variations in the KCNJ6 gene appear to influence both acute and chronic pain phenotypes. Abstract G‐protein coupled inwardly rectifying potassium (GIRK) channels are effectors determining degree of analgesia experienced upon opioid receptor activation by endogenous and exogenous opioids. The impact of GIRK‐related genetic variation on human pain responses has received little research attention. We used a tag single nucleotide polymorphism (SNP) approach to comprehensively examine pain‐related effects of KCNJ3 (GIRK1) and KCNJ6 (GIRK2) gene variation. Forty‐one KCNJ3 and 69 KCNJ6 tag SNPs were selected, capturing the known variability in each gene. The primary sample included 311 white patients undergoing total knee arthroplasty in whom postsurgical oral opioid analgesic medication order data were available. Primary sample findings were then replicated in an independent white sample of 63 healthy pain‐free individuals and 75 individuals with chronic low back pain (CLBP) who provided data regarding laboratory acute pain responsiveness (ischemic task) and chronic pain intensity and unpleasantness (CLBP only). Univariate quantitative trait analyses in the primary sample revealed that 8 KCNJ6 SNPs were significantly associated with the medication order phenotype (P < .05); overall effects of the KCNJ6 gene (gene set‐based analysis) just failed to reach significance (P = .054). No significant KCNJ3 effects were observed. A continuous GIRK Related Risk Score (GRRS) was derived in the primary sample to summarize each individual’s number of KCNJ6 “pain risk” alleles. This GRRS was applied to the replication sample, which revealed significant associations (P < .05) between higher GRRS values and lower acute pain tolerance and higher CLBP intensity and unpleasantness. Results suggest further exploration of the impact of KCNJ6 genetic variation on pain outcomes is warranted.

What do plasma beta‐endorphin levels reveal about endogenous opioid analgesic function?

Plasma levels of beta‐endorphin (BE), an endogenous opioid analgesic, are often reported as they relate to acute and chronic pain outcomes. However, little is known about what resting plasma BE levels might reveal about functioning of the endogenous opioid antinociceptive system. This study directly examined associations between resting plasma BE and subsequent endogenous opioid analgesic responses to acute pain in 39 healthy controls and 37 individuals with chronic low back pain (LBP). Resting baseline levels of plasma BE were assessed. Next, participants received opioid blockade (8 mg naloxone i.v.) or placebo in a double‐blind, randomized, crossover design. Participants then underwent two acute pain stimuli: finger pressure (FP) pain and ischaemic (ISC) forearm pain. Blockade effects (naloxone minus placebo pain ratings) were derived to index endogenous opioid analgesic function. In placebo condition analyses for both pain stimuli, higher resting BE levels were associated with subsequently greater reported pain intensity (ps < 0.05), with this effect occurring primarily in healthy controls (BE × Participant Type interactions, ps < 0.05). In blockade effect analyses across both pain tasks, higher resting plasma BE predicted less subsequent endogenous opioid analgesia (smaller blockade effects; ps < 0.05). For the ISC task, these links were significantly more prominent in LBP participants (BE × Participant Type Interactions, ps < 0.05). Results suggest that elevated resting plasma BE may be a potential biomarker for reduced endogenous opioid analgesic capacity, particularly among individuals with chronic pain. Potential clinical implications are discussed.

Endogenous opioids may buffer effects of anger arousal on sensitivity to subsequent pain

ABSTRACT Evidence suggests that anger and pain are related, yet it is not clear by what mechanisms anger may influence pain. We have proposed that effects of anger states and traits on pain sensitivity are partly opioid mediated. In this study, we test the extent to which analgesic effects of acute anger arousal on subsequent pain sensitivity are opioid mediated by subjecting healthy participants to anger‐induction and pain either under opioid blockade (oral naltrexone) or placebo. Participants were 160 healthy individuals. A double‐blind, placebo‐controlled, between‐subjects opioid blockade design is used, with participants assigned randomly to one of two drug conditions (placebo or naltrexone), and to one of two Task Orders (anger‐induction followed by pain or vice versa). Results of ANOVAs show significant Drug Condition × Task Order interactions for sensory pain ratings (MPQ‐Sensory) and angry and nervous affect during pain‐induction, such that participants who underwent anger‐induction prior to pain while under opioid blockade (naltrexone) reported more pain, and anger and nervousness than those who underwent the tasks in the same order, but did so on placebo. Results suggest that for people with intact opioid systems, acute anger arousal may trigger endogenous opioid release that reduces subsequent responsiveness to pain. Conversely, impaired endogenous opioid function, such as that found among some chronic pain patients, may leave certain people without optimal buffering from the otherwise hyperalgesic affects of anger arousal, and so may lead to greater pain and suffering following upsetting or angry events.

Endogenous opioid function mediates the association between laboratory-evoked pain sensitivity and morphine analgesic responses

Summary Individual differences in endogenous opioid function predict morphine analgesic responses, and these endogenous opioid differences mediate the association between greater laboratory‐evoked pain sensitivity and greater analgesic responses to morphine. ABSTRACT Predictors of responsiveness to opioid analgesic medications are not well understood. This study tested whether individual differences in endogenous opioid (EO) function are associated with analgesic responsiveness to morphine. In randomized, counterbalanced order over 3 sessions, 45 chronic low back pain participants and 31 healthy controls received an opioid antagonist (8 mg naloxone), morphine (0.08 mg/kg), or placebo. Participants then engaged in 2 laboratory‐evoked pain tasks (ischemic and thermal). Outcomes included pain threshold, pain tolerance, and pain ratings. Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition and naloxone or morphine condition, respectively. For all 7 pain measures across the 2 laboratory pain tasks, greater EO function was associated with significantly lower morphine analgesic responsiveness (P < 0.001–P = 0.02). Morphine reduced pain responses of low EO individuals to levels similar to those of high EO individuals receiving placebo. Higher placebo condition–evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures (P < 0.001–P = 0.02). These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes (all P values < 0.05). In the laboratory‐evoked pain context, opioid analgesic medications may supplement inadequate EO analgesia, with little incremental benefit in those with preexisting high EO function. Implications for personalized medicine are discussed.

Interacting effects of trait anger and acute anger arousal on pain: the role of endogenous opioids.

Objective: Elevated trait anger (TRANG; heightened propensity to experience anger) is associated with greater pain responsiveness, possibly via associations with deficient endogenous opioid analgesia. This study tested whether acute anger arousal moderates the impact of TRANG on endogenous opioid analgesia. Methods: Ninety-four chronic low back pain (LBP) participants and 85 healthy controls received opioid blockade (8 mg of naloxone) or placebo in a randomized, counterbalanced order in separate sessions. Participants were randomly assigned to undergo either a 5-minute anger recall interview (ARI) or a neutral control interview across both drug conditions. Immediately after the assigned interview, participants engaged sequentially in finger pressure and ischemic forearm pain tasks. Opioid blockade effects were derived (blockade minus placebo condition pain ratings) to index opioid antinociceptive function. Results: Placebo condition TRANG by interview interactions (p values < .05) indicated that TRANG was hyperalgesic only in the context of acute anger arousal (ARI condition; p values < .05). Blockade effect analyses suggested that these hyperalgesic effects were related to deficient opioid analgesia. Significant TRANG by interview interactions (p values < .05) for both pain tasks indicated that elevated TRANG was associated with smaller blockade effects (less endogenous opioid analgesia) only in the ARI condition (p values < .05). Results for ischemic task visual analog scale intensity blockade effects suggested that associations between TRANG and impaired opioid function were most evident in LBP participants when experiencing anger (type by interview by TRANG interaction; p < .05). Conclusions: Results indicate that hyperalgesic effects of TRANG are most prominent when acute anger is aroused and suggest that endogenous opioid mechanisms contribute.TRANG = trait anger; ARI = anger recall interview; NCI = neutral control interview; LBP = low back pain; BDI = Beck Depression Inventory; STAI = State-Trait Anxiety Inventory; MPQ-S = McGill Pain Questionnaire-Sensory subscale; MPQ-A = McGill Pain Questionnaire-Affective subscale; BP = blood pressure; FP = finger pressure; ISC = ischemic.