Ok Yung Chung

Interactions between the cardiovascular and pain regulatory systems: an updated review of mechanisms and possible alterations in chronic pain

Endogenous pain regulatory system dysfunction appears to play a role in the maintenance of chronic pain. An important component of the pain regulatory process is the functional interaction between the cardiovascular and pain regulatory systems, which results in an association between elevated resting blood pressure (BP) and diminished acute pain sensitivity. This BP/pain sensitivity relationship is proposed to reflect a homeostatic feedback loop helping restore arousal levels in the presence of painful stimuli. Evidence is emerging that this normally adaptive BP/pain sensitivity relationship is significantly altered in chronic pain conditions, affecting responsiveness to both acute and chronic pain stimuli. Several mechanisms that may underlie this adaptive relationship in healthy individuals are overviewed, including endogenous opioid, noradrenergic, and baroreceptor-related mechanisms. Theoretical models are presented regarding how chronic pain-related alterations in the mechanisms above and increased pain facilatory system activity (central sensitization) may contribute to altered BP/pain sensitivity interactions in chronic pain. Clinical implications are discussed.

Prospective examination of pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: a preliminary study

&NA; We hypothesized that preoperative emotional distress and pain intensity would predict the occurrence of signs and symptoms of complex regional pain syndrome (CRPS) following total knee arthroplasty (TKA). Depression (Beck Depression Inventory, BDI), anxiety (State Trait Anxiety Inventory, STAI), pain (McGill Pain Questionnaire–Short Form, MPQ), and signs/symptoms meeting IASP criteria for CRPS were assessed preoperatively, and at 1‐, 3‐, and 6‐months postoperatively in 77 patients undergoing TKA. The prevalence of subjects fulfilling CRPS criteria was 21.0% at 1 month, 13.0% at 3 months, and 12.7% at 6 months postoperative. Higher preoperative scores on the STAI predicted positive CRPS status at 1‐month follow‐up (P<0.05), with a similar non‐significant trend for preoperative BDI scores (P<0.10). Diagnostic sensitivity for the STAI was good (0.73), with moderate specificity (0.56). Neither measure predicted CRPS at later follow‐up (P>0.10). Greater preoperative pain intensity predicted positive CRPS status at 3‐month (MPQ‐Sensory and MPQ‐Affective; P<0.01) and 6‐month (MPQ‐Sensory) follow‐up (P<0.01), but not at 1‐month (P>0.10). Diagnostic sensitivity was high (0.83–1.00), with moderate specificity (0.53–0.60). Post‐TKA patients with CRPS were more depressed at 1‐month follow‐up (P<0.05) and more anxious at 6‐month follow‐up (P<0.05) than patients with ongoing non‐CRPS pain (all other comparisons non‐significant, P>0.10). Overall, results indicate that CRPS‐like phenomena occur in a significant number of patients early post‐TKA; however, it is not associated with significantly greater complaints of postoperative pain. There appears to be a modest utility for preoperative distress and pain in predicting CRPS signs and symptoms following TKA, although false positive rates are relatively high.

Psychological and Behavioral Aspects of Complex Regional Pain Syndrome Management

Psychological and behavioral factors can exacerbate the pain and dysfunction associated with complex regional pain syndrome (CRPS) and could help maintain the condition in some patients. Effective management of CRPS requires that these psychosocial and behavioral aspects be addressed as part of an integrated multidisciplinary treatment approach. Well-controlled studies to guide the development of a psychological approach to CRPS management are not currently available. A sequenced protocol for psychological care in CRPS is therefore proposed based on available data and clinical experience. Regardless of the duration of the condition, all CRPS patients and their families should receive education about the negative effects of disuse, the pathophysiology of the syndrome, and possible interactions with psychological/behavioral factors. Patients with acute CRPS (<6–8 weeks) may not need additional psychological care. All patients with chronic CRPS should receive a thorough psychological evaluation, followed by cognitive-behavioral pain management treatment, including relaxation training with biofeedback. Patients making insufficient overall treatment progress or in whom comorbid psychiatric disorders/major ongoing life stressors are identified should additionally receive general cognitive-behavioral therapy to address these issues. The psychological component of treatment can work synergistically with medical and physical/occupational therapies to improve function and increase patients’ ability to manage the condition successfully.

The relationship between resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain sufferers: the effects of opioid blockade

&NA; Resting blood pressure is inversely correlated with acute pain sensitivity in healthy normotensives. This study tested: (1) whether endogenous opioid activity is necessary for this adaptive relationship to occur, (2) whether this relationship is altered in chronic low back pain (LBP), and (3) whether endogenous opioid dysfunction underlies any such alterations. Fifty‐one pain‐free normotensives and 44 normotensive chronic LBP sufferers received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1‐min finger pressure (FP) pain task followed by an ischemic (ISC) forearm pain task. Among pain‐free normotensives, elevated resting systolic (SBP) and diastolic (DBP) blood pressure were associated with significantly higher ISC pain thresholds (P values <0.05). Elevated SBP was also associated with significantly lower FP pain ratings (P<0.05). Opioid blockade had no significant effect on the BP–pain relationships detected (P values >0.10). In combined groups analyses, a significant subject type×SBP interaction (P<0.005) was found on ISC pain threshold: elevated SBP was associated with higher pain threshold in pain‐free controls, but with lower pain threshold in LBP subjects. Although subject type×BP interactions on FP and ISC pain ratings were not significant, inclusion of LBP subjects in these analyses resulted in the overall relationship between BP and pain sensitivity becoming positive (P values <0.05). Opioid blockade exerted no significant main or interaction effects in these combined groups analyses (p values >0.10). Higher DBP was associated with greater clinical pain intensity among the LBP subjects (P<0.001). Overall, these results suggest: (1) endogenous opioids do not mediate the inverse relationship between resting blood pressure and acute pain sensitivity in pain‐free normotensives; (2) the BP–pain sensitivity relationship is altered in chronic pain, suggesting dysfunction in pain regulatory systems, and (3) these alterations are not related to opioid dysfunction.

Anger and pain sensitivity in chronic low back pain patients and pain-free controls: the role of endogenous opioids

&NA; The experience of anger (i.e. trait anger) and anger management style (i.e. anger‐in, anger‐out) are related to sensitivity to acute and chronic pain stimuli, although underlying mechanisms are unknown. This study tested whether anger variables are associated with impaired endogenous opioid antinociceptive activity, and whether these relationships differed between chronic pain patients and healthy normals. Forty‐three chronic low back pain (LBP) sufferers and 45 pain‐free normals received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1‐min finger pressure pain task followed by an ischemic forearm pain task (maximum duration 5 min), providing pain intensity ratings during and immediately following each task. As a measure of opioid antinociceptive function, drug effects were derived by subtracting placebo from blockade condition pain ratings. Multivariate general linear model analyses indicated that anger‐out, but not anger‐in, had significant main effects on both finger pressure drug effects (P<0.05) and ischemic task drug effects (P<0.05). As hypothesized, high anger‐out scores were associated with an absence of opioid analgesia during the acute pain tasks; low anger‐out scores were associated with effective opioid analgesia. A similar non‐significant trend was noted for trait anger on finger pressure drug effects (P<0.06). Anger‐out × LBP/normal interactions were non‐significant, suggesting that links between anger‐out and drug effects were similar for patients and normals. Controlling for depression did not eliminate the significant relationship between anger‐out and drug effects. Findings suggest that anger‐in and anger‐out affect pain sensitivity through different mechanisms: only the effects of anger‐out may be mediated by endogenous opioid dysfunction.

Differential effects of expressive anger regulation on chronic pain intensity in CRPS and non-CRPS limb pain patients

Research has shown that the anger management styles of both anger‐in (suppression of anger) and anger‐out (direct verbal or physical expression of anger) may be associated with elevated chronic pain intensity. Only the effects of anger‐out appear to be mediated by increased physiological stress responsiveness. Given the catecholamine‐sensitive nature of pain mechanisms in complex regional pain syndrome (CRPS), it was hypothesized that anger‐out, but not anger‐in, would demonstrate a stronger relationship with chronic pain intensity in CRPS patients than in non‐CRPS chronic pain patients. Thirty‐four chronic pain patients meeting IASP criteria for CRPS and 50 non‐CRPS (predominately myofascial) limb pain patients completed the McGill Pain Questionnaire‐Short Form (MPQ), the Anger Expression Inventory (AEI), and the Beck Depression Inventory (BDI). Analyses revealed no diagnostic group differences in mean scores on the anger‐in (AIS) and anger‐out (AOS) subscales of the AEI, or on the BDI (values of P>0.10). Results of general linear model analyses revealed significant AOS×diagnostic group interactions on both the sensory (MPQ‐S) and affective (MPQ‐A) subscales of the MPQ (values of P<0.05). In both cases, higher AOS scores were associated with more intense chronic pain in the CRPS group, but with less intense pain in the non‐CRPS limb pain group. Inclusion of BDI scores as a covariate did not substantially alter the AOS×diagnostic group interactions, indicating that these AOS interactions were not due solely to overlap with negative affect. Although higher AIS scores were associated with elevated MPQ‐A pain intensity as a main effect (P<0.05), no significant AIS×diagnostic group interactions were detected (values of P>0.10). The AIS main effect on MPQ‐A ratings was accounted for entirely by overlap with negative affect. Results are consistent with a greater negative impact of anger‐out on chronic pain intensity in conditions reflecting catecholamine‐sensitive pain mechanisms, presumably due to the association between anger‐out and elevated physiological stress responsiveness. These results further support previous suggestions that anger‐in and anger‐out may affect pain through different mechanisms.

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.

Prevalence of clinical hypertension in patients with chronic pain compared to nonpain general medical patients.

Objectives: In healthy individuals, elevated blood pressure is associated with diminished acute pain sensitivity. These cardiovascular/pain regulatory system interactions appear altered in patients with chronic pain; elevated blood pressure is associated with increased acute and chronic pain responsiveness. If these alterations reflect failure of overlapping systems modulating pain and blood pressure, it was expected that prevalence of clinical hypertension would be increased in the chronic pain population. Methods: A retrospective review was conducted on randomly selected records of 300 patients with chronic pain (Pain) evaluated at a tertiary care pain center and 300 nonpain internal medicine (Medicine) patients seen at the same institution. Results: Results revealed that 39% of the Pain group was diagnosed with clinical hypertension, compared with 21% of the Medicine group (P < 0.001). Analyses by sex revealed similar group differences in males (P < 0.05) and females (P < 0.001), although the difference in females was double in magnitude compared with males. In contrast to more frequent male hypertension in the general population and the Medicine sample, females were more often diagnosed with hypertension (41.2%) than males (35.6%) in the Pain group. Similar group differences were obtained for antihypertensive use (P < 0.001). Stepwise logistic regression in the Pain group revealed that chronic pain intensity was a significant predictor of hypertensive status independent of the effects of age, race/ethnicity, and parental hypertension (P < 0.05). Discussion: These results suggest that chronic pain may be associated with increased risk of hypertension. Factors that may underlie this association are discussed.

Anger Expression and Pain: An Overview of Findings and Possible Mechanisms

A tendency to manage anger via direct expression (anger-out) is increasingly recognized as influencing responses to pain. Elevated trait anger-out is associated with increased responsiveness to acute experimental and clinical pain stimuli, and is generally related to elevated chronic pain intensity in individuals with diverse pain conditions. Possible mechanisms for these links are explored, including negative affect, psychodynamics, central adipose tissue, symptom specific muscle reactivity, endogenous opioid dysfunction, and genetics. The opioid dysfunction hypothesis has some experimental support, and simultaneously can account for anger-out’s effects on both acute and chronic pain. Factors which may moderate the anger-out/pain link are described, including narcotic use, gender, and genetic polymorphisms. Pain exacerbating effects of trait anger-out are contrasted with the apparent pain inhibitory effects of behavioral anger expression exhibited in anger-provoking contexts. Conceptual issues related to the state versus trait effects of expressive anger regulation are discussed.

The association between anger expression and chronic pain intensity: evidence for partial mediation by endogenous opioid dysfunction.

&NA; Recent work suggests that an expressive anger management style (anger‐out) is associated with elevated acute pain sensitivity due to endogenous opioid antinociceptive dysfunction. We tested the hypothesis that this opioid dysfunction mediates the previously reported positive association between anger‐out and chronic pain intensity. To assess endogenous opioid antinociception in the laboratory, 71 subjects with chronic low back pain received opioid blockade (8 mg naloxone i.v.) or placebo in counterbalanced order in separate sessions. During each, subjects participated in a 1‐min finger pressure pain task followed by an ischemic forearm pain task, providing acute pain ratings on the McGill Pain Questionnaire–Short Form (MPQ) immediately following each task. Subjects also completed a 7‐day chronic pain diary based on the MPQ between laboratory sessions. To index opioid antinociceptive function, blockade effects were derived, subtracting placebo from blockade condition pain ratings. Greater anger‐out was associated with both smaller blockade effects (suggesting impaired opioid antinociception) and greater chronic pain intensity, and blockade effects were inversely associated with chronic pain intensity. Sequential hierarchical regressions suggested that opioid dysfunction partially mediates the positive association between anger‐out and total MPQ chronic pain intensity. Inclusion of blockade effects in the first step of the regression resulted in a decrease from 7 to 3% in chronic pain variance accounted for by anger‐out. Opioid dysfunction did not mediate the positive association between anger‐in and chronic pain. These results provide preliminary support for the hypothesis that the positive association between anger expression and chronic pain intensity is mediated by opioid antinociceptive system dysfunction.