Samuel A. McLean

Decreased Central μ-Opioid Receptor Availability in Fibromyalgia

The underlying neurophysiology of acute pain is fairly well characterized, whereas the central mechanisms operative in chronic pain states are less well understood. Fibromyalgia (FM), a common chronic pain condition characterized by widespread pain, is thought to originate largely from altered central neurotransmission. We compare a sample of 17 FM patients and 17 age- and sex-matched healthy controls, using μ-opioid receptor (MOR) positron emission tomography. We demonstrate that FM patients display reduced MOR binding potential (BP) within several regions known to play a role in pain modulation, including the nucleus accumbens, the amygdala, and the dorsal cingulate. MOR BP in the accumbens of FM patients was negatively correlated with affective pain ratings. Moreover, MOR BP throughout the cingulate and the striatum was also negatively correlated with the relative amount of affective pain (McGill, affective score/sensory score) within these patients. These findings indicate altered endogenous opioid analgesic activity in FM and suggest a possible reason for why exogenous opiates appear to have reduced efficacy in this population.

The development of persistent pain and psychological morbidity after motor vehicle collision: integrating the potential role of stress response systems into a biopsychosocial model.

Objectives: Persistent pain and psychological sequelae are common after motor vehicle collision (MVC), but their etiology remains poorly understood. Such common sequelae include whiplash-associated disorders (WAD), fibromyalgia, and posttraumatic stress disorder (PTSD). Increasing evidence suggests that these disorders share overlapping epidemiologic and clinical features. A model is proposed in which central neurobiological systems, including physiologic systems and neuroanatomical structures involved in the stress response, are an important substrate for the development of all 3 disorders and interact with psychosocial and other factors to influence chronic symptom development. Methods: Epidemiologic and clinical characteristics regarding the development of these disorders after MVC are reviewed. Evidence suggesting a role for stress response systems in the development of these disorders is presented. Results: Contemporary evidence supports a model of chronic symptom development that incorporates the potential for interactions between past experience, acute stress responses to trauma, post-MVC behavior, and cognitive/psychosocial consequences to alter activity within brain regions which process pain and to result in persistent pain, as well as psychological sequelae, after MVC. Such a model incorporates factors identified in prior biopsychosocial theories and places them in the landscape of our rapidly developing understanding of stress systems and CNS pain-modulating pathways. Conclusion: New models are needed to stimulate deeper examination of the interacting influences of initial tissue damage, acute pain, psychosocial contingencies, and central stress pathways during chronic symptom development after MVC. Deeper understanding could contribute to improved treatment approaches to reduce the immense personal and societal burdens of common trauma-related disorders. CRH = corticotrophin-releasing hormone; MVC = motor vehicle collision; WAD = whiplash-associated disorders; PTSD = posttraumatic stress disorder; HPA = hypothalamic-pituitary-adrenal; LC/NE=locus ceruleus/norepinephrine-sympathetic.

Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia

OBJECTIVE Fibromyalgia (FM) is a chronic widespread pain condition that is thought to arise from augmentation of central neural activity. Glutamate (Glu) is an excitatory neurotransmitter that functions in pain-processing pathways. This study was carried out to investigate the relationship between changing levels of Glu within the insula and changes in multiple pain domains in patients with FM. METHODS Ten patients with FM underwent 2 sessions of proton magnetic resonance spectroscopy (H-MRS) and 2 sessions of functional magnetic resonance imaging (FMRI), each conducted before and after a nonpharmacologic intervention to reduce pain. During H-MRS, the anterior and posterior insular regions were examined separately using single-voxel spectroscopy. The levels of Glu and other metabolites were estimated relative to levels of creatine (Cr) (e.g., the Glu/Cr ratio). During FMRI, painful pressures were applied to the thumbnail to elicit neuronal activation. Experimental pressure-evoked pain thresholds and clinical pain ratings (on the Short Form of the McGill Pain Questionnaire [SF-MPQ]) were also assessed prior to each imaging session RESULTS Both experimental pain (P = 0.047 versus pretreatment) and SF-MPQ-rated clinical pain (P = 0.043 versus pretreatment) were reduced following treatment. Changes from pre- to posttreatment in Glu/Cr were negatively correlated with changes in experimental pain thresholds (r = -0.95, P < 0.001) and positively correlated with changes in clinical pain (r = 0.85, P = 0.002). Changes in the FMRI-determined blood oxygenation level-dependent effect (a measure of neural activation) were positively correlated with changes in Glu/Cr within the contralateral insula (r = 0.81, P = 0.002). CONCLUSION Changes in Glu levels within the insula are associated with changes in multiple pain domains in patients with FM. Thus, H-MRS data may serve as a useful biomarker and surrogate end point for clinical trials of FM.

μ-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer.

Background: Preclinical studies suggest that opioids may promote tumor growth. Genetic polymorphisms have been shown to affect opioid receptor function and to modify the clinical effects of morphine. In this study we assessed the association between six common polymorphisms in the &mgr;-opioid receptor gene, including the well known A118G polymorphism, and breast cancer survival. Methods: A total of 2,039 women ages 23–74 yr (38% African-American, 62% European-American, 55% postmenopausal) diagnosed with breast cancer between 1993–2001 were followed through 2006. Genotyping was performed using the TaqMan platform (Applied Biosystems Inc., Foster City, CA). Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models were used to examine the association between each genotype and survival. Results: After Bonferroni correction for multiple testing, patient genotype at A118G was associated with breast cancer-specific mortality at 10 yr. Women with one or more copies of the G allele had decreased breast cancer-specific mortality (P < 0.001). This association was limited to invasive cases only; effect size appeared to increase with clinical stage. Cox regression model adjusted for age and ethnicity also showed decreased mortality in A/G and G/G genotypes compared with A/A genotype (hazard ratio = 0.57 [0.38, 0.85] and 0.32 [0.22, 0.49], respectively; P = 0.006). Conclusions: These results suggest that opioid pathways may be involved in tumor growth. Further studies examining the association between genetic variants influencing opioid system function and cancer survival are warranted.

The epidemiology of pain in the prehospital setting

Objective. To develop national estimates of the epidemiology of pain in the prehospital setting. Methods. Cross-sectional data on a probability sample of 21,103 emergency department (ED) visits from the 1999 National Hospital Ambulatory Medical Care Survey were analyzed. For patients arriving by ambulance, the frequencies (95% confidence intervals) of patients presenting with no level of pain reported (data unknown or missing) and those reporting no, mild, and moderate or severe pain were determined. The reasons for visit among those with moderate or severe pain, and the ED narcotic analgesic use among those with pain information reported and not reported, were also determined. >Results. Of the 102.8 million patients visiting the ED in 1999, 14.5 million arrived by ambulance. Fifty-three percent (49-58%) were female. Seven million six hundred thousand [52% (48-56%)] had no information on presenting level of pain reported, 2.0 million [14% (2-25%)] had no pain, 2.0 million [14% (3-25%)] had mild pain, and 2.9 million [20% (12-29%)] had moderate or severe pain. Among those with moderate or severe pain, the most common reasons for visit were injuries 27% (11-43%) and non-injury musculoskeletal symptoms 18% (0-39%). Narcotic analgesics were ordered or continued in 13% (0-29%) of those with no presenting level of pain recorded and 21% (9-34%) of those for whom the presenting level of pain was recorded. >Conclusion. Pain is a common condition among prehospital patients: 20% reported moderate to severe pain. Given the use of narcotic analgesics among those for whom pain information was not reported, this is likely a conservative estimate.

The Role of Tissue Damage in Whiplash Associated Disorders: Discussion Paper 1

Study Design. Nonsystematic review of cervical spine lesions in whiplash-associated disorders (WAD). Objective. To describe whiplash injury models in terms of basic and clinical science, to summarize what can and cannot be explained by injury models, and to highlight future research areas to better understand the role of tissue damage in WAD. Summary of Background Data. The frequent lack of detectable tissue damage has raised questions about whether tissue damage is necessary for WAD and what role it plays in the clinical context of WAD. Methods. Nonsystematic review. Results. Lesions of various tissues have been documented by numerous investigations conducted in animals, cadavers, healthy volunteers, and patients. Most lesions are undetected by imaging techniques. For zygapophysial (facet) joints, lesions have been predicted by bioengineering studies and validated through animal studies; for zygapophysial joint pain, a valid diagnostic test and a proven treatment are available. Lesions of dorsal root ganglia, discs, ligaments, muscles, and vertebral artery have been documented in biomechanical and autopsy studies, but no valid diagnostic test is available to assess their clinical relevance. The proportion of WAD patients in whom a persistent lesion is the major determinant of ongoing symptoms is unknown. Psychosocial factors, stress reactions, and generalized hyperalgesia have also been shown to predict WAD outcomes. Conclusion. There is evidence supporting a lesion-based model in WAD. Lack of macroscopically identifiable tissue damage does not rule out the presence of painful lesions. The best available evidence concerns zygapophysial joint pain. The clinical relevance of other lesions needs to be addressed by future research.

Cerebrospinal Fluid Corticotropin-Releasing Factor Concentration is Associated with Pain but not Fatigue Symptoms in Patients with Fibromyalgia

Previous studies have identified stress system dysregulation in fibromyalgia (FM) patients; such dysregulation may be involved in the generation and/or maintenance of pain and other symptoms. Corticotropin-releasing factor (CRF) is the principal known central nervous system mediator of the stress response; however, to date no studies have examined cerebrospinal fluid (CSF) CRF levels in patients with FM. The relationship between CSF CRF level, heart rate variability (HRV), and pain, fatigue, and depressive symptoms was examined in patients with FM. Among participants (n=26), CSF CRF levels were associated with sensory pain symptoms (r=0.574, p=0.003) and affective pain symptoms (r=0.497, p=0.011), but not fatigue symptoms. Increased HRV was also strongly associated with increased CSF CRF and FM pain. In multivariate analyses adjusting for age, sex, and depressive symptoms, the association between CSF CRF and sensory pain symptoms (t=2.54, p=0.027) persisted. Women with FM who reported a history of physical or sexual abuse had lower CSF CRF levels than women who did not report such a history. CSF CRF levels are associated with both pain symptoms and variation in autonomic function in FM. Differences in CSF CRF levels among women with and without a self-reported history of physical or sexual abuse suggest that subgroups of FM patients may exist with different neurobiological characteristics. Further studies are needed to better understand the nature of the association between CSF CRF and pain symptoms in FM.

Catechol O-Methyltransferase Haplotype Predicts Immediate Musculoskeletal Neck Pain and Psychological Symptoms After Motor Vehicle Collision

UNLABELLED Genetic variations in the catechol-O-methyltransferase (COMT) gene have been associated with experimental pain and risk of chronic pain development, but no studies have examined genetic predictors of neck pain intensity and other patient characteristics after motor vehicle collision (MVC). We evaluated the association between COMT genotype and acute neck pain intensity and other patient characteristics in 89 Caucasian individuals presenting to the emergency department (ED) after MVC. In the ED in the hours after MVC, individuals with a COMT pain vulnerable genotype were more likely to report moderate-to-severe musculoskeletal neck pain (76 versus 41%, RR = 2.11 (1.33-3.37)), moderate or severe headache (61 versus 33%, RR = 3.15 (1.05-9.42)), and moderate or severe dizziness (26 versus 12%, RR = 1.97 (1.19-3.21)). Individuals with a pain vulnerable genotype also experienced more dissociative symptoms in the ED, and estimated a longer time to physical recovery (median 14 versus 7 days, P = .002) and emotional recovery (median 8.5 versus 7 days, P = .038). These findings suggest that genetic variations affecting stress response system function influence the somatic and psychological response to MVC, and provide the first evidence of genetic risk for clinical symptoms after MVC. PERSPECTIVE The association of COMT genotype with pain symptoms, psychological symptoms, and recovery beliefs exemplifies the pleiotropic effects of stress-related genes, which may provide the biological substrate for the biopsychosocial model of post-MVC pain. The identification of genes associated with post-MVC symptoms may also provide new insights into pathophysiology.

How well can post‐traumatic stress disorder be predicted from pre‐trauma risk factors? An exploratory study in the WHO World Mental Health Surveys

Post‐traumatic stress disorder (PTSD) should be one of the most preventable mental disorders, since many people exposed to traumatic experiences (TEs) could be targeted in first response settings in the immediate aftermath of exposure for preventive intervention. However, these interventions are costly and the proportion of TE‐exposed people who develop PTSD is small. To be cost‐effective, risk prediction rules are needed to target high‐risk people in the immediate aftermath of a TE. Although a number of studies have been carried out to examine prospective predictors of PTSD among people recently exposed to TEs, most were either small or focused on a narrow sample, making it unclear how well PTSD can be predicted in the total population of people exposed to TEs. The current report investigates this issue in a large sample based on the World Health Organization (WHO)s World Mental Health Surveys. Retrospective reports were obtained on the predictors of PTSD associated with 47,466 TE exposures in representative community surveys carried out in 24 countries. Machine learning methods (random forests, penalized regression, super learner) were used to develop a model predicting PTSD from information about TE type, socio‐demographics, and prior histories of cumulative TE exposure and DSM‐IV disorders. DSM‐IV PTSD prevalence was 4.0% across the 47,466 TE exposures. 95.6% of these PTSD cases were associated with the 10.0% of exposures (i.e., 4,747) classified by machine learning algorithm as having highest predicted PTSD risk. The 47,466 exposures were divided into 20 ventiles (20 groups of equal size) ranked by predicted PTSD risk. PTSD occurred after 56.3% of the TEs in the highest‐risk ventile, 20.0% of the TEs in the second highest ventile, and 0.0‐1.3% of the TEs in the 18 remaining ventiles. These patterns of differential risk were quite stable across demographic‐geographic sub‐samples. These results demonstrate that a sensitive risk algorithm can be created using data collected in the immediate aftermath of TE exposure to target people at highest risk of PTSD. However, validation of the algorithm is needed in prospective samples, and additional work is warranted to refine the algorithm both in terms of determining a minimum required predictor set and developing a practical administration and scoring protocol that can be used in routine clinical practice.

Health status, not head injury, predicts concussion symptoms after minor injury.

OBJECTIVE Postconcussion (PC) syndrome etiology remains poorly understood. We sought to examine predictors of persistent PC symptoms after minor injury. METHODS Health status, symptom, and injury information were obtained on a sample of patients presenting to the emergency department after minor injury. Postconcussion and cognitive symptoms were assessed at 1, 3, and 12 months. RESULTS Among 507 patients enrolled, 339 had head injury. Repeated-measures logistic regression modeling of PC and cognitive symptom presence across time indicated that baseline mental health status and physical health status were most predictive of persistent symptoms. In contrast, head injury presence did not predict persistent PC syndrome. DISCUSSION Baseline mental health status and physical health status were associated with persistent PC syndrome after minor injury, but head injury status was not. Further studies of PC syndrome pathogenesis are needed.