Complex Multilocus Effects of Catechol-O-Methyltransferase Haplotypes Predict Pain and Pain Interference 6 Weeks After Motor Vehicle Collision

Catechol-O-methyltransferase, encoded by COMT gene, is the primary enzyme that metabolizes catecholamines. COMT haplotypes have been associated with vulnerability to persistent non-traumatic pain. In this prospective observational study, we investigated the influence of COMT on persistent pain and pain interference with life functions after motor vehicle collision (MVC) in 859 European American adults for whom overall pain (0–10 numeric rating scale) and pain interference (Brief Pain Inventory) were assessed at week 6 after MVC. Ten single nucleotide polymorphisms (SNPs) spanning the COMT gene were successfully genotyped, nine were present in three haploblocks: block 1 (rs2020917, rs737865, rs1544325), block 2 (rs4633, rs4818, rs4680, rs165774) and block 3 (rs174697, rs165599). After adjustment for multiple comparisons, haplotype TCG from block 1 predicted decreased pain interference (p =.004). The pain-protective effect of the low pain sensitivity (LPS, CGGG) haplotype from block 2 was only observed if at least one TCG haplotype was present in block 1 (haplotype × haplotype interaction p=.002 and <.0001 for pain and pain interference, respectively). Haplotype AG from block 3 was associated with pain and interference in males only (sex × haplotype interaction p=.005 and .0005, respectively). These results suggest that genetic variants in the distal promoter are important contributors to the development of persistent pain after MVC, directly and via the interaction with haplotypes in the coding region of the gene

μ-Opioid Receptor Gene A118G Polymorphism Predicts Survival in Patients With Breast Cancer

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 μ-opioid receptor gene, including the well known A118G polymorphism, and breast cancer survival

Older US Emergency Department Patients Are Less Likely to Receive Pain Medication Than Younger Patients: Results From a National Survey

The purpose of this study is to determine whether older adults presenting to the Emergency Department (ED) with pain are less likely to receive pain medication than younger adults

Chronic widespread pain after motor vehicle collision typically occurs through immediate development and nonrecovery: results of an emergency department-based cohort study

Motor vehicle collision (MVC) can trigger chronic widespread pain (CWP) development in vulnerable individuals. Whether such CWP typically develops via the evolution of pain from regional to widespread or via the early development of widespread pain with non-recovery is currently unknown. We evaluated the trajectory of CWP development (American College of Rheumatology criteria) among 948 European-American individuals who presented to the emergency department (ED) for care in the early aftermath of MVC. Pain extent was assessed in the ED and 6 weeks, 6 months, and 1 year after MVC on 100%, 91%, 89%, and 91% of participants, respectively. Individuals who reported prior CWP at the time of ED evaluation (n = 53) were excluded. Trajectory modeling identified a two-group solution as optimal, with the Bayes Factor value (138) indicating strong model selection. Linear solution plots supported a non-recovery model. While the number of body regions with pain in the non-CWP group steadily declined, the number of body regions with pain in the CWP trajectory group (192/895, 22%) remained relatively constant over time. These data support the hypothesis that individuals who develop CWP after MVC develop widespread pain in the early aftermath of MVC which does not remit

Genetic variant rs3750625 in the 3′UTR of ADRA2A affects stress-dependent acute pain severity after trauma and alters a microRNA-34a regulatory site

α2A adrenergic receptor (α2A-AR) activation has been shown in animal models to play an important role in regulating the balance of acute pain inhibition vs. facilitation after both physical and psychological stress. To our knowledge the influence of genetic variants in the gene encoding α2A-AR, ADRA2A, on acute pain outcomes in humans experiencing traumatic stress has not been assessed. In this study, we tested whether a genetic variant in the 3′UTR of ADRA2A, rs3750625, is associated with acute musculoskeletal pain (MSP) severity following motor vehicle collision (MVC, n = 948) and sexual assault (n = 84), and whether this influence was affected by stress severity. We evaluated rs3750625 because it is located in the seed binding region of miR-34a, a microRNA (miRNA) known to regulate pain and stress responses. In both cohorts, the minor allele at rs3750625 was associated with increased MSP in distressed individuals (stress*rs3750625 p = 0.043 for MVC cohort and p = 0.007 for sexual assault cohort). We further found that (1) miR-34a binds the 3′UTR of ADRA2A, (2) the amount of repression is greater when the minor (risk) allele is present, (3) miR-34a in the IMR-32 adrenergic neuroblastoma cell line affects ADRA2A expression, (4) miR-34a and ADRA2A are expressed in tissues known to play a role in pain and stress, (5) following forced swim stress exposure, rat peripheral nerve tissue expression changes are consistent with miR-34a regulation of ADRA2A. Together these results suggest that ADRA2A rs3750625 contributes to post-stress MSP severity by modulating miR-34a regulation

Modification of COMT-dependent pain sensitivity by psychological stress and sex

Catecholamine-O-methyltransferase (COMT) is a polymorphic gene whose variants affect enzymatic activity and pain sensitivity via adrenergic pathways. Although COMT represents one of the most studied genes in human pain genetics, findings regarding its association with pain phenotypes are not always replicated. Here, we investigated if interactions among functional COMT haplotypes, stress, and sex can modify the effect of COMT genetic variants on pain sensitivity. We tested these interactions in a cross-sectional study, including 2 cohorts, one of 2972 subjects tested for thermal pain sensitivity (Orofacial Pain: Prospective Evaluation and Risk Assessment) and one of 948 subjects with clinical acute pain after motor vehicle collision (post-motor vehicle collision). In both cohorts, the COMT high-pain sensitivity (HPS) haplotype showed robust interaction with stress and number of copies of the HPS haplotype was positively associated with pain sensitivity in nonstressed individuals, but not in stressed individuals. In the post-motor vehicle collision cohort, there was additional modification by sex: the HPS-stress interaction was apparent in males, but not in females. In summary, our findings indicate that stress and sex should be evaluated in association studies aiming to investigate the effect of COMT genetic variants on pain sensitivity

Using emergency department-based inception cohorts to determine genetic characteristics associated with long term patient outcomes after motor vehicle collision: Methodology of the CRASH study

<p>Abstract</p> <p>Background</p> <p>Persistent musculoskeletal pain and psychological sequelae following minor motor vehicle collision (MVC) are common problems with a large economic cost. Prospective studies of pain following MVC have demonstrated that demographic characteristics, including female gender and low education level, and psychological characteristics, including high pre-collision anxiety, are independent predictors of persistent pain. These results have contributed to the psychological and social components of a biopsychosocial model of post-MVC pain pathogenesis, but the biological contributors to the model remain poorly defined. Recent experimental studies indicate that genetic variations in adrenergic system function influence the vulnerability to post-traumatic pain, but no studies have examined the contribution of genetic factors to existing predictive models of vulnerability to persistent pain.</p> <p>Methods/Design</p> <p>The Project CRASH study is a federally supported, multicenter, prospective study designed to determine whether variations in genes affecting synaptic catecholamine levels and alpha and beta adrenergic receptor function augment social and psychological factors in a predictive model of persistent musculoskeletal pain and posttraumatic stress disorder (PTSD) following minor MVC. The Project CRASH study will assess pain, pain interference and PTSD symptoms at 6 weeks, 6 months, and 1 year in approximately 1,000 patients enrolled from 8 Emergency Departments in four states with no-fault accident laws.</p> <p>Discussion</p> <p>The results from this study will provide insights into the pathophysiology of persistent pain and PTSD following MVC and may serve to improve the ability of clinicians and researchers to identify individuals at high risk for adverse outcomes following minor MVC.</p

Opioid Receptor Gene A118 G Variants and Persistent Pain Symptoms Among Men and Women Experiencing Motor Vehicle Collision

AbstractThe μ-opioid receptor 1 (OPRM1) binds endogenous opioids. Increasing evidence suggests that endogenous OPRM1 agonists released at the time of trauma may contribute to the development of posttraumatic musculoskeletal pain (MSP). In this prospective observational study, we evaluated the hypothesis that individuals with an AG or GG genotype at the OPRM1 A118 G allele, which results in a reduced response to opioids, would have less severe MSP 6 weeks after motor vehicle collision (MVC). Based on previous evidence, we hypothesized that this effect would be sex-dependent and most pronounced among women with substantial peritraumatic distress. European American men and women ≥18 years of age presenting to the emergency department after MVC and discharged to home after evaluation (N = 948) were enrolled. Assessments included genotyping and 6-week evaluation of overall MSP severity (0–10 numeric rating scale). In linear regression modeling, a significant A118 G Allele × Sex interaction was observed: an AG/GG genotype predicted reduced MSP severity among women with substantial peritraumatic distress (β = –.925, P = .014) but not among all women. In contrast, men with an AG/GG genotype experienced increased MSP severity at 6 weeks (β = .827, P = .019). Further studies are needed to understand the biologic mechanisms mediating observed sex differences in A118 G effects.PerspectiveThese results suggest a sex-dependent mechanism by which an emotional response to trauma (distress) contributes to a biologic mechanism (endogenous opioid release) that increases MSP in the weeks after stress exposure. These results also support the hypothesis that endogenous opioids influence pain outcomes differently in men and women

Association of Epidemiologic Factors and Genetic Variants Influencing Hypothalamic-Pituitary-Adrenocortical Axis Function With Postconcussive Symptoms After Minor Motor Vehicle Collision

To determine the influence of epidemiologic factors and the influence of genetic variants affecting FKBP5, a protein known to modulate hypothalamic-pituitary-adrenocortical (HPA) axis function, on the severity of somatic symptoms commonly termed “post-concussive” six and twelve months after motor-vehicle collision (MVC)

Genetic Polymorphisms in the Dopamine Receptor 2 Predict Acute Pain Severity after Motor Vehicle Collision

Dopaminergic signaling is implicated in nociceptive pathways. These effects are mediated largely through dopamine receptors and modulated in part by dopamine transporters. This study tests the hypothesis that genetic variants in the genes encoding dopamine receptor 2 (DRD2) and the dopamine active transporter (SLC6A3) influence acute pain severity after motor vehicle collision (MVC)