Associations Between Catecholaminergic and Serotonergic Genes and Persistent Breast Pain Phenotypes After Breast Cancer Surgery

Genetic variations in the catecholaminergic and serotonergic pathways may contribute to the development and severity of persistent breast pain. However, investigations of these associations are limited. The purpose of this study was to evaluate for associations between breast pain phenotypes and single nucleotide polymorphisms among 15 genes involved in catecholaminergic and serotonergic neurotransmission. Women rated the presence and intensity of breast pain monthly for 6 months after breast cancer surgery. Distinct latent classes of patients were identified using growth mixture modeling. Logistic regression analyses identified significant differences between genotype or haplotype frequencies and the breast pain classes (ie, no breast pain [n?=?96] vs mild breast pain [n?=?141], moderate breast pain [n?=?46], and severe breast pain [n?=?27]). Polymorphisms in 5 genes were associated with membership in the mild pain class: ** beta-2-adrenergic receptor (ADRB2) rs2400707, beta adrenergic receptor kinase 2 (ADRBK2) HapA04, 5-hydroxytryptamine receptor 3A (HTR3A) rs10160548, solute-like carrier (SLC) family 6 member 2–noradrenaline transporter (SLC6A2) rs1566652, and tryptophan hydroxylase 2 (TPH2) rs11179000. Polymorphisms in 3 genes were associated with membership in the moderate pain class: 5-hydroxytryptamine receptor 2A (HTR2A) rs2296972, SLC6A2 rs17841327, and SLC6A3 rs403636. Polymorphisms in 3 genes were associated with membership in the severe pain class: COMT HPS haplotype, SLC family 6 member 2–noradrenaline transporter (SLC6A2) HapD01, and SLC family 6 member 3–noradrenaline transporter (SLC6A3) rs464049. The identification of these associations suggest possible underlying mechanisms that play a role in the development and severity of persistent breast pain.

Associations Between Cytokine Gene Variations and Severe Persistent Breast Pain in Women Following Breast Cancer Surgery

Persistent pain following breast cancer surgery is a significant clinical problem. Although immune mechanisms may play a role in the development and maintenance of persistent pain, few studies have evaluated for associations between persistent breast pain following breast cancer surgery and variations in cytokine genes. In this study, associations between previously identified extreme persistent breast pain phenotypes (ie, no pain vs severe pain) and single nucleotide polymorphisms (SNPs) spanning 15 cytokine genes were evaluated. In unadjusted analyses, the frequency of 13 SNPs and 3 haplotypes in 7 genes differed significantly between the no pain and severe pain classes. After adjustment for preoperative breast pain and the severity of average postoperative pain, 1 SNP (ie, interleukin [IL] 1 receptor 2 rs11674595) and 1 haplotype (ie, IL10 haplotype A8) were associated with pain group membership. These findings suggest a role for cytokine gene polymorphisms in the development of persistent breast pain following breast cancer surgery.PerspectiveThis study evaluated for associations between cytokine gene variations and the severity of persistent breast pain in women following breast cancer surgery. Variations in 2 cytokine genes were associated with severe breast pain. The results suggest that cytokines play a role in the development of persistent postsurgical pain.     

Neurotransmitter Gene Polymorphisms Are Associated with Symptom Clusters in Patients Undergoing Radiation Therapy

ObjectivesPurpose was to evaluate for associations between the severity of three distinct symptom clusters (ie, sickness-behavior, mood-cognitive, treatment-related) and polymorphisms for 16 genes involved in catecholaminergic, GABAergic, and serotonergic neurotransmission.Data SourcesPatients with breast and prostate cancer (n = 157) completed study questionnaires at the completion of radiation therapy. Memorial Symptom Assessment Scale was used to assess the severity of 32 common symptoms. Three distinct symptom clusters were identified using exploratory factor analysis. Associations between the symptom cluster severity scores and neurotransmitter gene polymorphisms were evaluated using regression analyses.ConclusionSeverity scores for the sickness-behavior symptom cluster were associated with polymorphisms for solute carrier family 6 (SLC6A) member 2 (SLC6A2), SLC6A3, SLC6A1, and 5-hydroxytryptamine receptor (HTR) 2A (HTR2A) genes. For the mood-cognitive symptom cluster, severity scores were associated with polymorphisms for adrenoreceptor alpha 1D, SLC6A2, SLC6A3, SLC6A1, HTR2A, and HTR3A. Severity scores for the treatment-related symptom cluster were associated with polymorphisms for SLC6A2, SLC6A3, catechol-o-methyltransferase, SLC6A1, HTR2A, SLC6A4, and tryptophan hydroxylase 2.Implications for Nursing PracticeFindings suggest that polymorphisms for several neurotransmitter genes are involved in the severity of sickness-behavior, mood-cognitive, and treatment-related symptom clusters in oncology patients at the completion of radiation therapy. Four genes with various associated polymorphisms were common across the three distinct symptom clusters (ie, SLC6A2, SLC6A3, SLC6A1, HTR2A) which suggest that these clusters have common underlying mechanisms.     

Association of serotonin-1A and -2A receptor promoter polymorphisms with depressive symptoms,functional recovery,and pain in patients 6 months after lumbar disc surgery

Single nucleotide polymorphisms (SNPs) in the serotonergic (5HT) system seem to have modulatory effects on depression and physical function. Preliminary evidence suggests that gene × environment interactions play a role in the development of depression, with somatic complaints serving as environmental stressors. We hypothesized that pain intensity may serve as a stress factor that modulates the association between SNPs in the 5HT system and depression. We investigated symptoms of pain, depression, physical functioning, and disability in 224 patients 6 months after lumbar disc surgery. Associations between these variables and functional promoter SNPs in the serotonin receptor genes 5HTR1A (rs6295) and 5HTR2A (rs6311) were analyzed. For 5HTR2A, we found a significant gene × environment × sex interaction, as female patients carrying at least one A allele of the −1438A/G promoter SNP had significantly higher depression scores when confronted with severe pain compared to women harboring the GG genotype (P = .005). For 5HTR1A, patients homozygous for the −1019 G allele presented higher Beck Depression Inventory scores relative to the CG/CC group, indicating a major effect of this SNP on depression. Furthermore, women homozygous for either the 5HTR1A G allele or the 5HTR2A A allele had lower levels of physical functioning than patients with the other genotypes. These results suggest that 5HTR1A and 5HTR2A promoter variations have gender-dependent modulatory effects on depression and physical function in patients with pain. Furthermore, this study demonstrates that pain after lumbar surgery modulates the association between 5HT gene polymorphisms and depression.     

The Association of Single Nucleotide Polymorphisms in the Catechol-O-Methyltransferase Gene and Pain Scores in Female Patients With Major Depressive Disorder

We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene are associated with baseline pain levels in patients with major depressive disorder (MDD). Pain levels were quantified using a visual analog scale (VAS) for pain. Data from 159 female and 93 male self-reported white patients with MDD were analyzed. The associations between a haplotype previously associated with pain sensitivity created using COMT SNPs rs6269, rs4633, rs4818, and rs4680, and the proportion of female patients with “Pain While Awake” and “Overall Pain” at baseline were statistically significant (P < .05). In male patients, no statistically significant associations between COMT haplotypes and baseline pain scores were seen. The rs165599 SNP, which has previously been associated with response of depressive symptoms to treatment in patients with MDD, did not impact baseline pain in either gender. In conclusion, baseline pain levels appear to be associated with the COMT pain sensitivity haplotype in female patients with MDD.PerspectiveThis article presents associations of the COMT pain sensitivity haplotype and baseline pain levels in female patients with MDD. This finding could potentially help clinicians who seek to assess how genetic polymorphisms may contribute to a patient's pain experience.     

Identification of patient subgroups and risk factors for persistent arm/shoulder pain following breast cancer surgery

PurposeIn this prospective, longitudinal study, we extend our findings on persistent breast pain in patients (n = 398) following breast cancer surgery and evaluate the prevalence and characteristics of persistent pain in the arm/shoulder. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the arm pain classes, were evaluated.Methods and samplePatients were recruited from Breast Care Centers located in a Comprehensive Cancer Center, two public hospitals, and four community practices. Patients were assessed prior to and monthly for six months following breast cancer surgery.ResultsUsing growth mixture modeling, patients were classified into no (41.6%), mild (23.6%), and moderate (34.8%) arm pain classes based on ratings of worst arm/shoulder pain. Compared to the no pain class, patients in the moderate pain class were significantly younger, had a higher body mass index, and were more likely to report preoperative breast pain and swelling in the affected breast. In addition, patients in the moderate pain class reported higher levels of depression, anxiety, and sleep disturbance than the no pain class.ConclusionsFindings suggest that approximately 35% of women experience persistent levels of moderate arm/shoulder pain in the first six months following breast cancer surgery. Moderate arm/shoulder pain is associated with clinically meaningful decrements in functional status and quality of life.     

Persistent Arm Pain Is Distinct From Persistent Breast Pain Following Breast Cancer Surgery

Persistent pain following breast cancer surgery is well documented. However, it is not well characterized in terms of the anatomic site affected (ie, breast, arm). In 2 separate growth mixture modeling analyses, we identified subgroups of women (N = 398) with distinct breast pain and arm pain trajectories. The fact that these latent classes differed by anatomic site, types of tissue affected, and neural innervation patterns suggests the need for separate evaluations of these distinct persistent pain conditions. The purposes of this companion study were to identify demographic and clinical characteristics that differed between the 2 arm pain classes and determine if differences existed over time in sensitivity in the upper inner arm and axillary lymph node dissection sites, pain qualities, pain interference, and hand and arm function, as well as to compare findings with persistent breast pain. Higher occurrence rates for depression and lymphedema were found in the moderate arm pain class. Regardless of pain group membership, sensory loss was observed in the upper inner arm and axillary lymph node dissection site. Arm pain was described similarly to neuropathic pain and interfered with daily functioning. Persistent arm pain was associated with sustained impairments in shoulder mobility.PerspectiveFor persistent breast and arm pain, changes in sensation following breast cancer surgery were notable. Persistent arm pain was associated with sustained interference with daily functioning and upper body mobility impairments. Long-term management of persistent pain following breast cancer surgery is warranted to improve the quality of survivorship for these women.     

Biopsychosocial Influence on Exercise-Induced Injury: Genetic and Psychological Combinations Are Predictive of Shoulder Pain Phenotypes

Chronic pain is influenced by biological, psychological, social, and cultural factors. The current study investigated potential roles for combinations of genetic and psychological factors in the development and/or maintenance of chronic musculoskeletal pain. An exercise-induced shoulder injury model was used, and a priori selected genetic (ADRB2, COMT, OPRM1, AVPR1 A, GCH1, and KCNS1) and psychological (anxiety, depressive symptoms, pain catastrophizing, fear of pain, and kinesiophobia) factors were included as predictors. Pain phenotypes were shoulder pain intensity (5-day average and peak reported on numerical rating scale), upper extremity disability (5-day average and peak reported on the QuickDASH), and shoulder pain duration (in days). After controlling for age, sex, and race, the genetic and psychological predictors were entered as main effects and interaction terms in separate regression models for the different pain phenotypes. Results from the recruited cohort (N = 190) indicated strong statistical evidence for interactions between the COMT diplotype and 1) pain catastrophizing for 5-day average upper extremity disability and 2) depressive symptoms for pain duration. There was moderate statistical evidence for interactions for other shoulder pain phenotypes between additional genes (ADRB2, AVPR1 A, and KCNS1) and depressive symptoms, pain catastrophizing, or kinesiophobia. These findings confirm the importance of the combined predictive ability of COMT with psychological distress and reveal other novel combinations of genetic and psychological factors that may merit additional investigation in other pain cohorts.PerspectiveInteractions between genetic and psychological factors were investigated as predictors of different exercise-induced shoulder pain phenotypes. The strongest statistical evidence was for interactions between the COMT diplotype and pain catastrophizing (for upper extremity disability) or depressive symptoms (for pain duration). Other novel genetic and psychological combinations were identified that may merit further investigation.     

Association of COMT gene variability with pain intensity in patients after total hip replacement

Pain is one of the most interdisciplinary clinical symptoms of a disease. The aim of the study was to evaluate the association of COMT gene polymorphism with pain perception in patients after total hip replacement (THR). The study included 195 patients qualified for surgical treatment (THR) due to osteoarthritis. Patients previously undergoing hip replacement subsequently underwent multimodal pain management therapy, in accordance with the recommendations for treating postoperative pain. The intensity of pain was measured three times at pre-defined time intervals: 1.5, 6 and 12 months after hip replacement, using the visual analogue scale. Single nucleotide polymorphism (SNP) in the COMT gene rs4680: A>G (Val158Met), rs6269: A>G (promoter region), rs4633: C>T (His62His) and rs4818: C>G (Leu136Leu) was genotyped. COMT SNP frequency distribution was analysed. For rs6269 and rs4818, the minor allele was the G allele (38.7 and 38.5%, respectively). It was also observed that rs4633 (T) allele frequency (50%) equalled that of the rs4680 (A) allele (50%). We assessed COMT haplotype frequency in the patients studied. The most frequent haplotype was haplotype M (ATCA) (50%), the rarest haplotype was haplotype R (ATGG), with a frequency of 0.3%. The most frequent diplotype was H/M, which was found in 37.95% of the patients. The frequency of other diplotypes was: M/M–24.10%, H/H–15.90% and L/M–13.33%. The study showed a significant association of rs4818?G allele and equivalent COMT H haplotype with lower sensitivity to pain after hip replacement.     

Persistent Breast Pain Following Breast Cancer Surgery Is Associated With Persistent Sensory Changes,Pain Interference,and Functional Impairments

Interindividual variability exists in persistent breast pain following breast cancer surgery. Recently, we used growth mixture modeling to identify 3 subgroups of women (N = 398) with distinct persistent breast pain trajectories (ie, mild, moderate, severe) over 6 months following surgery. The purposes of this study were to identify demographic and clinical characteristics that differed among the breast pain classes and, using linear mixed effects modeling, to examine how changes over time and in sensitivity in the breast scar area, pain qualities, pain interference, and hand and arm function differed among these classes. Several demographic and clinical characteristics differentiated the breast pain classes. Of note, 60 to 80% of breast scar sites tested were much less sensitive than the unaffected breast. Significant group effects were observed for pain qualities and interference scores, such that, on average, women in the severe pain class reported higher scores than women in the moderate pain class. In addition, women in the moderate pain class reported higher scores than women in the mild pain class. Compared to women in the mild pain class, women in the severe pain class had significantly impaired grip strength, and women in the moderate and severe pain classes had impaired flexion and abduction.PerspectiveSubgroups of women with persistent postsurgical breast pain differed primarily with respect to the severity rather than the nature or underlying mechanisms of breast pain. Pervasive sensory loss and the association between persistent breast pain and sustained interference with function suggest the need for long-term clinical follow-up.     

Genetic variation in the beta2-adrenergic receptor but not catecholamine-O-methyltransferase predisposes to chronic pain: Results from the 1958 British Birth Cohort Study

More than 1 in 10 adults in the general population experience chronic widespread body pain (CWP), which lies at one end of a continuous spectrum of pain ranging in both severity and duration. Neuroendocrine factors can modify the effect of known psychological and psychosocial risk factors for progression along the spectrum of pain and development of CWP, and genetic variants that affect neuroendocrine and neural processing potentially affect susceptibility to chronic pain development. We have examined variants across genes encoding the beta2-adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT) – key neuroendocrine signalling factors – in a large population-based sample to determine whether these may be involved in pain progression and CWP development. A nested association study was conducted using individuals from the 1958 British Birth Cohort Study who had been assessed for pain status. Genotypes were available for nine single nucleotide polymorphisms (SNPs) across ADRB2 and 11 SNPs across COMT. ADRB2 SNPs rs12654778 and rs1042713 were associated either with CWP alone (p = 0.02 for both) or with position along pain spectrum (pain status; p = 0.04). Common functional ADRB2 haplotype combinations were also associated with pain status (p_model = 0.002) and, further, with both extent and duration of pain (p_model = 0.003 and p_model = 0.002, respectively). There were no associations of either CWP or pain status with COMT genotypes or haplotypes. These results are the first to suggest that functional ADRB2 variants are involved in regulating pain status at a population level. A role for COMT in chronic pain development was not identified, though could not be excluded.     

OXTR rs53576 Variation with Breast and Nipple Pain in Breastfeeding Women

BackgroundThirty percent of women who seek professional breastfeeding support require assistance with ongoing breast and nipple pain and < 50% of women report resolution of their pain. It is unknown if there is a molecular risk for ongoing breast and nipple pain during breastfeeding. Aim –To evaluate associations among breast and nipple pain sensitivity and candidate pain sensitivity single-nucleotide polymorphisms [SNPs], (COMT rs6269, rs4633, rs4818, rs4680 and OXTR rs2254298, rs53576) in breastfeeding women. Design - A secondary analysis of a pilot randomized controlled trial of a pain self-management intervention conducted over 6 weeks postpartum. Setting and Participants - Sixty women were recruited from two hospital settings after birth. Methods – All participants underwent standardized mechanical somatosensory testing for an assessment of pain sensitivity and provided baseline buccal swabs for genetic analysis. At 1, 2, and 6 weeks postpartum, women self-reported breast and nipple pain severity using a visual analogue scale. Results - Women with the minor allele OXTR rs53576 reported 8.18-fold higher breast and nipple pain severity over time. For every 1-unit increase in Mechanical detection threshold and windup ratio, women reported 16.51-fold and 4.82-fold higher breast and nipple pain severity respectively. Six women with the OXTR rs2254298 minor allele reported allodynia. Conclusion - The presence of OXTR alleles in women with enhanced pain sensitivity suggests a phenotype of genetic risk for ongoing breast and nipple with potential for pain-associated breastfeeding cessation. Somatosensory testing identified women who reported higher breast and nipple pain during the first weeks of breastfeeding.     

Pain modality- and sex-specific effects of COMT genetic functional variants

The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions, including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to interindividual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain, and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3′UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female vs male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics.     

COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia

Forty-five women with fibromyalgia (FM) engaged in a 30-day electronic diary assessment, recording daily ratings of pain and 2 forms of maladaptive coping: pain catastrophizing and pain attention. Participants were genotyped for the val¹⁵⁸met single nucleotide polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene. COMT genotype moderated the daily relations of both maladaptive coping processes and pain. FM women with the homozygous met/met genotype evidenced more pain on days when pain catastrophizing was elevated relative to heterozygous and homozygous val¹⁵⁸ carriers. FM women with the homozygous met/met genotype evidenced more pain on days when pain attention was elevated relative to those with the homozygous val/val genotype. Evidence is presented to suggest that these are independent effects. The findings provide multimeasure and multimethod support for genetic moderation of a maladaptive coping and pain process, which has been previously characterized in a sample of postoperative shoulder pain patients. Further, the findings advance our understanding of the role of COMT in FM, suggesting that genetic variation in the val¹⁵⁸met polymorphism may affect FM pain through pathways of pain-related cognition.     

An Opposite-Direction Modulation of the COMT Val158Met Polymorphism on the Clinical Response to Intrathecal Morphine and Triptans

Genetic variation in the COMT gene is thought to have clinical implications for pain perception and pain treatment. In the present study, we first evaluated the association between COMT rs4680 and the analgesic response to intrathecal morphine in patients with chronic low back pain to provide confirmation of previously reported positive findings. Next, we assessed the relationship between rs4680 and headache response to triptans in 2 independent cohorts of migraine patients. In patients with chronic low back pain (n = 74), logistic stepwise regression analysis showed that age (odds ratio [OR]: .90, 95% confidence interval [CI]: .85–.96, P = .002) and the presence of the COMT Met allele (vs Val/Val, OR: .21, 95% CI: .04–.98, P = .048) were predictive factors for lower risk of poor analgesic response to intrathecal morphine. Intriguingly, in migraine patients, the COMT rs4680 polymorphism influenced headache response to triptans in the opposite direction. Indeed, in an exploratory cohort of migraine patients without aura (n = 75), homozygous carriers of the COMT 158Met allele were found at increased risk to be poor responders to frovatriptan when compared to homozygous patients for the Val allele (OR: 5.20, 95% CI: 1.25–21.57, P = .023). In the validation cohort of migraine patients treated with triptans other than frovatriptan (n = 123), logistic stepwise regression analysis showed that use of prophylactic medications (OR: .43, 95% CI: .19–.99, P = .048) and COMT Met/Met genotype (vs Val/Val, OR: 4.29, 95% CI: 1.10–16.71, P = .036) were independent risk factors for poor response to triptans.     

Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure

Individual vulnerability factors influencing the function of the hypothalamic-pituitary-adrenal axis may contribute to the risk of the development of persistent musculoskeletal pain after traumatic stress exposure. The objective of the study was to evaluate the association between polymorphisms in the gene encoding FK506 binding protein 51, FKBP5, a glucocorticoid receptor co-chaperone, and musculoskeletal pain severity 6 weeks after 2 common trauma exposures. The study included data from 2 prospective emergency department-based cohorts: a discovery cohort (n = 949) of European Americans experiencing motor vehicle collision and a replication cohort of adult European American women experiencing sexual assault (n = 53). DNA was collected from trauma survivors at the time of initial assessment. Overall pain and neck pain 6 weeks after trauma exposure were assessed using a 0–10 numeric rating scale. After adjustment for multiple comparisons, 6 FKBP5 polymorphisms showed significant association (minimum P < 0.0001) with both overall and neck pain in the discovery cohort. The association of rs3800373, rs9380526, rs9394314, rs2817032, and rs2817040 with neck pain and/or overall pain 6 weeks after trauma was replicated in the sexual assault cohort, showing the same direction of the effect in each case. The results of this study indicate that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced during the weeks after motor vehicle collision and sexual assault. These results suggest that glucocorticoid pathways influence the development of persistent posttraumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma.     

Systematic Review and Meta-Analysis of Genetic Risk of Developing Chronic Postsurgical Pain

Chronic postsurgical pain (CPSP) is a significant detriment to postsurgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated heritability for chronic pain is 45% and that genetic factors partially explain individual susceptibility to CPSP. The aim of this study was to systematically review, assess quality, and summarize the studies in humans that have investigated genetic factors associated with CPSP. We also conducted a meta-analysis to derive a single effect size for evaluable genetic associations with CPSP. Our comprehensive literature search included review of 21 full-text articles evaluating variants of 69 genes for association with CPSP. We found significant gene variant associations reported for variants/haplotypes of 26 genes involved in neurotransmission, pain signaling, immune responses and neuroactive ligand–receptor interaction, with CPSP. Six variants of 5 genes (COMT: rs4680 and rs6269, OPRM1: rs1799971, GCH1: rs3783641, KCNS1: rs734784 and TNFA: rs1800629), were evaluated by more than one study and were included in the meta-analysis. At rs734784 (A>G) of KCNS1, presence of G allele marginally increased risk of CPSP (Additive genetic model; Odds ratio: 1.511; 95% CI 1–2.284; P value: .050), while the other variants did not withstand meta-analyses criteria. Our findings demonstrate the role of genetic factors with different functions in CPSP, and also emphasize that single genetic factors have small effect sizes in explaining complex conditions like CPSP. Heterogeneity in surgical cohorts, population structure, and outcome definitions, as well as small number of available studies evaluating same variants, limit the meta-analysis. There is a need for large-scale, homogenous, replication studies to validate candidate genes, and understand the underlying biological networks underpinning CPSP.PerspectiveOur systematic review comprehensively describes 21 studies evaluating genetic association with CPSP, and limitations thereof. A meta-analysis of 6 variants (5 genes) found marginally increased risk for CPSP associated with rs734784 A>G of the potassium voltage-gated channel gene (KCNS1). Understanding genetic predisposition for CPSP will enable prediction and personalized management.     

Financial and Psychological Risk Attitudes Associated with Two Single Nucleotide Polymorphisms in the Nicotine Receptor (CHRNA4) Gene

With recent advances in understanding of the neuroscience of risk taking, attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes. In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature. To develop a long-term prospective study, we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that are significantly associated with harm avoidance, a risk attitude measurement drawn from the psychology literature. Novelty seeking, another risk attitude measure from the psychology literature, is associated with several COMT (catechol-O-methyl transferase) SNPs while economic risk attitude measures are associated with several VMAT2 (vesicular monoamine transporter) SNPs, but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes.     

Perioperative Pregabalin and Intraoperative Lidocaine Infusion to Reduce Persistent Neuropathic Pain After Breast Cancer Surgery: A Multicenter,Factorial, Randomized,Controlled Pilot Trial

Persistent postsurgical pain is defined as pain localized to the area of surgery of a duration of ≥2 months and is, unfortunately, a common complication after breast cancer surgery. Although there is insufficient evidence to support any preventative strategy, prior literature suggests the possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2 × 2 factorial, randomized, placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/h) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for 9 days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients was accomplished within 42 weeks, with a follow-up rate of 100% and study drug compliance of ≥80%. At 3 months, 53% of patients reported persistent neuropathic pain. Although there was no interaction between lidocaine and pregabalin, lidocaine decreased the development of persistent neuropathic pain (43.1% vs 63.3%; relative risk = .68; 95% confidence interval = .47–1.0). Pregabalin did not reduce persistent pain (60% vs 46%; relative risk = 1.3; 95% confidence interval = .90–1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions during breast cancer surgeries.Clinical trial number: NCT02240199PerspectiveThis article reports the findings of a pilot randomized, controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated the feasibility of conducting a larger trial and provided promising data that these interventions may decrease the development of persistent pain.