AAAPT Diagnostic Criteria for Acute Pain Following Breast Surgery.

Acute pain after breast surgery decreases the quality of life of cancer survivors. Previous studies using a variety of definitions and methods report prevalence rates between 10% and 80%, which suggests the need for a comprehensive framework that can be used to guide assessment of acute pain and pain-related outcomes after breast surgery. A multidisciplinary task force with clinical and research expertise performed a focused review and synthesis and applied the 5 dimensional framework of the AAAPT (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks [ACTTION], American Academy of Pain Medicine [AAPM], American Pain Society [APS] Pain Taxonomy) to acute pain after breast surgery. Application of the AAAPT taxonomy yielded the following: 1) Core Criteria: Location, timing, severity, and impact of breast surgery pain were defined; 2) Common Features: Character and expected trajectories were established in relevant surgical subgroups, and common pain assessment tools for acute breast surgery pain identified; 3) Modulating Factors: Biological, psychological, and social factors that modulate interindividual variability were delineated; 4) Impact/Functional Consequences: Domains of impact were outlined and defined; 5) Neurobiologic Mechanisms: Putative mechanisms were specified ranging from nerve injury, inflammation, peripheral and central sensitization, to affective and social processing of pain. PERSPECTIVE: The AAAPT provides a framework to define and guide improved assessment of acute pain after breast surgery, which will enhance generalizability of results across studies and facilitate meta-analyses and studies of interindividual variation, and underlying mechanism. It will allow researchers and clinicians to better compare between treatments, across institutions, and with other types of acute pain.

Nicotine Evoked Currents in Human Primary Sensory Neurons.

Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated with tissue injury. However, there are marked differences between rats and mice with respect to both the properties and distribution of nAChR currents in sensory neurons. Because both species are used to understand pain signaling in humans, we sought to determine whether the currents present in either species was reflective of those present in human sensory neurons. Neurons from the L4/L5 dorsal root ganglia were obtained from adult male and female organ donors. Nicotine evoked currents were detected in 40 of 47 neurons (85%). In contrast with the naïve mouse, in which almost all nAChR currents are transient, or the rat, in which both mouse-like transient and more slowly activating and inactivating currents are detected, all the currents in human DRG neurons were slow, but slower than those in the rat. Currents were blocked by the nAChR antagonists mecamylamine (30 µmol/L), but not by the TRPA1 selective antagonist HC-030031 (10 µmol/L). Single cell polymerase chain reaction analysis of nicotinic receptor subunit expression in human DRG neurons are consistent with functional data indicating that receptor expression is detected 85 ± 2.1% of neurons assessed (n = 48, from 4 donors). The most prevalent coexpression pattern was α3/ß2 (95 ± 4% of neurons with subunits), but α7 subunits were detected in 70 ± 3.4% of neurons. These results suggest that there are not only species differences in the sensory neuron distribution of nAChR currents between rodent and human, but that the subunit composition of the channel underlying human nAChR currents may be different from those in the mouse or rat. PERSPECTIVE: The properties and distribution of nicotine evoked currents in human sensory neurons were markedly different from those previously observed in mice and rats. These observations add additional support to the suggestion that human sensory neurons may be an essential screening tool for those considering moving novel therapeutics targeting primary afferents into clinical trials.

CACNG2 polymorphisms associate with chronic pain after mastectomy.

Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery (Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisante A, Darvasi A. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 2010;20:1180-90). This information is important because in principle, it can inform the surgical, radiological, and chemotherapeutic decision-making process in ways that could mitigate the increased risk of chronic pain. In this study, we revisited this claim by independently evaluating the proposed marker haplotype using 2 different patient cohorts recruited in different research settings. Meta-analysis of these new postmastectomy cohorts and the original cohort confirmed significant association of the CACNG2 haplotype with PMP. In addition, we tested whether the same markers would predict chronic postsurgical pain in men who underwent surgery for inguinal hernia repair, and whether there is significant genetic association with cutaneous thermal sensitivity in postmastectomy and postherniotomy patients. We found that the biomarker is selective because it did not predict pain after laparoscopic hernia repair and was not associated with pain sensitivity to experimentally applied noxious thermal stimuli. We conclude that the A-C-C haplotype at the 3 single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is associated with increased risk of developing PMP. This information may advance current knowledge on pathophysiology of PMP and serve as a step forward in the prediction of clinical outcomes and personalized pain management.

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 × 10). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 × 10). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 × 10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.

Second edition of SIMPAR's "Feed Your Destiny" workshop: the role of lifestyle in improving pain management.

This review is aimed to summarize the latest data regarding pain and nutrition, which have emerged during the second edition of Feed Your Destiny (FYD). Theme presentations and interactive discussions were held at a workshop on March 30, 2017, in Florence, Italy, during the 9th Annual Meeting of Study in Multidisciplinary Pain Research, where an international faculty, including recognized experts in nutrition and pain, reported the scientific evidence on this topic from various perspectives. Presentations were divided into two sections. In the initial sessions, we analyzed the outcome variables and methods of measurement for health claims pertaining to pain proposed under Regulation EC No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Moreover, we evaluated how the Mediterranean diet can have a potential impact on pain, gastrointestinal disorders, obesity, cancer, and aging. Second, we discussed the evidence regarding vitamin D as a nutraceutical that may contribute to pain control, evaluating the interindividual variability of pain nature and nurture, and the role of micro-RNAs (miRNAs), polyunsaturated omega 3 fatty acids, and phenolic compounds, with a final revision of the clinical role of nutrition in tailoring pain therapy. The key take-home message provided by the FYD workshop was that a balanced, personalized nutritional regimen might play a role as a synergic strategy that can improve management of chronic pain through a precision medicine approach.

Effect of gastroretentive gabapentin (Gralise) on postmastectomy pain syndrome: a proof-of-principle open-label study.

INTRODUCTION: Chronic pain is a common and debilitating complication following breast surgery. One of the most challenging for treatment is the neuropathic pain condition, postmastectomy pain syndrome (PMPS). Gabapentin is a pharmacotherapy for neuropathic pain disorders; however, its once-daily, gastroretentive formulation, Gralise, has not been evaluated in PMPS. OBJECTIVE: To evaluate the safety and effectiveness of Gralise in patients with moderate-to-severe PMPS. METHODS: The primary effectiveness endpoint was a change in the worst pain intensity score from baseline to completion of 8 weeks of Gralise therapy. The secondary endpoints included the change in mood, coping behavior, sleep, and function. Sensitivity to experimental stimuli was tested before and after treatment via quantitative sensory testing. The incidence and type of adverse event were used to evaluate the safety and tolerability of Gralise. RESULTS: Twenty-one patients with confirmed moderate-to-severe PMPS were enrolled. Nineteen of 21 (90.5%) patients completed the 8-week treatment with Gralise. A significant positive change was found in pain intensity, pain impact, and sleep. There was no change in sensory testing scores. Of total, 63.16% of patients reported reduction in present pain, 78.95% in average pain, 89.47% in worst pain, and 84.21% in overall pain severity at posttreatment visit. No significant adverse effects were noted in the study. LIMITATIONS: Variation in type of breast surgery, small sample size, lack of placebo control. CONCLUSION: There was a significant improvement in pain and sleep, and Gralise was well tolerated in patients with PMPS. Further investigation is warranted.

Human Genetic Variability Contributes to Postoperative Morphine Consumption.

UNLABELLED: High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor µ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P = .007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy. PERSPECTIVE: This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752.

Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group.

DESCRIPTION: Pain in patients with chronic pancreatitis (CP) remains the primary clinical complaint and source of poor quality of life. However, clear guidance on evaluation and treatment is lacking. METHODS: Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain assessment and pain treatment in CP. Levels of evidence were assigned using the Oxford system, and consensus was based on GRADE. A consensus meeting was held during PancreasFest 2012 with substantial post-meeting discussion, debate, and manuscript refinement. RESULTS: Twelve discussion questions and proposed guidance statements were presented. Conference participates concluded: Disease Mechanism: Pain etiology is multifactorial, but data are lacking to effectively link symptoms with pathologic feature and molecular subtypes. Assessment of Pain: Pain should be assessed at each clinical visit, but evidence to support an optimal approach to assessing pain character, frequency and severity is lacking. MANAGEMENT: There was general agreement on the roles for endoscopic and surgical therapies, but less agreement on optimal patient selection for medical, psychological, endoscopic, surgical and other therapies. CONCLUSIONS: Progress is occurring in pain biology and treatment options, but pain in patients with CP remains a major problem that is inadequately understood, measured and managed. The growing body of information needs to be translated into more effective clinical care.

Association of functional variations in COMT and GCH1 genes with postherniotomy pain and related impairment.

Persistent postoperative pain is a well-established clinical problem with potential severe personal and socioeconomic implications. The prevalence of persistent pain varies across surgery types. Severe persistent pain and related impairment occur in 5% to 10% of patients after groin hernia repair. The substantial interindividual variability in pain-related phenotypes within each surgery type cannot be explained by environmental factors alone, suggesting that genetic variation may play a role. We investigated the contribution of COMT and GCH1 to persistent postherniotomy pain (PPP)-related functional impairment. Prospective data from 429 Caucasian male patients with hernia were collected. Three COMT and 2 GCH1 tagging single-nucleotide polymorphisms (SNPs) were genotyped and analyzed for association with PPP-related activity impairment at 6 months after herniotomy. Fifty-five (12.8%) patients had moderate-to-severe pain-related activity impairment 6 months postoperatively as measured by Activity Assessment Scale (≥8.3). Patients with the G allele of COMT SNP rs6269 and C allele of COMT SNP rs4633 had less impairment (P = 0.03 and 0.01, respectively); in addition, the COMT haplotype GCG was associated with less impairment. For GCH1, the A allele of SNP rs3783641, T allele of rs8007267, and AT haplotype showed a protective effect trend (although nonsignificant; P = 0.08, 0.06, and 0.08, respectively). A prediction model of substantial PPP-related activity impairment, combining COMT and GCH1 SNPs with clinical, psychophysical, and psychological risk factors, had a "good" (0.8 < area under curve < 0.9) discriminatory power. These data suggest that functional variations in COMT and GCH1 combined with clinical factors are predictive of PPP-related impairment after groin herniotomy.

Predicting, preventing and managing persistent pain after breast cancer surgery: the importance of psychosocial factors.

Persistent pain after breast cancer surgery (PPBCS) is increasingly recognized as a potential problem facing a sizeable subset of the millions of women who undergo surgery as part of their treatment of breast cancer. Importantly, an increasing number of studies suggest that individual variation in psychosocial factors such as catastrophizing, anxiety, depression, somatization and sleep quality play an important role in shaping an individual's risk of developing PPBCS. This review presents evidence for the importance of these factors and puts them within the context of other surgical, medical, psychophysical and demographic factors, which may also influence PPBCS risk, as well as discusses potential perioperative therapies to prevent PPBCS.

The design and methods of genetic studies on acute and chronic postoperative pain in patients after total knee replacement.

OBJECTIVE: Total knee replacement (TKR) is the treatment option of choice for the millions of individuals whose osteoarthritis pain can no longer be managed through non-invasive methods. Over 500,000 TKRs are performed annually in the United States. Although most patients report improvement in pain and functioning following TKR, up to 30% report persistent pain that interferes with daily function. However, the reasons for poor outcomes are not clear. To best determine which patients are at risk for pain post TKR, a detailed and comprehensive approach is needed. In this article, we present the methodology of a study designed to identify a set of genetic, proteomic, clinical, demographic, psychosocial, and psychophysical risk factors for severe acute and chronic pain post TKR. DESIGN: Prospective longitudinal observational study. SETTING: University Hospital System. SUBJECTS: Patients scheduled for unilateral TKR with a target number of 150. METHODS: Prior to surgery, we collect demographic, psychosocial, and pain data. Biological data, including blood samples for genetic analyses, and serum, urine, and joint fluid for cytokine assessment are collected intraoperatively. Pain assessments as well as medication use are collected during each of the three days postsurgery. Additionally, pain and psychosocial information is collected 6 and 12 months following surgery. CONCLUSIONS: This study, for the first time, captures the information on both genetic and "environmental" risk factors for acute and chronic pain post-TKR and has the potential to lead to the next step-multicenter large-scale studies on predictors and biomarkers of poor TKR outcomes as well as on tailored interventions and personalized medicine approaches for those at risk.

Persistent postmastectomy pain in breast cancer survivors: analysis of clinical, demographic, and psychosocial factors.

UNLABELLED: Persistent postmastectomy pain (PPMP) is increasingly recognized as a major individual and public health problem. Although previous studies have investigated surgical, medical, and demographic risk factors, in this study we aimed to more clearly elucidate the relationship of psychosocial factors to PPMP. Postmastectomy patients (611) were queried about pain location, severity, and burden 38.3 ± 35.4 months postoperatively. Validated questionnaires for depressive symptoms, anxiety, sleep, perceived stress, emotional stability, somatization, and catastrophizing were administered. Detailed surgical, medical, and treatment information was abstracted from patients' medical records. One third (32.5%) of patients reported PPMP, defined as ≥3/10 pain severity in the breast, axilla, side, or arm, which did not vary according to time since surgery. Multiple regression analysis revealed significant and independent associations between PPMP and psychosocial factors, including catastrophizing, somatization, anxiety, and sleep disturbance. Conversely, treatment-related factors including surgical type, axillary node dissection, surgical complication, recurrence, tumor size, radiation, and chemotherapy were not significantly associated with PPMP. These data confirm previous studies suggesting that PPMP is relatively common and provide new evidence of significant associations between psychosocial characteristics such as catastrophizing with PPMP, regardless of the surgical and medical treatment that patients receive, which may lead to novel strategies in PPMP prevention and treatment. PERSPECTIVE: This cross-sectional cohort study of 611 postmastectomy patients investigated severity, location, and frequency of pain a mean of 3.2 years after surgery. Significant associations between pain severity and individual psychosocial attributes such as catastrophizing were found, whereas demographic, surgical, medical, and treatment-related factors were not associated with persistent pain.

Chronic pain after lower abdominal surgery: do catechol-O-methyl transferase/opioid receptor µ-1 polymorphisms contribute?

BACKGROUND: Preoperative pain, type of operation and anesthesia, severity of acute postoperative pain, and psychosocial factors have been identified as risk factors for chronic postsurgical pain (CPP). Recently, it has been suggested that genetic factors also contribute to CPP. In this study, we aimed to determine whether the catechol-O-methyl transferase (COMT) and opioid receptor µ-1 (OPRM1) common functional polymorphisms rs4680 and rs1799971 were associated with the incidence, intensity, or duration of CPP in patients after lower abdominal surgery. METHODS: One hundred and two patients with American Society of Anesthesiologists (ASA) physical status I/II underwent either abdominal radical prostatectomy (n = 45) or hysterectomy (n = 57). The incidences of CPP in the pelvic and scar areas were evaluated in all patients three months after surgery. RESULTS: Thirty-five (34.3%) patients experienced CPP after lower abdominal surgery. Within this group, six (17.1%) patients demonstrated symptoms of neuropathic pain. For COMT rs4680, 22 (21.6%) patients had Met158Met, 55 (53.9%) patients had Val158Met, and 25 (24.5%) patients had Val158Val. No association was found between CPP phenotypes (incidence, intensity, and duration) and different rs4680 genotypes. For OPRM1 rs1799971, only CPP patients carrying at least one copy of the G allele had higher pain intensity than A118A carriers (p=0.02). No associations with other phenotypes were found. No combined effect of COMT/OPRM1 polymorphisms on CPP phenotypes was observed. CONCLUSIONS: OPRM1 genotype influences CPP following lower abdominal surgery. COMT didn't affect CPP, suggesting its potential modality-specific effects on human pain.

Persistent pain in postmastectomy patients: comparison of psychophysical, medical, surgical, and psychosocial characteristics between patients with and without pain.

Persistent postmastectomy pain (PPMP) is a major individual and public health problem. Increasingly, psychosocial factors such as anxiety and catastrophizing are being revealed as crucial contributors to individual differences in pain processing and outcomes. Furthermore, differences in patients' responses to standardized quantitative sensory testing (QST) may aid in the discernment of who is at risk for acute and chronic pain after surgery. However, characterization of the variables that differentiate those with PPMP from those whose acute postoperative pain resolves is currently incomplete. The purpose of this study was to investigate important surgical, treatment-related, demographic, psychophysical, and psychosocial factors associated with PPMP by comparing PPMP cases with PPMP-free controls. Pain was assessed using the breast cancer pain questionnaire to determine the presence and extent of PPMP. Psychosocial and demographic information were gathered via phone interview, and women underwent a QST session. Consistent with most prior research, surgical and disease-related variables did not differ significantly between cases and controls. Furthermore, treatment with radiation, chemotherapy, or hormone therapy was also not more common among those with PPMP. In contrast, women with PPMP did show elevated levels of distress-related psychosocial factors such as anxiety, depression, catastrophizing, and somatization. Finally, QST in nonsurgical body areas revealed increased sensitivity to mechanical stimulation among PPMP cases, while thermal pain responses were not different between the groups. These findings suggest that an individual's psychophysical and psychosocial profile may be more strongly related to PPMP than their surgical treatment.

Alteration in pain modulation in women with persistent pain after lumpectomy: influence of catastrophizing.

CONTEXT: Persistent pain is common after surgical treatment of breast cancer, but fairly little is known about the changes in sensory processing that accompany such pain syndromes. OBJECTIVES: This study used quantitative sensory testing to compare psychophysical responses to standardized noxious stimulation in two groups of women who had previously undergone breast cancer surgery: women with (n=37) and without (n=34) persistent postoperative pain. METHODS: Participants underwent a single testing session in which responses to a variety of noxious stimuli were assessed. RESULTS: Findings suggested that women with chronic pain after breast cancer surgery display enhanced temporal summation of mechanical pain, deficits in endogenous pain inhibition, and more intense painful aftersensations compared with those without long-term pain. Some of these group differences were mediated by higher levels of pain catastrophizing in the group of women with persistent pain. CONCLUSION: These findings suggest that persistent postoperative pain is associated with alterations in central nervous system pain-modulatory processes. Future treatment studies might benefit from targeting these pain-modulatory systems, and additional studies using functional neuroimaging methods might provide further valuable information about the pathophysiology of long-term postsurgical pain in women treated for breast cancer.

Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception.

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.

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 µ-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.

Polymorphic variation of the guanosine triphosphate cyclohydrolase 1 gene predicts outcome in patients undergoing surgical treatment for lumbar degenerative disc disease.

STUDY DESIGN: Prospective observational study. OBJECTIVE: To determine whether polymorphic variations of the guanosine triphosphate (GTP) cyclohydrolase 1 gene (GCH1) are associated with different outcomes in patients undergoing surgical treatment for lumbar degenerative disc disease (DDD). SUMMARY OF BACKGROUND DATA: GCH1, the gene encoding the rate-limiting enzyme in tetrahydrobiopterin synthesis, has been strongly implicated as a determinant of pain experience in previous animal and human studies. METHODS.: A total of 69 patients undergoing surgical treatment for lumbar DDD were prospectively enrolled. Genomic DNA was extracted from a venous blood sample, and DNA sequence analysis was performed of GCH1. Surgery included 65 instrumented fusions and 4 disc arthroplasty procedures. Patients were observed prospectively for 1 year following surgery. Allelic and genotype frequencies were calculated for each of 14 single nucleotide polymorphisms (SNPs). One-year postoperative Oswestry Disability Index (ODI) scores were compared to preoperative scores and the absolute change in ODI score was used to perform genetic association analyses on the basis of both individual SNP markers as well as commonly observed haplotypes for the entire gene sequence. RESULTS: Single marker analysis revealed 1 SNP (rs998259; minor allele T) that was significantly associated with improvement in both absolute ODI score (P = 0.030) and Numerical Rating Scale back pain scores (P = 0.033) following surgery. Haplotype analysis identified a common GCH1 haplotype ("CACTTGTTTGAC") with a sample frequency of 12.3%, which was highly associated with improvement in absolute ODI score (P = 0.04). This haplotype frequency reflects the existence of both heterozygous and homozygous individuals in the study population. The presence of 1 unit of this haplotype was associated with an improvement in postoperative ODI score of 15.34 relative to the absence of this haplotype (P = 0.04). CONCLUSION: Preliminary results from this pilot genetic study of patients undergoing surgery for DDD suggests that the T allele at rs998259 of GCH1 may be associated with improved outcomes 1 year following surgery.

Association of catechol-O-methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease.

BACKGROUND CONTEXT: Surgical treatment for lumbar degenerative disc disease (DDD) has been associated with highly variable results in terms of postoperative pain relief and functional improvement. Many experts believe that DDD should be considered a chronic pain disorder as opposed to a degenerative disease. Genetic variation of the catechol-O-methyltransferase (COMT) gene has been associated with variation in human pain sensitivity and response to analgesics in previous studies. PURPOSE: To determine whether genetic variation of COMT is associated with clinical outcome after surgical treatment for DDD. STUDY DESIGN: Prospective genetic association study. PATIENT SAMPLE: Sixty-nine patients undergoing surgical treatment for lumbar DDD. Diagnosis was based on documentation of chronic disabling low back pain (LBP) present for a minimum of 6 months and unresponsive to supervised nonoperative treatment, including activity modification, medication, physical therapy, and/or injection therapy. Plain radiographs and magnetic resonance imaging revealed intervertebral disc desiccation, tears, and/or collapse without focal herniation, nerve root compression, stenosis, spondylolisthesis, spondylolysis, or alternative diagnoses. OUTCOME MEASURES: Oswestry Disability Index (ODI) and visual analog score (VAS) for LBP. METHODS: Surgical treatment included 65 instrumented fusions and four disc arthroplasty procedures. All patients completed preoperative and 1-year postoperative ODI questionnaires. DNA was extracted from a sample of venous blood, and genotype analysis was performed for five common COMT single nucleotide polymorphisms (SNPs). Potential genetic association between these COMT SNPs and the primary outcome variable, 1-year change in ODI, was investigated using both single-marker and haplotype association analyses. Association with VAS scores for LBP was analyzed as a secondary outcome variable. RESULTS: Single-marker analysis revealed that the COMT SNP rs4633 was significantly associated with greater improvement in ODI score 1 year after surgery (p=.03), with individuals homozygous for the less common "T" allele demonstrating the largest improvement in ODI. Haplotype analysis of four COMT SNPs, rs6269, rs4633, rs4818, and rs4680, also identified a common haplotype "ATCA" (haplotype frequency of 39.3% in the study population) associated with greater improvement in ODI (p=.046). The greatest mean improvement in ODI was observed in patients homozygous for the "ATCA"COMT haplotype. A nonsignificant trend was observed between SNP rs4633 and greater improvement in VAS score for LBP. CONCLUSIONS: This is the first study to report an association between surgical treatment success in DDD patients and genetic variation in the putative pain sensitivity gene COMT. These findings require replication in other DDD populations but suggest that genetic testing for pain-relevant genetic markers such as COMT may provide useful clinical information in terms of predicting outcome after surgery for patients diagnosed with DDD.

Linkage of large-vessel carotid atherosclerotic stroke to inflammatory genes via a systematic screen.

BACKGROUND: Inflammatory cytokines including the IL-1 family, TNF-alpha and IL-6 mediate the formation of thrombosis on the luminal surface of atherosclerotic plaques. Gene polymorphisms that regulate these cytokines' expression may explain part of the variation in susceptibility to stroke in patients with carotid atherosclerosis. The aim of this study was to evaluate the role of single-nucleotide polymorphisms (SNPs) and haplotypes in inflammatory genes as they relate to symptomatic carotid atherosclerosis. METHODS: The study included 95 subjects with symptomatic (transient ischaemic attacks or stroke) and 113 subjects with asymptomatic carotid atherosclerotic disease. A panel of evenly spaced SNPs including previously reported functionally significant polymorphisms were genotyped for IL-1beta (10 SNPs), IL-1alpha (nine SNPs), IL-1RN (11 SNPs), IL-6 (seven SNPs) and TNF-alpha and TNF-beta (seven SNPs). RESULTS: Using single SNP analysis, IL-1RN rs315934 (P=0.025), IL-1RN rs315946 (P=0.042), IL-1RN rs315921 (P=0.035), IL-6 rs1180243 (P=0.018) and IL-1alpha rs2071373 (P=0.025) were associated with decreased odds of symptomatic carotid disease. Additionally, two diplotypes of the IL-1RN gene (P=0.023 and 0.0064) and one diplotype in the IL-1alpha gene (P=0.02) were associated with a protective affect from cerebral ischaemic events. Logistic analysis for interaction of the protective SNPs reveals an additive effect of all SNP pair combinations. CONCLUSION: These results suggest that genetic polymorphisms in proinflammatory genes may contribute to interindividual differences in the development of symptomatic carotid atherosclerotic disease.