Mitchell B Max

Publications (35)191.57 Total impact

• Article: Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.

  Michael Costigan, Inna Belfer, Robert S Griffin, Feng Dai, Lee B Barrett, Giovanni Coppola, Tianxia Wu, Carly Kiselycznyk, Minakshi Poddar, Yan Lu, [......], Lone Nikolajsen, Jaro Karppinen, Minna Männikkö, Anthi Kelempisioti, David Goldman, William Maixner, Daniel H Geschwind, Mitchell B Max, Ze'ev Seltzer, Clifford J Woolf
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  ABSTRACT: Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.
  Brain 09/2010; 133(9):2519-27. · 9.46 Impact Factor
• Article: Linkage of large-vessel carotid atherosclerotic stroke to inflammatory genes via a systematic screen.

  Inna Belfer, Tianxia Wu, Heather Hipp, Joan Walter, Michele Scully, Paul A Nyquist, Antonella Bollettino, David Goldman, Mitchell B Max, Thomas J DeGraba
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  ABSTRACT: 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. 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). 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. These results suggest that genetic polymorphisms in proinflammatory genes may contribute to interindividual differences in the development of symptomatic carotid atherosclerotic disease.
  International Journal of Stroke 06/2010; 5(3):145-51. · 2.38 Impact Factor
• Source

  Available from: Luda Diatchenko

  Article: Pain perception is altered by a nucleotide polymorphism in SCN9A.

  Frank Reimann, James J Cox, Inna Belfer, Luda Diatchenko, Dmitri V Zaykin, Duncan P McHale, Joost P H Drenth, Feng Dai, Jerry Wheeler, Frances Sanders, [......], Mitchell B Max, Carly Kiselycznyk, Minakshi Poddar, Rene H M Te Morsche, Shad Smith, Dustin Gibson, Anthi Kelempisioti, William Maixner, Fiona M Gribble, C Geoffrey Woods
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  ABSTRACT: The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the A allele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype.
  Proceedings of the National Academy of Sciences 03/2010; 107(11):5148-53. · 9.68 Impact Factor
• Article: Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2).

  Robert H Dworkin, Dennis C Turk, Dennis A Revicki, Gale Harding, Karin S Coyne, Sarah Peirce-Sandner, Dileep Bhagwat, Dennis Everton, Laurie B Burke, Penney Cowan, John T Farrar, Sharon Hertz, Mitchell B Max, Bob A Rappaport, Ronald Melzack
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  ABSTRACT: The objective of the present research was to develop a single measure of the major symptoms of both neuropathic and non-neuropathic pain that can be used in studies of epidemiology, natural history, pathophysiologic mechanisms, and treatment response. We expanded and revised the Short-form McGill Pain Questionnaire (SF-MPQ) pain descriptors by adding symptoms relevant to neuropathic pain and by modifying the response format to a 0-10 numerical rating scale to provide increased responsiveness in longitudinal studies and clinical trials. The reliability, validity, and subscale structure of the revised SF-MPQ (SF-MPQ-2) were examined in responses from 882 individuals with diverse chronic pain syndromes and in 226 patients with painful diabetic peripheral neuropathy who participated in a randomized clinical trial. The data suggest that the SF-MPQ-2 has excellent reliability and validity, and the results of both exploratory and confirmatory factor analyses provided support for four readily interpretable subscales-continuous pain, intermittent pain, predominantly neuropathic pain, and affective descriptors. These results provide a basis for use of the SF-MPQ-2 in future clinical research, including clinical trials of treatments for neuropathic and non-neuropathic pain conditions.
  Pain 05/2009; 144(1-2):35-42. · 5.78 Impact Factor
• Source

  Available from: Cornelia Kamp

  Article: A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster.

  Robert H Dworkin, Richard L Barbano, Stephen K Tyring, Robert F Betts, Michael P McDermott, Janet Pennella-Vaughan, Gary J Bennett, Erhan Berber, John W Gnann, Carrie Irvine, Cornelia Kamp, Karl Kieburtz, Mitchell B Max, Kenneth E Schmader
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  ABSTRACT: Although acute pain in patients with herpes zoster can be severe and has a substantial impact on health-related quality of life, there have been no randomized clinical trials of oral medications specifically for its ongoing treatment. A randomized clinical trial was conducted in which 87 subjects >or=50 years of age with herpes zoster within 6 calendar days of rash onset and with worst pain in the past 24h >or=3 on a 0-10 rating scale initiated 7 days of treatment with famciclovir in combination with 28 days of treatment with either controlled-release (CR) oxycodone, gabapentin, or placebo. Subjects were evaluated for adverse effects of treatment, acute pain, and health-related quality of life. The results showed that CR-oxycodone and gabapentin were generally safe and were associated with adverse events that reflect well-known effects of these medications. Discontinuing participation in the trial, primarily associated with constipation, occurred more frequently in subjects randomized to CR-oxycodone (27.6%) compared with placebo (6.9%). Treatment with CR-oxycodone reduced the mean worst pain over days 1-8 (p=0.01) and days 1-14 (p=0.02) relative to placebo but not throughout the entire 28-day treatment period as pain resolved in most subjects. Gabapentin did not provide significantly greater pain relief than placebo, although the data for the first week were consistent with a modest benefit. By demonstrating that CR-oxycodone is safe, generally adequately tolerated, and appears to have efficacy for relieving acute pain, the results of this clinical trial provide a foundation for evidence-based treatment for acute pain in herpes zoster.
  Pain 03/2009; 142(3):209-17. · 5.78 Impact Factor
• Source

  Available from: Nikolay A Spiridonov

  Article: Expansion of the human mu-opioid receptor gene architecture: novel functional variants.

  Svetlana A Shabalina, Dmitri V Zaykin, Pavel Gris, Aleksey Y Ogurtsov, Josee Gauthier, Kyoko Shibata, Inna E Tchivileva, Inna Belfer, Bikashkumar Mishra, Carly Kiselycznyk, Margaret R Wallace, Roland Staud, Nikolay A Spiridonov, Mitchell B Max, David Goldman, Roger B Fillingim, William Maixner, Luda Diatchenko
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  ABSTRACT: The mu-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5'-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.
  Human Molecular Genetics 01/2009; 18(6):1037-51. · 7.64 Impact Factor
• Source

  Available from: Susan Martin

  Article: Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.

  Dennis C Turk, Robert H Dworkin, Michael P McDermott, Nicholas Bellamy, Laurie B Burke, Julie M Chandler, Charles S Cleeland, Penney Cowan, Rozalina Dimitrova, John T Farrar, [......], Patrick McGrath, Henry J McQuay, Steve Quessy, Bob A Rappaport, Dennis A Revicki, Margaret Rothman, Joseph W Stauffer, Ola Svensson, Richard E White, James Witter
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  ABSTRACT: The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.
  Pain 09/2008; 139(3):485-93. · 5.78 Impact Factor
• Source

  Available from: immpactpain.org

  Article: Identifying important outcome domains for chronic pain clinical trials: an IMMPACT survey of people with pain.

  Dennis C Turk, Robert H Dworkin, Dennis Revicki, Gale Harding, Laurie B Burke, David Cella, Charles S Cleeland, Penney Cowan, John T Farrar, Sharon Hertz, Mitchell B Max, Bob A Rappaport
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  ABSTRACT: This two-phase study was conducted to identify relevant domains of patient-reported outcomes from the perspective of people who experience chronic pain. In Phase 1, focus groups were conducted to generate a pool of patient outcome-related domains and their components. The results of the focus groups identified 19 aspects of their lives that were significantly impacted by the presence of their symptoms and for which improvements were important criteria they would use in evaluating the effectiveness of any treatment. Phase 2 was conducted to examine the importance and relevance of domains identified from a much larger and diverse sample of people with chronic pain. A survey was developed and posted on the American Chronic Pain Association website. Participants were asked to rate the importance of each item or domain identified by the focus groups on a scale of 0 to10 (i.e., 0="not at all important" and 10="extremely important"). The survey was completed by 959 individuals. The results indicate that all 19 aspects of daily life derived from the focus groups were considered important with a majority of respondents indicating a score of 8 or greater. In addition to pain reduction, the most important aspects were enjoyment of life, emotional well-being, fatigue, weakness, and sleep-related problems. Chronic pain clearly impacts health-related quality of life. The results of the two phases of the study indicate that people with chronic pain consider functioning and well-being as important areas affected by the presence of symptoms and as appropriate targets of treatment. These multiple outcomes should be considered when evaluating the efficacy and effectiveness of chronic pain treatments.
  Pain 08/2008; 137(2):276-85. · 5.78 Impact Factor
• Article: Morphine versus mexiletine for treatment of postamputation pain: a randomized, placebo-controlled, crossover trial.

  Christopher L Wu, Shefali Agarwal, Prabhav K Tella, Brendan Klick, Michael R Clark, Jennifer A Haythornthwaite, Mitchell B Max, Srinivasa N Raja
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  ABSTRACT: Stump and phantom pains are debilitating sequelae of amputations that are often resistant to treatment. The efficacy of pharmacologic therapies, including opioids and sodium channel blockers, for postamputation pain is uncertain. The authors conducted a double-blind, randomized, placebo-controlled, crossover study in adult patients with postamputation pain of 6 months or longer and greater than 3 on a 0-10 numeric pain rating scale. Each of the three treatment periods (morphine, mexiletine, or placebo) included a 1-week drug-free interval followed by 4-week titration, 2-week maintenance, and 2-week drug-taper phases. The primary outcome measure was change in average pain intensity from the drug-free baseline to the last week of maintenance. Sixty amputees were enrolled; data were analyzed from 56 subjects for one drug period, 45 subjects for two drug periods, and 35 subjects who completed all three drug periods. The mean morphine and mexiletine dosages were 112 and 933 mg, respectively. Morphine treatment provided lower pain scores compared with placebo and mexiletine (P = 0.0003). The mean percent pain relief during treatment with placebo, mexiletine, and morphine was 19, 30, and 53%, respectively (P < 0.0001, morphine vs. placebo and mexiletine). The numbers needed to treat to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively. Treatment with morphine was associated with a higher rate of side effects. Therapy with morphine, but not mexiletine, resulted in a decrease in intensity of postamputation pain but was associated with a higher rate of side effects and no improvement in self-reported levels of overall functional activity and pain-related interference in daily activities.
  Anesthesiology 08/2008; 109(2):289-96. · 5.36 Impact Factor
• Article: Low intensity permanent magnets in the treatment of chronic lumbar radicular pain.

  Suzan Khoromi, Marc R Blackman, Albert Kingman, Athos Patsalides, Leigh Ann Matheny, Sandra Adams, Arthur A Pilla, Mitchell B Max
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  ABSTRACT: We assessed the pain-relieving efficacy of static magnetic fields produced by 200 Gauss (G) magnets compared with 50G magnets in a double-blind, randomized, two-phase crossover study in patients with chronic lumbar radicular pain. The surface field strengths of the magnets were 200 and 50G. Phase I included four random periods of two-week duration: two periods with 200G, one period with 50G, and one period of "no treatment." The magnets were positioned either vertically or horizontally in standard lumbosacral elastic corsets. Phase II consisted of two five-week periods with the most effective magnet from Phase I and its corresponding 50 or 200G device. The primary outcome was average daily leg pain score (0-10 scale) in each period of Phase II. Thirty-eight of 40 randomized patients completed Phase I, and 28 of 31 Phase II participants completed the study. In Phase I, pain scores did not differ significantly between 200 and 50G magnets. Phase II average leg pain scores tended to be lower with 200 vs. 50G magnets (3.2+/-2.1 for 200G vs. 3.9+/-2.2 for 50G magnets [P=0.08]) after excluding one unblinded patient. The relative treatment effect of the 200G magnets appeared to increase throughout the five-week period. Although these data cannot rule out a chance effect, the positive trends suggest that larger, longer-duration, sham-controlled trials with 200G magnets be considered in patients with chronic lumbar radicular pain.
  Journal of Pain and Symptom Management 11/2007; 34(4):434-45. · 2.50 Impact Factor
• Article: Symptoms of distress as prospective predictors of pain-related sciatica treatment outcomes.

  Robert R Edwards, Brendan Klick, Luis Buenaver, Mitchell B Max, Jennifer A Haythornthwaite, Robert B Keller, Steven J Atlas
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  ABSTRACT: Prior studies evaluating predictors of pain-related outcomes following treatment for sciatica have been limited by methodological problems, including retrospective study design, use of unvalidated outcome measures, and short-term follow-up periods. Despite these limitations, some reports have suggested that symptoms of psychological distress may predict individual differences in pain treatment-related outcomes (e.g., higher levels of depressive and anxious symptomatology are associated with greater pain and disability after treatment). In this study, we sought to determine whether acute symptoms of depression and anxiety were prospectively associated with treatment outcomes over a 3-year follow-up period in surgically treated and non-surgically treated patients with sciatica. Patients were recruited from the practices of community-based physicians throughout the state of Maine, and underwent in-person baseline assessments, with mailed follow-up questionnaires at 3, 6, 12, 24, and 36 months. Study outcomes included patient-reported symptoms of pain and disability. For each outcome variable, we examined whether baseline mood (i.e., mood assessed prior to the initiation of treatment), as well as mood at the immediately preceding assessment point, prospectively predicted outcomes over 3 years in multivariate repeated-measures analyses. In most analyses, symptoms of depression and anxiety, both at baseline and at the preceding time point, were significant independent predictors of worse pain and function after controlling for relevant covariates. Collectively, elevated distress appears to be a significant risk factor for reduced treatment benefit (i.e., less improvement in pain and disability) over short and medium-term follow-up periods in patients with sciatica. Future research should determine whether the prospective identification and treatment of patients with high levels of distress (a "yellow flag") is associated with improved treatment outcomes.
  Pain 08/2007; 130(1-2):47-55. · 5.78 Impact Factor
• Article: Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain.

  Suzan Khoromi, Lihong Cui, Lisa Nackers, Mitchell B Max
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  ABSTRACT: Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15-90 mg), nortriptyline (25-100 mg), their combination, and a benztropine "active placebo" (0.25-1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0-10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was, 14% for nortriptyline (95% CI=[-2%, 30%]), 7% for morphine (95% CI=[-8%, 22%]), and 7% for the combination treatment (95% CI=[-4%, 18%]). Mean doses were: nortriptyline alone, 84+/-24.44 (SD) mg/day; morphine alone, 62+/-29 mg/day; and combination, morphine, 49+/-27 mg/day plus nortriptyline, 55 mg+/-33.18 mg/day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.
  Pain 08/2007; 130(1-2):66-75. · 5.78 Impact Factor
• Article: Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms.

  Jörn Lötsch, Inna Belfer, Anja Kirchhof, Bikash K Mishra, Mitchell B Max, Alexandra Doehring, Michael Costigan, Clifford J Woolf, Gerd Geisslinger, Irmgard Tegeder
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  ABSTRACT: A haplotype in the GTP cyclohydrolase 1 (dopa-responsive dystonia) gene (GCH1) is associated with decreased persistent pain. The aim of the present study was to develop a screening method for the pain-protective haplotype. Complete genetic information for all 15 GCH1 DNA positions constituting the pain-protective GCH1 haplotype was available from 278 patients. In silico analyses, including discriminant analysis of the most frequent haplotypes, identified distinctive DNA positions that allow detection of the pain-protective haplotype at high sensitivity and specificity with the smallest possible number of DNA positions. Pyrosequencing(trade mark) assays were subsequently developed for these DNA positions, established with 662 DNA samples from healthy volunteers, and prospectively validated with a random selection of DNA samples genotyped for all 15 DNA positions. Diagnosis of the pain-protective GCH1 haplotype was possible with 100% sensitivity and specificity by screening for just 3 GCH1 genetic variants that span the entire DNA range of the haplotype: c.-9610G>A (dbSNP rs8007267G>A) in the 5' untranslated region, c.343 + 8900A>T (dbSNP rs3783641A>T) in intron 1, and c.*4279 (dbSNP rs10483639C>G) in the 3' untranslated region. Test sensitivity and specificity were still >95% with 2 or even just 1 of these GCH1 DNA positions. In silico analysis of complex GCH1 gene haplotypes reduced the requisite number of tested DNA positions from 15 to 3 while maintaining the reliability, specificity, and sensitivity of the genetic diagnosis. This screening method could reduce laboratory diagnostic efforts and facilitate investigations of the pain-protective GCH1 haplotype.
  Clinical Chemistry 07/2007; 53(6):1010-5. · 7.91 Impact Factor
• Source

  Available from: Colin Hodgkinson

  Article: Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

  Bikash K Mishra, Tianxia Wu, Inna Belfer, Colin A Hodgkinson, Leonardo G Cohen, Carly Kiselycznyk, Albert Kingman, Robert B Keller, Qiaoping Yuan, David Goldman, Steven J Atlas, Mitchell B Max
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  ABSTRACT: Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire. We genotyped a total of 121 single nucleotide polymorphisms (SNPs) in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor alpha1 subunit, GABA-A receptor alpha2 subunit, GABA-A receptor beta1 subunit, alpha-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor beta1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025) almost strong enough to correct for testing 22 haplotype blocks. If confirmed, the current results may suggest that a common haplotype in the GABA-A beta1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement.
  Molecular Pain 02/2007; 3:20. · 3.53 Impact Factor
• Article: Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.

  Luda Diatchenko, Andrea G Nackley, Gary D Slade, Kanokporn Bhalang, Inna Belfer, Mitchell B Max, David Goldman, William Maixner
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  ABSTRACT: Variations in the gene encoding catechol-O-methyltransferase (COMT) are linked to individual differences in pain sensitivity. A single nucleotide polymorphism (SNP) in codon 158 (val(158)met), which affects COMT protein stability, has been associated with the human experience of pain. We recently demonstrated that three common COMT haplotypes, which affect the efficiency of COMT translation, are strongly associated with a global measure of pain sensitivity derived from individuals' responses to noxious thermal, ischemic, and pressure stimuli. Specific haplotypes were associated with low (LPS), average (APS), or high (HPS) pain sensitivity. Although these haplotypes included the val(158)met SNP, a significant association with val(158)met variants was not observed. In the present study, we examined the association between COMT genotype and specific pain-evoking stimuli. Threshold and tolerance to thermal, ischemic, and mechanical stimuli, as well as temporal summation to heat pain, were determined. LPS/LPS homozygotes had the least, APS/APS homozygotes had average, and APS/HPS heterozygotes had the greatest pain responsiveness. Associations were strongest for measures of thermal pain. However, the rate of temporal summation of heat pain did not differ between haplotype combinations. In contrast, the val(158)met genotype was associated with the rate of temporal summation of heat pain, but not with the other pain measures. This suggests that the val(158)met SNP plays a primary role in variation in temporal summation of pain, but that other SNPs of the COMT haplotype exert a greater influence on resting nociceptive sensitivity. Here, we propose a mechanism whereby these two genetic polymorphisms differentially affect pain perception.
  Pain 01/2007; 125(3):216-24. · 5.78 Impact Factor
• Article: Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations.

  Dennis C Turk, Robert H Dworkin, Laurie B Burke, Richard Gershon, Margaret Rothman, Jane Scott, Robert R Allen, J Hampton Atkinson, Julie Chandler, Charles Cleeland, [......], Joseph W Stauffer, Gerold Stucki, Jane Tollett, Thorsten von Stein, Mark S Wallace, Joachim Wernicke, Richard E White, Amanda C Williams, James Witter, Kathleen W Wyrwich
  Pain 01/2007; 125(3):208-15. · 5.78 Impact Factor
• Source

  Available from: Andrew J Allchorne

  Article: GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.

  Irmgard Tegeder, Michael Costigan, Robert S Griffin, Andrea Abele, Inna Belfer, Helmut Schmidt, Corina Ehnert, Jemiel Nejim, Claudiu Marian, Joachim Scholz, [......], Swetha Sama, Steven J Atlas, William A Carlezon, Aram Parsegian, Jörn Lötsch, Roger B Fillingim, William Maixner, Gerd Geisslinger, Mitchell B Max, Clifford J Woolf
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  ABSTRACT: We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury-evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.
  Nature Medicine 12/2006; 12(11):1269-77. · 22.46 Impact Factor
• Article: Effects of chronic osteoarthritis pain on neuroendocrine function in men.

  Suzan Khoromi, Ranganath Muniyappa, Lisa Nackers, Nora Gray, Howard Baldwin, Kelli Anne Wong, Leigh Ann Matheny, Barbara Moquin, Aliya Rainer, Suvimol Hill, Alan Remaley, Laura Lee Johnson, Mitchell B Max, Marc R Blackman
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  ABSTRACT: Chronic pain has been associated with elevated cortisol, reduced LH and testosterone (T), and/or augmented circulating or excreted catecholamines. Most endocrine studies have been conducted in patients in whom the potentially confounding effects of depression, inflammatory disease, or coexistent medication use have not been controlled. The objective of the study was to test the hypothesis that chronic pain activates ACTH-cortisol and suppresses LH-T. This was a case control study conducted at a clinical research center. Participants included 16 opioid-naive men with chronic osteoarthritis pain, aged 35-65 yr with body mass index 20-30 kg/m2, and 12 healthy, opioid- and pain-free men of similar ages and body mass indexes. We compared circulating concentrations of ACTH, cortisol, LH, and T derived from every 20-min blood sampling (2000-0800 h), and 24-h urinary excretion of cortisol, epinephrine, norepinephrine, and dopamine. There were no significant differences in mean or integrated concentrations of ACTH, cortisol, LH, or T, or in the corresponding approximate entropy scores in osteoarthritis patients, compared with control subjects. The 0800-h serum LH concentrations were elevated in patients vs. controls (6.42 +/- 1.65 vs. 3.99 +/- 1.54 IU/liter, mean +/- sd, P = 0.02), whereas there were no significant group differences in total or free T, SHBG, cortisol binding globulin, dehydroepiandrosterone sulfate, or urinary cortisol and catecholamines. These data suggest that neuroendocrine function is not significantly altered in otherwise healthy men with chronic musculoskeletal pain and that prior reports of such hormonal abnormalities may have resulted from the confounding effects of coexistent illness or medication use.
  Journal of Clinical Endocrinology &amp Metabolism 12/2006; 91(11):4313-8. · 6.50 Impact Factor
• Article: GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence

  Irmgard Tegeder, Michael Costigan, Robert S Griffin, Andrea Abele, Inna Belfer, Helmut Schmidt, Corina Ehnert, Jemiel Nejim, Claudiu Marian, Joachim Scholz, [......], Swetha Sama, Steven J Atlas, William A Carlezon, Aram Parsegian, J|[ouml]|rn L|[ouml]|tsch, Roger B Fillingim, William Maixner, Gerd Geisslinger, Mitchell B Max, Clifford J Woolf
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  ABSTRACT: We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury–evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.
  Nature Medicine. 10/2006; 12(11):1269-1277.
• Article: Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder.

  Luda Diatchenko, Amy D Anderson, Gary D Slade, Roger B Fillingim, Svetlana A Shabalina, Tomas J Higgins, Swetha Sama, Inna Belfer, David Goldman, Mitchell B Max, Bruce S Weir, William Maixner
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  ABSTRACT: Adrenergic receptor beta(2) (ADRB2) is a primary target for epinephrine. It plays a critical role in mediating physiological and psychological responses to environmental stressors. Thus, functional genetic variants of ADRB2 will be associated with a complex array of psychological and physiological phenotypes. These genetic variants should also interact with environmental factors such as physical or emotional stress to produce a phenotype vulnerable to pathological states. In this study, we determined whether common genetic variants of ADRB2 contribute to the development of a common chronic pain condition that is associated with increased levels of psychological distress and low blood pressure, factors which are strongly influenced by the adrenergic system. We genotyped 202 female subjects and examined the relationships between three major ADRB2 haplotypes and psychological factors, resting blood pressure, and the risk of developing a chronic musculoskeletal pain condition-Temporomandibular Joint Disorder (TMD). We propose that the first haplotype codes for lower levels of ADRB2 expression, the second haplotype codes for higher ADRB2 expression, and the third haplotype codes for higher receptor expression and rapid agonist-induced internalization. Individuals who carried one haplotype coding for high and one coding for low ADRB2 expression displayed the highest positive psychological traits, had higher levels of resting arterial pressure, and were about 10 times less likely to develop TMD. Thus, our data suggest that either positive or negative imbalances in ADRB2 function increase the vulnerability to chronic pain conditions such as TMD through different etiological pathways that imply the need for tailored treatment options.
  American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2006; 141B(5):449-62. · 3.70 Impact Factor