RESUMEN
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.
Asunto(s)
Canal de Potasio Kv.1.1/genética , Dolor/genética , Polimorfismo Genético/genética , Valina/genética , Animales , Enfermedad Crónica , Estudios de Cohortes , Comprensión , Biología Computacional/métodos , Comparación Transcultural , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de Neurofilamentos , Neuropéptidos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Dolor/etiología , RatasRESUMEN
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.
Asunto(s)
Aterosclerosis/genética , Aterosclerosis/patología , Arterias Carótidas/patología , Inflamación/genética , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patología , Anciano , Estudios de Cohortes , ADN/genética , Femenino , Marcadores Genéticos , Pruebas Genéticas , Haplotipos , Humanos , Interleucina-1/genética , Interleucina-6/genética , Recuento de Leucocitos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
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.
Asunto(s)
Dolor/genética , Percepción , Polimorfismo de Nucleótido Simple/genética , Canales de Sodio/genética , Adulto , Alelos , Fenómenos Biofísicos/genética , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Proteínas Mutantes/genética , Canal de Sodio Activado por Voltaje NAV1.7 , Dolor/fisiopatología , Umbral del Dolor , Análisis de RegresiónRESUMEN
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.
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Dimensión del Dolor/métodos , Dimensión del Dolor/normas , Dolor/diagnóstico , Encuestas y Cuestionarios/normas , Anciano , Neuropatías Diabéticas , Análisis Factorial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/clasificación , Dolor/epidemiología , Dolor/fisiopatología , Reproducibilidad de los Resultados , Índice de Severidad de la EnfermedadRESUMEN
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.
Asunto(s)
Aminas/uso terapéutico , Ensayos Clínicos como Asunto/tendencias , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Preparaciones de Acción Retardada/administración & dosificación , Medicina Basada en la Evidencia/tendencias , Herpes Zóster/tratamiento farmacológico , Oxicodona/administración & dosificación , Dolor/tratamiento farmacológico , Ácido gamma-Aminobutírico/uso terapéutico , Enfermedad Aguda , Anciano , Analgésicos Opioides/administración & dosificación , Femenino , Gabapentina , Herpes Zóster/epidemiología , Humanos , Masculino , New York/epidemiología , Dolor/epidemiología , Efecto Placebo , Texas/epidemiología , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Polimorfismo de Nucleótido Simple/genética , Receptores Opioides mu/genética , Adolescente , Adulto , Alelos , Animales , Secuencia de Bases , Estudios de Cohortes , Exones/genética , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Intrones/genética , Ratones , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Dolor/genética , Isoformas de Proteínas/genética , Empalme del ARN/genéticaRESUMEN
BACKGROUND: Pain is often a dominant clinical feature of chronic pancreatitis but the frequency and severity is highly variable between subjects. We hypothesized that genetic polymorphisms contribute to variations in clinical pain patterns. Since genetic variations in the GTP cyclohydrolase (GCH1) gene have been reported to protect some patients from pain, we investigated the effect of the "pain protective haplotype" in well characterized patients with chronic pancreatitis (CP) or recurrent acute pancreatitis (RAP) from the North American Pancreatitis Study 2 (NAPS2). RESULTS: Subjects in the NAPS2 study were asked to rank their pain in one of 5 categories reflecting different levels of pain frequency and severity. All subjects were genotyped at rs8007267 and rs3783641 to determine the frequency of the GCH1 pain-protective haplotype. In Caucasian subjects the frequency of the pain-protective GCH1 haplotype was no different in the control group (n = 236), CP patients (n = 265), RAP patients (N = 131), or in CP patients subclassified by pain category compared to previously reported haplotype frequencies in the general Caucasian population. CONCLUSION: The GCH1 pain-protective haplotype does not have a significant effect on pain patterns or severity in RAP or CP. These results are important for helping to define the regulators of visceral pain, and to distinguish different mechanisms of pain.
Asunto(s)
GTP Ciclohidrolasa/genética , Haplotipos , Umbral del Dolor , Dolor/genética , Pancreatitis Crónica/genética , Anciano , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Dolor/metabolismo , Pancreatitis Crónica/metabolismo , Sensibilidad y EspecificidadAsunto(s)
Investigación Biomédica/economía , Organización de la Financiación/estadística & datos numéricos , Manejo del Dolor , Apoyo a la Investigación como Asunto/estadística & datos numéricos , Investigación Biomédica/métodos , Financiación Gubernamental/economía , Financiación Gubernamental/estadística & datos numéricos , Financiación Gubernamental/tendencias , Organización de la Financiación/economía , Organización de la Financiación/tendencias , Política de Salud/economía , Humanos , National Institutes of Health (U.S.)/economía , National Institutes of Health (U.S.)/estadística & datos numéricos , Dolor/diagnóstico , Apoyo a la Investigación como Asunto/economía , Apoyo a la Investigación como Asunto/tendencias , Estados UnidosRESUMEN
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.
Asunto(s)
Ensayos Clínicos como Asunto/estadística & datos numéricos , Determinación de Punto Final/estadística & datos numéricos , Manejo del Dolor , Factores de Confusión Epidemiológicos , Humanos , Análisis de los Mínimos Cuadrados , Análisis Multivariante , Teoría de la Probabilidad , Proyectos de Investigación/estadística & datos numéricosRESUMEN
Recent candidate gene studies have identified and replicated the first associations between several common polymorphisms and pain severity in humans. Moreover, human studies in twins suggest high heritability for responses to experimental pain stimuli. Human genome-wide association studies of pain phenotypes might identify novel analgesic targets, help to prioritize research among current targets, and increase the likelihood of success for analgesic candidates emerging from animal studies. However, clinical research in pain has largely focused on small neurophysiology-based studies, so expansion of epidemiological understanding will be essential to the success of genetic or proteomic dissection of complex pain disorders. This Perspective outlines how methods of molecular epidemiology, proved effective in the study of other diseases, can enhance the returns from human genomic studies and expedite the development of new drugs to prevent or treat pain.
Asunto(s)
Diseño de Fármacos , Epidemiología Molecular/tendencias , Dolor/tratamiento farmacológico , Tecnología Farmacéutica/tendencias , Humanos , Epidemiología Molecular/métodos , Dolor/epidemiología , Dolor/genética , Tecnología Farmacéutica/métodosRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Asunto(s)
Amputación Quirúrgica , Antiarrítmicos/uso terapéutico , Mexiletine/uso terapéutico , Morfina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Miembro Fantasma/tratamiento farmacológico , Antiarrítmicos/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Mexiletine/efectos adversos , Persona de Mediana Edad , Morfina/efectos adversos , Dolor Postoperatorio/clasificación , Miembro Fantasma/clasificación , Miembro Fantasma/etiologíaRESUMEN
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.
Asunto(s)
Ensayos Clínicos como Asunto/normas , Encuestas de Atención de la Salud/métodos , Evaluación de Resultado en la Atención de Salud/métodos , Dimensión del Dolor/métodos , Dolor Intratable/psicología , Calidad de Vida/psicología , Actividades Cotidianas/psicología , Adulto , Enfermedad Crónica/psicología , Enfermedad Crónica/terapia , Ensayos Clínicos como Asunto/métodos , Evaluación de la Discapacidad , Femenino , Grupos Focales/métodos , Humanos , Masculino , Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Dolor Intratable/terapia , Satisfacción del Paciente , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Dolor de la Región Lumbar/prevención & control , Magnetismo/uso terapéutico , Dimensión del Dolor/efectos de la radiación , Radiculopatía/terapia , Ciática/prevención & control , Adolescente , Adulto , Anciano , Enfermedad Crónica , Femenino , Humanos , Dolor de la Región Lumbar/diagnóstico , Vértebras Lumbares , Masculino , Persona de Mediana Edad , Dosis de Radiación , Radiculopatía/diagnóstico , Ciática/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.
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Actividad Motora/genética , Movimiento/fisiología , Dolor/genética , Actividades Cotidianas , Enfermedad Aguda , Algoritmos , Alelos , Estudios de Cohortes , ADN/genética , ADN/aislamiento & purificación , Discectomía , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Haplotipos , Homocigoto , Humanos , Modelos Lineales , Dolor de la Región Lumbar/fisiopatología , Masculino , Dimensión del Dolor , Polimorfismo de Nucleótido Simple , Receptores Adrenérgicos alfa 2/genética , Receptores de GABA-A/genética , Ciática/fisiopatología , Ciática/cirugía , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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GTP Ciclohidrolasa/genética , Dolor/genética , Polimorfismo de Nucleótido Simple , Haplotipos , Heterocigoto , Homocigoto , Humanos , Técnicas de Diagnóstico Molecular , Dolor/diagnóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Análisis de Secuencia de ADNRESUMEN
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.
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Síntomas Afectivos/diagnóstico , Discectomía/psicología , Dolor Postoperatorio/psicología , Ciática/psicología , Ciática/cirugía , Adulto , Afecto , Ansiedad/diagnóstico , Depresión/diagnóstico , Evaluación de la Discapacidad , Femenino , Estudios de Seguimiento , Humanos , Desplazamiento del Disco Intervertebral/psicología , Desplazamiento del Disco Intervertebral/cirugía , Vértebras Lumbares , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Morfina/administración & dosificación , Nortriptilina/administración & dosificación , Radiculopatía/tratamiento farmacológico , Ciática/tratamiento farmacológico , Adulto , Anciano , Analgésicos Opioides/efectos adversos , Antidepresivos Tricíclicos/efectos adversos , Enfermedad Crónica , Estudios Cruzados , Quimioterapia Combinada , Femenino , Humanos , Vértebras Lumbares , Masculino , Persona de Mediana Edad , Morfina/efectos adversos , Nortriptilina/efectos adversos , Placebos , Raíces Nerviosas Espinales , Resultado del TratamientoAsunto(s)
Ensayos Clínicos como Asunto/normas , Evaluación de Resultado en la Atención de Salud/normas , Dimensión del Dolor/normas , Dolor/clasificación , Dolor/diagnóstico , Guías de Práctica Clínica como Asunto , Encuestas y Cuestionarios/normas , Ensayos Clínicos como Asunto/métodos , Humanos , Evaluación de Resultado en la Atención de Salud/métodos , Dimensión del Dolor/métodos , Pautas de la Práctica en Medicina/normas , Estados UnidosRESUMEN
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.