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

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.

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.

Pain perception is altered by a nucleotide polymorphism in SCN9A.

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.

Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2).

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.

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

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.

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

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.

Does the pain-protective GTP cyclohydrolase haplotype significantly alter the pattern or severity of pain in humans with chronic pancreatitis?

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).

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

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.

Morphine versus mexiletine for treatment of postamputation pain: a randomized, placebo-controlled, crossover trial.

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.

The molecular epidemiology of pain: a new discipline for drug discovery.

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.

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

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.

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

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.

Low intensity permanent magnets in the treatment of chronic lumbar radicular pain.

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.

Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms.

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.

Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain.

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.

Symptoms of distress as prospective predictors of pain-related sciatica treatment outcomes.

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.

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.

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.

Effects of chronic osteoarthritis pain on neuroendocrine function in men.

Context: 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.

Objective: The objective of the study was to test the hypothesis that chronic pain activates ACTH-cortisol and suppresses LH-T.

Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.

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.

Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder.

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.

Basal heat pain thresholds predict opioid analgesia in patients with postherpetic neuralgia.

Background: A variety of analgesics have been studied in the treatment of postherpetic neuralgia, with several medications demonstrating some degree of efficacy. However, existing trials have documented large individual differences in treatment responses, and it is important to identify patient characteristics that predict the analgesic effectiveness of particular interventions. Several animal studies have indicated that reduced basal nociceptive sensitivity, in the form of relatively high heat pain thresholds, is associated with greater opioid analgesia, but this finding has not been applied to human studies of opioid treatment for chronic pain.

Use of the cumulative proportion of responders analysis graph to present pain data over a range of cut-off points: making clinical trial data more understandable.

In randomized controlled trials, no single definition of response is ideal for all purposes. We propose a method to present in a simple fashion the likelihood of response over a full range of response levels, which will facilitate a better understanding of clinical trial data. We present the technique called the cumulative proportion of responders analysis (CPRA) and its application to four pain clinical trial data sets as examples.