The journal of pain : official journal of the American Pain Society
-
Glial cell line-derived neurotrophic factor (GDNF), a survival-promoting factor for a subset of nociceptive small-diameter neurons, has been shown to exert analgesic effects on neuropathic pain. However, its detailed mechanisms of action are still unknown. In the present study, we investigated the site-specific analgesic effects of GDNF in the neuropathic pain state using lentiviral vector-mediated GDNF overexpression in mice with left fifth lumbar (L5) spinal nerve ligation (SNL) as a neuropathic pain model. A lentiviral vector expressing both GDNF and enhanced green fluorescent protein (EGFP) was constructed and injected into the left dorsal spinal cord, uninjured fourth lumbar (L4) dorsal root ganglion (DRG), injured L5 DRG, or plantar skin of mice. In SNL mice, injection of the GDNF-EGFP-expressing lentivirus into the dorsal spinal cord or uninjured L4 DRG partially but significantly reduced the mechanical allodynia in association with an increase in GDNF protein expression in each virus injection site, whereas injection into the injured L5 DRG or plantar skin had no effects. These results suggest that GDNF exerts its analgesic effects in the neuropathic pain state by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by the uninjured DRG neurons. ⋯ This article shows that GDNF exerts its analgesic effects on neuropathic pain by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by these neurons. Therefore, research focusing on these GDNF-dependent neurons in the uninjured DRG would provide a new strategy for treating neuropathic pain.
-
Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1,442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3,295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously reported associations between TMD and 2 genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD, and they identify potential targets for therapeutic intervention. ⋯ Genetic risk factors for TMD pain were explored in the case-control component of the OPPERA cooperative agreement, a large population-based prospective cohort study. Over 350 candidate pain genes were assessed using a candidate gene panel, with several genes displaying preliminary evidence for association with TMD status.
-
Randomized Controlled Trial Multicenter Study
Study methods, recruitment, sociodemographic findings, and demographic representativeness in the OPPERA study.
This paper describes methods used in the project "Orofacial Pain Prospective Evaluation and Risk Assessment" (OPPERA) and evaluates sociodemographic characteristics associated with temporomandibular disorders (TMD) in the OPPERA case-control study. Representativeness was investigated by comparing sociodemographic profiles of OPPERA participants with population census profiles of counties near study sites and by comparing age and gender associations with TMD in OPPERA and the 2007 to 2009 US National Health Interview Survey. Volunteers aged 18 to 44 years were recruited at 4 US study sites: 3,263 people without TMD were enrolled into the prospective cohort study; 1,633 of them were selected as controls for the baseline case-control study. Cases were 185 volunteers with examiner-classified TMD. Distributions of some demographic characteristics among OPPERA participants differed from census profiles, although there was less difference in socioeconomic profiles. Odds of TMD was associated with greater age in this 18 to 44 year range; females had 3 times the odds of TMD as males; and relative to non-Hispanic-Whites, other racial groups had one-fifth the odds of TMD. Age and gender associations with chronic TMD were strikingly similar to associations observed in the US population. Assessments of representativeness in this demographically diverse group of community volunteers suggest that OPPERA case-control findings have good internal validity. ⋯ Demographic associations with TMD were consistent with population benchmarks and with other studies, suggesting broad applicability of these OPPERA findings. Greater occurrence of TMD in non-Hispanic-Whites than in other racial/ethnic groups and the lack of a socioeconomic gradient contradicts the disparities seen in many other health conditions.
-
Randomized Controlled Trial Multicenter Study
Efficacy and safety of buprenorphine transdermal system (BTDS) for chronic moderate to severe low back pain: a randomized, double-blind study.
In this enriched design study, 1,160 opioid-experienced patients with chronic, moderate to severe low back pain entered an open-label run-in period; 660 demonstrated analgesic benefit from and tolerability to buprenorphine transdermal system 20 mcg/hour (BTDS 20) treatment and were randomized to receive either BTDS 20, BTDS 5 mcg/hour (BTDS 5), or the active control (immediate release oxycodone 40-mg/day) during an 84-day double-blind phase. The primary endpoint, "average pain in the last 24 hours" during double-blind weeks 4, 8, and 12, was significantly lower for patients receiving BTDS 20 compared with patients receiving BTDS 5 (P < .001, treatment difference of -.67). A treatment difference of -.75 in favor of oxycodone 40 mg/day versus BTDS 5 (P < .001) indicated the assay sensitivity of the study. Four sensitivity analyses, secondary, and exploratory analyses supported the results of the primary analysis. Incidences of treatment-emergent adverse events were 56% during the open-label period, and 59, 77, and 73% for the BTDS 5, BTDS 20, and oxycodone 40 mg/day treatment groups, respectively, during the double-blind phase. One death considered unrelated to study treatment occurred in a patient receiving BTDS 10 during the run-in period. BTDS 20 treatment was demonstrated to be efficacious and generally well tolerated. ⋯ This article presents results of a pivotal Phase 3 study that assesses a new treatment for the management of chronic low back pain: a transdermal patch containing the opioid buprenorphine (BTDS). In this active controlled, superiority study with an enriched design, BTDS 20 was found to be efficacious and generally well tolerated.