The journal of pain : official journal of the American Pain Society
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In pain clinical trials, the rescue analgesic medication such as patient-controlled analgesia morphine is often made available for patients for breakthrough pain. The patient-controlled analgesia morphine usage decreases the study agent's effect on pain relative to placebo and introduces greater variability in attainment of pain scores. For assessment of analgesic efficacy, the isolated statistical analysis of pain score or morphine consumption as a surrogate marker for pain not only loses statistical efficiency but also may incur increased false-positive findings because of multiple testing. The aim of this article is to review the research to date for choices of statistical tests for pain or morphine consumption outcome, with a focus on systematically evaluating a means for collective analgesic assessment of pain and morphine consumption using an integrated outcome. A case example is illustrated for data visualization, statistical comparison, and effect size estimation using the new endpoint. Some implications for clinical practice and further research are discussed. ⋯ This article provides statistical evidence to conclude that an integrated outcome of pain score and morphine consumption provides an efficient means for integrated analgesic assessment.
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Neuropathic pain is frequently characterized by spontaneous pain (ie, pain at rest) and, in some cases, by cold- and touch-induced allodynia. Mechanisms underlying the chronicity of neuropathic pain are not well understood. Rats received spinal nerve ligation (SNL) and were monitored for tactile and thermal thresholds. While heat hypersensitivity returned to baseline levels within approximately 35 to 40 days, tactile hypersensitivity was still present at 580 days after SNL. Tactile hypersensitivity at post-SNL day 60 (D60) was reversed by microinjection of 1) lidocaine; 2) a cholecystokinin 2 receptor antagonist into the rostral ventromedial medulla; or 3) dorsolateral funiculus lesion. Rostral ventromedial medulla lidocaine at D60 or spinal ondansetron, a 5-hydroxytryptamine 3 antagonist, at post-SNL D42 produced conditioned place preference selectively in SNL-treated rats, suggesting long-lasting spontaneous pain. Touch-induced FOS was increased in the spinal dorsal horn of SNL rats at D60 and prevented by prior dorsolateral funiculus lesion, suggesting that long-lasting tactile hypersensitivity depends upon spinal sensitization, which is mediated in part by descending facilitation, in spite of resolution of heat hypersensitivity. ⋯ These data suggest that spontaneous pain is present for an extended period of time and, consistent with likely actions of clinically effective drugs, is maintained by descending facilitation.
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The rostroventromedial medulla (RVM) is an important area of the endogenous pain-regulating system, in which 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) are 2 main transmitters involved in pain modulation. However, whether 5-HT and GABA are colocalized is poorly understood. By using glutamate decarboxylase 67-green fluorescence protein (GAD67-GFP) knock-in mouse, we confirmed the colocalization of 5-HT and GABA in the RVM, with a main distribution in the raphe magnus nucleus and paragigantocellular reticular nucleus. Interestingly, more than half (51.6%) of the 5-HT/GABA-immunoreactive (ir) neurons expressed neurokinin-1 receptors (NK-1R) and one-third (30.1%) of the 5-HT/GABA/NK-1R-ir neurons projected to the spinal cord, suggesting that substance P (SP) should regulate the activity of 5-HT/GABA-ir spinal cord-projecting neurons. By combining retrograde and anterograde tracing methods, we observed that the cuneiform nucleus, dorsal raphe nucleus, and lateral periaqueductal gray are the main origin nuclei for the SP-ir fibers and terminals in the RVM. Finally, after formalin injection into the mice hind paw, 29.2% SP-ir RVM-projecting neurons from supra-RVM nuclei and 33.1% NK-1R-ir spinal cord-projecting neurons in the RVM were activated. The present study provides potent morphological evidence that 5-HT and GABA are coexistent in RVM-spinal cord-projecting neurons that are also regulated by SPergic projections. ⋯ The results will greatly enhance our understanding for the modulation of nociceptive information in the descending pain-regulating system.
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Randomized Controlled Trial
How good is the neurophysiology of pain questionnaire? A Rasch analysis of psychometric properties.
The Neurophysiology of Pain Questionnaire (NPQ) was devised to assess how an individual conceptualizes the biological mechanisms that underpin his or her pain. Despite its widespread use, its psychometric properties have not been comprehensively interrogated. Rasch analysis was undertaken on NPQ data from a convenience sample of 300 spinal pain patients, and test-retest reliability was assessed in a sample of 45 low back pain patients. The NPQ effectively targeted the ability of the sample and had acceptable internal consistency and test-retest reliability. However, some items functioned erratically for persons of differing abilities or were psychometrically redundant. The NPQ was reanalyzed with 7 questionable items excluded, and superior psychometric properties were observed. These findings suggest that the NPQ could be improved, but future prospective studies including qualitative measures are needed. In summary, the NPQ is a useful tool for assessing a patient's conceptualization of the biological mechanisms that underpin his or her pain and for evaluating the effects of cognitive interventions in clinical practice and research. These findings suggest that it has adequate psychometric properties for use with chronic spinal pain patients. ⋯ Rasch analysis was used to analyze the NPQ. Despite several limitations, these results suggest that it is a useful tool with which to assess a patient's conceptualization of the biological mechanisms that underpin his or her pain and to evaluate the effects of cognitive interventions in clinical practice and research.
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Back pain is common and many people experience long-term problems, yet little is known about what prognostic factors predict long-term outcomes. This study's objective was to determine which factors predict short- and long-term outcomes in primary care consulters with low back pain (LBP). Analysis was carried out on 488 patients who had consulted their physician about LBP. Patients were followed up at 6 months and 5 years. Clinically significant LBP at follow-up was defined as a score of 2, 3, or 4 on the Chronic Pain Grade, indicating substantial pain and disability. Cox regression was used to estimate relative risks (RRs) with 95% confidence intervals (CIs) on 32 potential predictive factors, organized into domains (demographic, physical, psychological, and occupational). Baseline pain intensity conferred a 12% increase in risk (RR = 1.12, 95% CI = 1.03-1.20), and patients' belief that their LBP would persist conferred a 4% increase in risk (RR = 1.04, 95% CI = 1.01-1.07) for poor outcome at 6 months. Outcome at 5 years was best predicted by a model with the same factors as in the 6-month model: pain intensity increased risk by 9% (RR = 1.09, 95% CI = .997-1.20), and a belief that their LBP would persist increased risk by 6% (RR = 1.06, 95% CI = 1.03-1.09). Both predictors have the potential to be targets for clinical intervention. ⋯ Few studies have investigated factors that predict long-term back pain. This study has shown that pain intensity experienced during a period of primary care consultation, and patients' perception about whether their back pain will persist, were significant predictors of poor outcome at 6 months and at 5 years.