The journal of pain : official journal of the American Pain Society
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Chronic neuropathic pain is often difficult to treat with current pain medications. Gene therapy is presently being explored as a therapeutic approach for the treatment of neuropathic and cancer pain. In this study, we sought to use an injury-specific promoter to deliver the mu-opioid receptor (MOR) transgene such that expression would occur during the injured state only in response to release of injury-specific galanin. To determine whether an injury-specific promoter can produce neuron-specific MOR expression and enhanced antinociception, we compared animals infected with a galanin promoter virus (galMOR) or a human cytomegalovirus promoter virus (cmvMOR). In behavioral assays, we found an earlier onset and a larger magnitude of antinociception in animals infected with galMOR compared with cmvMOR. Immunohistochemical analysis of dorsal root ganglion neurons revealed a significant increase in MOR-positive staining in cmvMOR- and galMOR-treated mice. Spinal cord sections from galMOR-treated mice showed a greater increase in density but not area of MOR-positive staining. These results suggest that using injury-specific promoters to drive gene expression in primary afferent neurons can influence the onset and magnitude of antinociception in a rodent model of neuropathic pain and can be used to upregulate MOR expression in populations of neurons that are potentially injury specific. ⋯ An injury-specific promoter (galMOR) was used to drive MOR expression in a population- and injury-specific manner. GalMOR increased antinociception and density of MOR staining in the spinal cord. This article presents evidence that promoter selection is an important component in successful gene expression in an injury- and population-specific manner.
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Motivational accounts of pain behavior and disability suggest that persisting attempts to avoid or control pain may paradoxically result in heightened attention to pain-related information. We investigated whether attempts to control pain prioritized attention to the location where pain was expected, using a tactile change detection paradigm. Thirty-seven undergraduate students had to detect changes between 2 consecutively presented patterns of tactile stimuli at various body locations. One of the locations was made threatening by occasionally administering a pain-eliciting stimulus. Half of the participants (pain control group) were encouraged to actively avoid the administering of pain by pressing a button as quickly as possible, whereas the other participants (comparison group) were not. The actual amount of painful stimuli was the same in both groups. Results showed that in the comparison group, the anticipation of pain resulted in better detection of tactile changes at the pain location than at the other locations, indicating an attentional bias for the threatened location. Crucially, the pain control group showed a similar attentional bias, but also when there was no actual presence of threat. This suggests that although threat briefly prioritized the threatened location, the goal to control pain did so in a broader, more context-driven manner. ⋯ This study investigates the impact of attempts to control pain on somatosensory processing at the pain location. It provides further insight into the motivational mechanisms of pain-related attention. It also points to the negative consequences of trying to control uncontrollable pain, such as is often the case in chronic pain.
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Randomized Controlled Trial
Effect of types and anatomic arrangement of painful stimuli on conditioned pain modulation.
Reduced pain perception during painful stimulation to another body region (ie, conditioned pain modulation [CPM]) is considered important for pain modulation and development of pain disorders. The various methods used to study CPM limit comparison of findings. We investigated the influence of key methodologic variations on CPM and the properties of CPM when the back is used for the test stimulus or the conditioning stimulus (CS). Two different test stimuli (pressure pain threshold and pain response to suprathreshold heat [Pain-45, ie, pain rated at 45 on a 0-100 numeric rating scale]) were assessed before and during application of a noxious or non-noxious (sham) CS. Eight blocks of trials varied the anatomic location (back and forearms) and arrangement (body side) of the stimuli. Pressure pain threshold (as the test stimulus) increased during application of noxious, but not non-noxious, CS when stimuli were applied to opposite body sides or heterotopic sites on one body side. Inconsistent with pain-induced CPM, Pain-45 decreased during both noxious and non-noxious CS. These findings indicate that 1) pressure pain threshold can be more confidently interpreted with respect to CPM evoked by a painful stimulus than Pain-45, 2) the back and forearm are equally effective as sites for stimuli, and 3) stimuli arrangement does not influence CPM, except for identical anatomic regions on the same body side. ⋯ This study indicates that pressure pain threshold as the test stimulus provides a more valid measure of pain-induced CPM than pain response to a suprathreshold heat stimulus. Induction and magnitude of CPM is independent of stimuli arrangement, as long as ipsilateral homotopic sites are avoided. These findings clarify methods to study CPM.
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The Pain Self-Efficacy Questionnaire (PSEQ) is an established 10-item measure of pain self-efficacy that is widely used in clinical and research settings. However, a shorter measure would reduce patient and researcher burden and save valuable time in busy clinical settings. The aim of this study was to develop and confirm the psychometric properties of a valid and reliable 2-item short form of the PSEQ (PSEQ-2). We used a large sample of 1,418 chronic pain patients, which we randomly split into 2 smaller groups. We identified the 2 short-form items in Sample 1 and confirmed their properties in Sample 2. In order to identify the 2 items for the short-form measure, we selected the first item based on the highest item-total correlation. The second item was identified after a series of additional analyses. The 2 items identified from the PSEQ reflected confidence in one's ability to work and lead a normal life despite pain. The PSEQ-2's validity and internal consistency were found to be sound. Test-retest reliability, sensitivity to change, and convergent validity were confirmed in a separate patient sample (n = 140) that had recently completed an intervention designed, in part, to modify self-efficacy beliefs. The PSEQ-2 appears to be a robust measure of pain self-efficacy. ⋯ Pain self-efficacy is a belief in one's ability to carry out activities even when in pain and is important in coping effectively with pain. A short measure of pain self-efficacy was developed and evaluated. It appears to be suitable for use in clinical and research settings.
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Review Meta Analysis
Placebo responses in long-standing complex regional pain syndrome: a systematic review and meta-analysis.
The typical placebo response (ie, the nonspecific effects in the placebo group including benign natural course, regression to the mean, expectation/conditioning effects, and others) in randomized trials in complex regional pain syndrome (CRPS) is unknown. We recently observed a surprising near-absence of placebo response in a randomized controlled trial we conducted on patients with long-standing (≥6 months) CRPS. To investigate the idea that there may be an absence of placebo response in long-standing CRPS further, we conducted a systematic review and meta-analysis of placebo responses in randomized controlled trials conducted in patients with CRPS of ≥6 months. We systematically identified suitable randomized controlled trials published between 1966 and September 2013. We calculated the mean difference and standard error of the mean difference for placebo responses and synthesized individual effect sizes at 4 specified time periods of interest (15-30 minutes, 1 week, 3-4 weeks, and 6 weeks or more) via meta-analysis using the method of inverse-variance. Heterogeneity was assessed according to the I(2) statistic. For primary analysis, we pooled trial-specific effect sizes over the 4 time points. We analyzed data from 340 participants from 18 trials out of a possible 361 participants from 20 trials (94% of participants analyzed). Significant heterogeneity was present between trials; therefore, we interpreted trends from visual inspection of individual trials and pooled estimates. Placebo response was significant at the earliest time period (15-30 minutes). There was no significant evidence of placebo response at any of the other time periods. These results inform the design of future trials, and they caution against the "therapeutic" use of placebo in long-standing CRPS. ⋯ In this meta-analysis of placebo responses in randomized controlled trials in long-standing CRPS, published during 1966 to 2013, we found no evidence for placebo analgesia, except at very early time points. Results inform the design of future placebo analgesia research in long-standing CRPS.