The journal of pain : official journal of the American Pain Society
-
Macrophages play a role in innate immunity within the body, are located in muscle tissue, and can release inflammatory cytokines that sensitize local nociceptors. In this study we investigate the role of resident macrophages in the noninflammatory muscle pain model induced by 2 pH 4.0 preservative-free sterile saline (pH 4.0) injections 5 days apart in the gastrocnemius muscle. We showed that injecting 2 pH 4.0 injections into the gastrocnemius muscle increased the number of local muscle macrophages, and depleting muscle macrophages with clodronate liposomes before acid injections attenuated the hyperalgesia produced by this model. To further examine the contribution of local macrophages to this hyperalgesia, we injected mice intramuscularly with C34, a toll-like receptor 4 (TLR4) antagonist. When given before the first pH 4.0 injection, C34 attenuated the muscle and tactile hyperalgesia produced by the model. However, when given before the second injection C34 had no effect on the development of hyperalgesia. Then to test whether activation of local macrophages sensitizes nociceptors to normally non-nociceptive stimuli we replaced either the first or second acid injection with the immune cell activator lipopolysaccharide, or the inflammatory cytokine interleukin (IL)-6. Injecting LPS or IL-6 instead of the either the first or second pH 4.0 injection resulted in a dose-dependent increase in paw withdrawal responses and decrease in muscle withdrawal thresholds. The highest doses of LPS and IL-6 resulted in development of hyperalgesia bilaterally. The present study showed that resident macrophages in muscle are key to development of chronic muscle pain. ⋯ This article presents evidence for the role of macrophages in the development of chronic muscle pain using a mouse model. These data suggest that macrophages could be a potential therapeutic target to prevent transition of acute to chronic muscle pain particularly in tissue acidosis conditions.
-
Accurate classification of chronic pain conditions requires reliable and valid pain assessment. Moreover, pain assessment serves several additional functions, including documenting the severity of the pain condition, tracking the longitudinal course of pain, and providing mechanistic information. Thorough pain assessment must address multiple domains of pain, including the sensory and affective qualities of pain, temporal dimensions of pain, and the location and bodily distribution of pain. Where possible, pain assessment should also incorporate methods to identify pathophysiological mechanisms underlying the pain. This article discusses assessment of chronic pain, including approaches available for assessing multiple pain domains and for addressing pathophysiological mechanisms. We conclude with recommendations for optimal pain assessment. ⋯ Pain assessment is a critical prerequisite for accurate pain classification. This article describes important features of pain that should be assessed, and discusses methods that can be used to assess the features and identify pathophysiological mechanisms contributing to pain.
-
Randomized Controlled Trial
An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain from Spinal Cord Injury and Disease.
Using 8-hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, most of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta 9-THC on 3 separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was used to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model showed a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (eg, good drug effect, feeling high, etc) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all P < .0004). Psychoactive and subjective effects were dose-dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. Because the 2 active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. ⋯ A crossover, randomized, placebo-controlled human laboratory experiment involving administration of vaporized cannabis was performed in patients with neuropathic pain related to spinal cord injury and disease. This study supports consideration of future research that would include longer duration studies over weeks to months to evaluate the efficacy of medicinal cannabis in patients with central neuropathic pain.
-
The past few decades have witnessed a huge leap forward in our understanding of the mechanistic underpinnings of pain, in normal states where it helps protect from injury, and also in pathological states where pain evolves from a symptom reflecting tissue injury to become the disease itself. However, despite these scientific advances, chronic pain remains extremely challenging to manage clinically. Although the number of potential treatment targets has grown substantially and a strong case has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively treat their patients. The gulf between pain research and pain management is as wide as ever. We are still currently unable to apply an evidence-based approach to chronic pain management that reflects mechanistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual response to treatment cannot be predicted. In this article we take a common and difficult to treat pain condition, chronic low back pain, and use its presentation in clinical practice as a framework to highlight what is known about pathophysiological pain mechanisms and how we could potentially detect these to drive rational treatment choice. We discuss how present methods of assessment and management still fall well short, however, of any mechanism-based or precision medicine approach. Nevertheless, substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach were to evolve, one designed to identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such an approach, highlighting the major problems in identifying mechanisms in patients, and develop a framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive identification of 3 steps: pain state, pain mechanism, and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as 1 of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is consistent with and an extension of the AAPT. ⋯ We discuss how identifying the specific mechanisms that operate in the nervous system to produce chronic pain in individual patients could provide the basis for a targeted and rational precision medicine approach to controlling pain, using chronic low back pain as our example.
-
Cognitive appraisals inform and shape individuals' pain experiences. As researchers examine mechanisms of cognitive-behavioral interventions for chronic pain, psychometrically sound measures based in cognitive theory are needed to directly assess pain beliefs. The Pain Beliefs Questionnaire (PBQ), a 32-item self-report measure informed by coping and appraisal theory, was designed to assess children's pain threat appraisals, problem-focused pain coping efficacy, and emotion-focused pain coping efficacy. The present study aimed to: 1) create a short form of the PBQ, and 2) evaluate the psychometric properties of the reduced measure in a large database of pediatric patients with functional abdominal pain (n = 871). Item reduction analyses identified an 18-item short form of the PBQ (PBQ-SF) that exhibited psychometric properties similar to the original measure. All 3 subscales of the PBQ-SF exhibited strong internal consistency (α levels ranged from .79 to .80) and adequate test-retest reliability at 2 weeks. Evidence for construct validity was provided by examining patterns of partial correlations for each subscale. The PBQ-SF represents a valid and reliable measure for evaluating children's pain beliefs. Future studies should investigate the treatment sensitivity of the PBQ-SF to evaluate its appropriateness for use in clinical trials. ⋯ This article presents the psychometric properties of a reduced 18-item version of a measure used to assess children's pain beliefs in a large sample of children with functional abdominal pain. This measure could help identify processes and individual differences underlying children's responses to psychological treatments for chronic pain.