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This article presents an overview of fundamental statistical principles of clinical trials of pain treatments. Statistical considerations relevant to phase 2 proof of concept and phase 3 confirmatory randomized trials investigating efficacy and safety are discussed, including (1) research design; (2) endpoints and analyses; (3) sample size determination and statistical power; (4) missing data and trial estimands; (5) data monitoring and interim analyses; and (6) interpretation of results. Although clinical trials of pharmacologic treatments are emphasized, the key issues raised by these trials are also directly applicable to clinical trials of other types of treatments, including biologics, devices, nonpharmacologic therapies (eg, physical therapy and cognitive-behavior therapy), and complementary and integrative health interventions.
Learn More >To evaluate the patterns of treatment among patients with fibromyalgia (FM) in Spain and to assess patient satisfaction and perceived tolerability of the treatment received.
Learn More >Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the μ-opioid receptor and interaction with β-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit β-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that β-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance.
Learn More >The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat breast cancer, is peripheral neuropathy (PIPN). PIPN, which persists into survivorship, has a negative impact on patient's mood, functional status, and quality of life. Currently, no interventions are available to treat PIPN. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie PIPN. While data from preclinical studies suggest that disrupting cytoskeleton- and axon morphology-related processes are a potential mechanism for PIPN, clinical evidence is limited. The purpose of the present study in breast cancer survivors was to evaluate whether differential gene expression and co-expression patterns in these pathways are associated with PIPN. Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology were identified between survivors who received paclitaxel and did (n=25) or did not (n=25) develop PIPN. Pathway impact analysis identified four significantly perturbed cytoskeleton- and axon morphology-related signaling pathways. Weighted gene co-expression network analysis identified three co-expression modules. One module was associated with PIPN group membership. Functional analysis found that this module was associated with four signaling pathways and two ontology annotations related to cytoskeleton and axon morphology. This study, which is the first to apply systems biology approaches using circulating whole blood RNA-seq data in a sample of breast cancer survivors with and without chronic PIPN, provides molecular evidence that cytoskeleton- and axon morphology-related mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy, are found in breast cancer survivors and suggests pathways and a module of genes for validation and as potential therapeutic targets.
Learn More >Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache.
Learn More >Contributors to the ongoing epidemic of prescription opioid abuse, addiction, and death include opioid tolerance, withdrawal symptoms, and possibly opioid-induced hyperalgesia (OIH). Thirty stable chronic non-malignant pain patients entered a six-month long, randomized, double-blind, dose-response, two-center trial of the potent opioid levorphanol, conducted over a decade ago during an era of permissive opioid prescribing. Eleven were taking no opioids at study entry and eleven were taking between 35-122 morphine equivalents (MEQ). Five weeks titration preceded twenty weeks stable dosing. Tolerance and OIH were inferred individually based on chronic pain ratings, Brief Pain Inventory scores, and results of the Brief Thermal Sensitization (BTS) model at five opioid dosing sessions. Seventeen patients completed. The average final daily opioid dose was 132; range 14-300; average addition 105 MEQ. After observed dosing, the BTS area of hyperalgesia changed minimally but the painfulness of skin heating was reduced. Weekly 0-100 VAS pain ratings (average 64 at study entry, 48 at end titration, 45 at end stable dosing) decreased a median 19%, but eight completed with higher VAS ratings. Three completers had evidence of both tolerance and hyperalgesia. A fully-powered trial similar to this feasibility study is ethically questionable. A large-scale pragmatic trial is more realistic. Trial Registration: NCT00275249 Evolution of Analgesic Tolerance With Opioids Perspective: A double-blind, six-month, high-dose opioid feasibility trial, completed years ago, provides critically important data for clinically defining analgesic tolerance and opioid-induced hyperalgesia (OIH). Overall benefit was small, and 18% of patients had evidence of both tolerance and OIH. Future work requires a different approach than a classic RCT design.
Learn More >We aimed to evaluate associations of human leukocyte antigen variants with migraine or headache in hospital and population-based settings.
Learn More >The efficacy and safety of high-dose intravenous immunoglobulin (IVIG) in treatment-resistant diabetic painful polyneuropathy (DPN) were assessed.
Learn More >Both inhibiting ascending nociceptive transmission and activating descending inhibition are involved in the opioid analgesic effect. The spinal dorsal horn is a critical site for modulating nociceptive transmission by descending pathways elicited by opioids in the brain. μ-Opioid receptors (MORs, encoded by Oprm1) are highly expressed in primary sensory neurons and their central terminals in the spinal cord. In the present study, we tested the hypothesis that MORs expressed in primary sensory neurons contribute to the descending inhibition and supraspinal analgesic effect induced by centrally administered opioids. We generated Oprm1 conditional knockout (Oprm1-cKO) mice by crossing Advillin mice with Oprm1 mice. Immunocytochemcal labeling in Oprm1-cKO mice showed that MORs are completely ablated from primary sensory neurons and are profoundly reduced in the superficial spinal dorsal horn. Intracerebroventricular injection of morphine or fentanyl produced a potent analgesic effect in wild-type mice, but such an effect was significantly attenuated in Oprm1-cKO mice. Furthermore, the analgesic effect produced by morphine or fentanyl microinjected into the periaqueductal gray was significantly greater in wild-type mice than in Oprm1-cKO mice. Blocking MORs at the spinal cord level diminished the analgesic effect of morphine and fentanyl microinjected into the periaqueductal gray in both groups of mice. Our findings indicate that MORs expressed at primary afferent terminals in the spinal cord contribute to the supraspinal opioid analgesic effect. These presynaptic MORs in the spinal cord may serve as an interface between ascending inhibition and descending modulation that are involved in opioid analgesia.
Learn More >It is increasingly recognized that chronic opioid use leads to maladaptive changes in the composition and localization of gut bacteria. Recently, this "opioid-induced dysbiosis" (OID) has been linked to antinociceptive tolerance development in preclinical models and may therefore identify promising targets for new opioid-sparing strategies. Such developments are critical to curb dose escalations in the clinical setting and combat the ongoing opioid epidemic. In this article, we review the existing literature that pertains to OID, including the current evidence regarding its qualitative nature, influence on antinociceptive tolerance, and future prospects. Perspective: This article reviews the current literature on opioid-induced dysbiosis (OID) of gut bacteria, including its qualitative nature, influence on antinociceptive tolerance, and future prospects. This work may help identify targets for new opioid-sparing strategies.
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