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RationaleMinocycline, a tetracycline antibiotic, inhibits activation of microglia. In preclinical studies, minocycline prevented development of opioid tolerance and opioid-induced hyperalgesia (OIH). The goal of this study was to determine if minocycline changes pain threshold and tolerance in individuals with opioid use disorder who are maintained on agonist treatment.MethodsIn this double-blind, randomized human laboratory study, 20 participants were randomized to either minocycline (200 mg/day) or placebo treatment for 15 days. The study had three test sessions (days 1, 8, and 15 of treatment) and one follow-up visit 1 week after the end of treatment. In each test session, participants were assessed on several subjective and cognitive measures, followed by assessment of pain sensitivity using the Cold Pressor Test (CPT). Daily surveys and cognitive measures using Ecological Momentary Assessment (EMA) were also collected four times a day on days 8 through 14 of treatment, and proinflammatory serum cytokines were assessed before and on the last day of treatment.ResultsMinocycline treatment did not change pain threshold or tolerance on the CPT. Similarly, minocycline did not change severity of pain, opioid craving, withdrawal, or serum cytokines. Minocycline treatment increased accuracy on a Go/No-Go task.ConclusionsWhile these findings do not support minocycline’s effects on OIH, minocycline may have a potential use as a cognitive enhancer for individuals with opioid use disorder, a finding that warrants further systematic studies.

Depression and anxiety co-occur with chronic pain, and all three are thought to be caused by dysregulation of shared brain systems related to emotional processing associated with body sensations. Understanding the connection between emotional states, pain, and bodily sensations may help understand chronic pain conditions. We developed a mobile platform for measuring pain, emotions, and associated bodily feelings in chronic pain patients in their daily life conditions. Sixty-five chronic back pain patients reported the intensity of their pain, 11 emotional states, and the corresponding body locations. These variables were used to predict pain 2 weeks later. Applying machine learning, we developed two predictive models of future pain, emphasizing interpretability. One model excluded pain-related features as predictors of future pain, and the other included pain-related predictors. The best predictors of future pain were interactive effects of (a) body maps of fatigue with negative affect and (b) positive affect with past pain. Our findings emphasize the contribution of emotions, especially emotional experience felt in the body, to understanding chronic pain above and beyond the mere tracking of pain levels. The results may contribute to the generation of a novel artificial intelligence framework to help in the development of better diagnostic and therapeutic approaches to chronic pain.

Objective. Opioids are frequently prescribed for chronic low back pain (CLBP), but there are broad individual differences in the benefits and risks of opioid therapy, including the development opioid-induced hyperalgesia. This study examined quantitative sensory testing (QST) data among a group of CLBP patients undergoing sustained oral opioid treatment. We investigated whether individual differences in psychological characteristics were related to opioid-induced changes in pain perception and pain modulation. Design. The six-month, open-label trial evaluated patients with low to high levels of negative affect (e.g., symptoms of distress, depression and anxiety); participants underwent QST at baseline (prior to initiating treatment) and during oral opioid treatment. Setting. A chronic pain management center. Patients. The 31 study participants had chronic discogenic back pain, with a pain intensity rating >3/10. Participants were divided into groups with high vs. low levels of Negative Affect (NA). Results. In the previously-published manuscript describing the clinical outcomes of the trial, high NA patients achieved only about half of the analgesic effect observed in the low NA group (Wasan AD, Michna E, Edwards RR, et al. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain. Anesthesiology 2015;123:861–72). The QST findings reported here suggested that tolerance to experimental (cold pressor) pain and conditioned pain modulation tended to decrease in the high NA group over the course of opioid treatment, while temporal summation of mechanical pain declined in the low NA group. Conclusions. These results reveal that while the low NA group seemed to exhibit a generally adaptive, analgesic pattern of changes during opioid management, the high NA group showed a pattern more consistent with opioid-induced hyperalgesic processes. A greater susceptibility to hyperalgesia-promoting changes in pain modulation among patients with high levels of distress may contribute to a lower degree of benefit from opioid treatment in high NA patients.

AbstractObjectiveTo assess whether percutaneous transforaminal endoscopic discectomy (PTED) is non-inferior to conventional open microdiscectomy in reduction of leg pain caused by lumbar disc herniation.DesignMulticentre randomised controlled trial with non-inferiority design.SettingFour hospitals in the Netherlands.Participants613 patients aged 18-70 years with at least six weeks of radiating leg pain caused by lumbar disc herniation. The trial included a predetermined set of 125 patients receiving PTED who were the learning curve cases performed by surgeons who did not do PTED before the trial.InterventionsPTED (n=179) compared with open microdiscectomy (n=309).Main outcome measuresThe primary outcome was self-reported leg pain measured by a 0-100 visual analogue scale at 12 months, assuming a non-inferiority margin of 5.0. Secondary outcomes included complications, reoperations, self-reported functional status as measured with the Oswestry Disability Index, visual analogue scale for back pain, health related quality of life, and self-perceived recovery. Outcomes were measured until one year after surgery and were longitudinally analysed according to the intention-to-treat principle. Patients belonging to the PTED learning curve were omitted from the primary analyses.ResultsAt 12 months, patients who were randomised to PTED had a statistically significantly lower visual analogue scale score for leg pain (median 7.0, interquartile range 1.0-30.0) compared with patients randomised to open microdiscectomy (16.0, 2.0-53.5) (between group difference of 7.1, 95% confidence interval 2.8 to 11.3). Blood loss was less, length of hospital admission was shorter, and timing of postoperative mobilisation was earlier in the PTED group than in the open microdiscectomy group. Secondary patient reported outcomes such as the Oswestry Disability Index, visual analogue scale for back pain, health related quality of life, and self-perceived recovery, were similarly in favour of PTED. Within one year, nine (5%) in the PTED group compared with 14 (6%) in the open microdiscectomy group had repeated surgery. Per protocol analysis and sensitivity analyses including the patients of the learning curve resulted in similar outcomes to the primary analysis.ConclusionsPTED was non-inferior to open microdiscectomy in reduction of leg pain. PTED resulted in more favourable results for self-reported leg pain, back pain, functional status, quality of life, and recovery. These differences, however, were small and may not reach clinical relevance. PTED can be considered as an effective alternative to open microdiscectomy in treating sciatica.Trial registrationNCT02602093ClinicalTrials.gov NCT02602093.

RationaleDozens of preclinical studies have reported cannabinoid agonist potentiation of the analgesic effects of μ-opioid agonists.ObjectivesThe aim of this study was to determine if a cannabinoid agonist could potentiate opioid analgesia in humans using several laboratory pain models.MethodsHealthy participants (n = 10) with/out current drug use/pain conditions completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Nine 8-h sessions were completed during which dronabinol (0, 2.5, 5 mg, p.o.) was administered 1 h before oxycodone (0, 5, 10 mg, p.o.) for a total of 9 test conditions. Outcomes included sensory threshold and tolerance from four experimental pain models (cold pressor, pressure algometer, hot thermode, cold hyperalgesia), along with participant- and observer-rated, performance and physiological effects.ResultsOxycodone produced miosis (p < 0.05) and analgesic responses (e.g., pressure algometer [p < 0.05]), while dronabinol did not (p > 0.05). Depending on the dose combination, dronabinol attenuated or did not alter oxycodone analgesia; for example, dronabinol (2.5 mg) decreased the analgesic effects of oxycodone (10 mg) on pressure tolerance. Conversely, dronabinol increased oxycodone subjective effects (e.g., drug liking) (p < 0.05); oxycodone (5 mg) ratings of “high” were potentiated by 5 mg dronabinol (p < 0.05; placebo = 1.1 [± 0.7]; 5 mg oxycodone = 4.7 [± 2.2]; 5 mg dronabinol = 9.9 [± 8.4]; 5 mg oxycodone + 5 mg dronabinol = 37.4 [± 11.3]).ConclusionsThis study indicates that dronabinol did not enhance the analgesic effects of oxycodone and increased abuse- and impairment-related subjective effects. These data suggest that dronabinol may not be an effective or appropriate opioid adjuvant; it could potentially increase opioid dose requirements, while increasing psychoactive opioid effects.

Objective. To assess benefits of mindfulness meditation and cognitive behavioral therapy (CBT)-based intervention for opioid-treated chronic low back pain (CLBP). Design. 26-week parallel-arm pilot randomized controlled trial (Intervention and Usual Care versus Usual Care alone). Setting. Outpatient. Subjects. Adults with CLBP, prescribed ≥30 mg/day of morphine-equivalent dose (MED) for at least 3 months. Methods. The intervention comprised eight weekly group sessions (meditation and CLBP-specific CBT components) and 30 minutes/day, 6 days/week of at-home practice. Outcome measures were collected at baseline, 8, and 26 weeks: primary-pain severity (Brief Pain Inventory) and function/disability (Oswestry Disability Index); secondary-pain acceptance, opioid dose, pain sensitivity to thermal stimuli, and serum pain-sensitive biomarkers (Interferon-γ; Tumor Necrosis Factor-α; Interleukins 1ß and 6; C-reactive Protein). Results. Thirty-five (21 experimental, 14 control) participants were enrolled and completed the study. They were 51.8 ± 9.7 years old, 80% female, with severe CLBP-related disability (66.7 ± 11.4), moderate pain severity (5.8 ± 1.4), and taking 148.3 ± 129.2 mg/day of MED. Results of the intention-to-treat analysis showed that, compared with controls, the meditation-CBT group reduced pain severity ratings during the study (P = 0.045), with between-group difference in score change reaching 1 point at 26 weeks (95% Confidence Interval: 0.2,1.9; Cohen’s d = 0.86), and decreased pain sensitivity to thermal stimuli (P < 0.05), without adverse events. Exploratory analyses suggested a relationship between the extent of meditation practice and the magnitude of intervention benefits. Conclusions. Meditation-CBT intervention reduced pain severity and sensitivity to experimental thermal pain stimuli in patients with opioid-treated CLBP.

PURPOSE:To compare the sensitivity to change and the responsiveness to intervention of the PROMIS Pain Interference short forms, Brief Pain Inventory (BPI), 3-item PEG scale, and SF-36 Bodily Pain subscale in a sample of patients with persistent musculoskeletal pain of moderate severity. METHODS:Standardized response means, standardized effect sizes, and receiver operating curve analyses were used to assess change between baseline and 3-month assessments in 250 participants who participated in a randomized clinical effectiveness trial of collaborative telecare management for moderate to severe and persistent musculoskeletal pain. RESULTS:The BPI, PEG, and SF-36 Bodily Pain measures were more sensitive to patient-reported global change than the PROMIS Pain Interference short forms, especially for the clinically improved group, for which the change detected by the PROMIS short forms was not statistically significant. The BPI was more responsive to the clinical intervention than the SF-36 Bodily Pain and PROMIS Pain Interference measures. Post hoc analyses exploring these findings did not suggest that differences in content or rating scale structure (number of response options or anchoring language) adequately explained the observed differences in the detection of change. CONCLUSIONS:In this clinical trial, the BPI and PEG measures were better able to detect change than the SF-36 Bodily Pain and PROMIS Pain Interference measures.

RationaleAnimal studies and anecdotal human reports suggest that cannabinoids have antinociceptive effects. Controlled human studies have produced mixed results.ObjectivesWe sought to reduce existing variability by investigating the effects of intravenous delta-9-tetrahydrocannabinol (THC) in several pain paradigms within the same human subjects, addressing some of the limitations to the published literature.MethodsIn this exploratory randomized, double-blind, placebo-controlled, cross-over study, healthy human subjects received 0.01 mg/kg or 0.03 mg/kg intravenous THC or placebo (ethanol vehicle) infused over 10 min on three test days, each separated by at least 72 h. Capsaicin (250 μg) was injected intradermally to induce chemical pain and hyperalgesia. Four other forms of acute pain were induced: mechanical (von Frey filament), hot and cold (thermode), and electrical (pulse generator). Pain ratings were obtained before drug administration, at peak drug effects, and 2 h after drug administration and included both objective and subjective measures. THC drug effects and vital signs were also collected during experimental sessions. Nonparametric analysis with repeated measures was performed.ResultsTHC induced euphoria, perceptual and cognitive alterations, and tachycardia in a dose-related manner, but failed to have significant effects in experimentally induced acute chemical, mechanical, thermal, or electrical pain and capsaicin-induced hyperalgesia.ConclusionsIn this exploratory controlled study, intravenous THC lacked significant antinociceptive properties in experimental models of acute pain and capsaicin-induced hyperalgesia in healthy human subjects. Continued study of THC and other cannabinoids through high-quality, controlled studies in both healthy volunteers and patients with pain conditions is warranted to inform the growing demand for the clinical application of cannabinoids in pain management.

Background and ObjectivesWe examined whether liposome bupivacaine (Exparel) given in the interscalene brachial plexus block lowers pain in the setting of multimodal postoperative pain management for major shoulder surgery.MethodsFifty-two adult patients were randomized to receive either 5 mL of 0.25% bupivacaine HCl immediately followed by 10 mL of liposome bupivacaine 133 mg (n = 26) or 15 mL of 0.25% standard bupivacaine alone (n = 26) in interscalene brachial plexus block. The primary outcome (worst pain in the first postoperative week) was assessed by the Modified Brief Pain Inventory short form. Secondary outcomes were overall satisfaction with analgesia (OBAS), functionality of the surgical arm, sleep duration, time to first opioid (tramadol) request and opioid consumption (mEq), sensory-motor block characteristics, and the occurrence of adverse effects.ResultsWorst pain was lower in patients given liposome bupivacaine added to standard bupivacaine than in patients given standard bupivacaine alone (generalized estimating equation [GEE] estimated marginal mean values, 3.6 ± 0.3 vs 5.3 ± 0.4 points on the Numeric Rating Scale, respectively, although the effect was modest, 1.6 ± 0.5; 95% confidence interval, 0.8–2.5). Total OBAS scores indicated greater satisfaction (GEE estimated marginal mean values, 1.8 ± 0.3 vs 3.3 ± 0.4 on total OBAS, respectively, with modest effect, difference, 1.4 ± 0.5; 95% confidence interval, 0.5–2.4). There were no differences in any of the other secondary outcomes.ConclusionsLiposome bupivacaine added to standard bupivacaine may lower pain and enhance patient's satisfaction in the first postoperative week even in the setting of multimodal analgesia for major shoulder surgery.This study was registered with clinicaltrials.gov (NCT02554357) on July 11, 2015, by Principal Investigator Catherine Vandepitte, MD.