Effect of Mobile Device-Assisted N-of-1 Trial Participation on Analgesic Prescribing for Chronic Pain: Randomized Controlled Trial.

OBJECTIVES: Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for chronic musculoskeletal pain, despite limited evidence of effectiveness and well-documented adverse effects. We assessed the effects of participating in a structured, personalized self-experiment ("N-of-1 trial") on analgesic prescribing in patients with chronic musculoskeletal pain. METHODS: We randomized 215 patients with chronic pain to participate in an N-of-1 trial facilitated by a mobile health app or to receive usual care. Medical records of participating patients were reviewed at enrollment and 6 months later to assess analgesic prescribing. We established thresholds of ≥ 50, ≥ 20, and > 0 morphine milligram equivalents (MMEs) per day to capture patients taking relatively high doses only, patients taking low-moderate as well as relatively high doses, and patients taking any dose of opioids, respectively. RESULTS: There was no significant difference between the N-of-1 and control groups in the percentage of patients prescribed any opioids (relative odds ratio (ROR) = 1.05; 95% confidence interval [CI] = 0.61 to 1.80, p = 0.87). There was a clinically substantial but statistically not significant reduction of the percentage of patients receiving ≥ 20 MME (ROR = 0.58; 95% CI = 0.33 to 1.04, p = 0.07) and also in the percentage receiving ≥ 50 MME (ROR = 0.50; 95% CI = 0.19 to 1.34, p = 0.17). There was a significant reduction in the proportion of patients in the N-of-1 group prescribed NSAIDs compared with control (relative odds ratio = 0.53; 95% CI = 0.29 to 0.96, p = 0.04), with no concomitant increase in average pain intensity. There was no significant change in use of adjunctive medications (acetaminophen, gabapentenoids, or topicals). DISCUSSION: These exploratory results suggest that participation in N-of-1 trials may reduce long-term use of NSAIDs; there is also a weak signal for an effect on use of opioids. Additional research is needed to confirm these results and elucidate possible mechanisms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02116621.

Factors Associated with Opioid Dose Increases: A Chart Review of Patients' First Year on Long-Term Opioids.

Objective: To examine encounter-level factors associated with opioid dose increases during patients' first year on opioid therapy for chronic pain. Design: Case-control study analyzing all opioid prescriptions for patients with chronic pain during their first year after opioid initiation. Cases were patients who experienced an overall dose escalation of ≥ 30 mg morphine equivalents over the 1-year period; controls did not experience overall dose escalation. Main measures were encounter type, opioid dose change, documented prescribing rationale, documentation of guideline-concordant opioid-prescribing practices. Two coders reviewed all encounters associated with opioid prescriptions. Analysis of factors associated with dose increases and provider documentation of prescribing rationale was conducted using multiple logistic regression. Results: There were 674 encounters coded for 66 patients (22 cases, 44 controls). Fifty-three percent of opioid prescriptions were associated with telephone encounters; 13% were associated with e-mail encounters. No prescribing rationale was documented for 43% of all opioid prescriptions and 25% of dose increases. Likelihood of dose increase and documentation of prescribing rationale did not significantly differ for cases versus controls. Compared with face-to-face encounters, dose increases were significantly less likely for telephone (OR 0.18, 95% CI 0.11-0.28) and e-mail (OR 0.23, 95% CI 0.12-0.47) encounters; documentation of prescribing rationale was significantly more likely for e-mail (OR 5.06, 95% CI 1.87-13.72) and less likely for telephone (OR 0.30, 95% CI 0.18-0.51) encounters. Conclusion: Most opioid prescriptions were written without face-to-face encounters. One quarter of dose increases contained no documented prescribing rationale. Documented encounter-level factors were not significantly associated with overall opioid dose escalation.

Dose escalation during the first year of long-term opioid therapy for chronic pain.

OBJECTIVE: To identify patient factors and health care utilization patterns associated with dose escalation during the first year of long-term opioid therapy for chronic pain. DESIGN: Retrospective cohort study using electronic health record data. SETTING: University health system. SUBJECTS: Opioid naïve adults with musculoskeletal pain who received a new outpatient opioid prescription between July 1, 2011 and June 30, 2012 and stayed on opioids for 1 year. METHODS: Mixed-effects regression was used to estimate patients' rate of opioid dose escalation. Demographics, clinical characteristics, and health care utilization for patients with and without dose escalation were compared. RESULTS: Twenty-three (9%) of 246 patients in the final cohort experienced dose escalation (defined as an increase in mean daily opioid dose of ≥30-mg morphine equivalents over 1 year). Compared with patients without dose escalation, patients with escalation had higher rates of substance use diagnoses (17% vs 1%, P = 0.01) and more total outpatient encounters (51 vs 35, P = 0.002) over 1 year. Differences in outpatient encounters were largely due to more non face-to-face encounters (e.g., telephone calls, emails) among patients with dose escalation. Differences in age, race, concurrent benzodiazepine use, and mental health diagnoses between patients with and without dose escalation were not statistically significant. Primary care clinicians prescribed 89% of opioid prescriptions. CONCLUSIONS: Dose escalation during the first year of long-term opioid therapy is associated with higher rates of substance use disorders and more frequent outpatient encounters, especially non face-to-face encounters.

Increasing trends in Schedule II opioid use and doctor shopping during 1999-2007 in California.

PURPOSE: To examine the age and gender-specific trends of Schedule II opioid use among California residents, with special reference to multiple provider users (doctor shoppers). METHODS: Utilizing data from the California Prescription Drug Monitoring Program, we examined age and gender-specific trends of Schedule II opioid use during calendar years 1999-2007. Specifically, we analyzed the following: (1) the prevalence of Schedule II opioid users among California's population and (2) the proportion of these opioid users who were doctor shoppers (defined as an individual who used more than five different prescribers for all Schedule II opioids he or she obtained in a calendar year). RESULTS: Among all age and gender groups, the prevalence of Schedule II opioid users in California increased by 150%-280% and the prevalence of doctor shoppers among users increased by 111%-213% over 9 years. The prevalence of opioid users was lowest among 18-44 year old men (1.25%) and highest among 65-year and older women (5.31%) by 2007. The prevalence of doctor shoppers was approximately 1.4% among those up to age 64 years and 0.5% among those 65 years and older. The gender difference in doctor shoppers among all age groups was negligible. On average, the cumulative morphine-equivalent amount of Schedule II opioid per individual obtained per year was threefold to sixfold higher for doctor shoppers than for the general population across different age and gender groups. CONCLUSIONS: Age and gender differences in opioid use were relatively small, whereas the trends for use of opioids and multiple providers grew at a disquieting rate.

An analysis of the number of multiple prescribers for opioids utilizing data from the California Prescription Monitoring Program.

BACKGROUND: Prescription monitoring programs scrutinize the prescribing of controlled substances to diminish the utilization of multiple prescribers (aka. "doctor shopping"). The use of multiple prescribers is not a problem per se and can be legitimate, as when the patient's regular physician is not available or a concurrent painful condition is being cared for by a different practitioner. PURPOSE: The primary objective of this study was to determine if those patients who used a few prescribers (two to five) in a 1-year period were distinguishable from those who used only one prescriber. METHODS: We performed a secondary data analysis of the California Prescription Monitoring Program, the Controlled Substance Utilization Review and Evaluation System, by using data collected during 1999-2007. RESULTS: The group who used a few providers (two to five) differed substantially from those who visited one provider over a 1-year period. However, the dissimilarity did not suggest that these patients were more prone to the abuse of opioids. CONCLUSIONS: The decision not to investigate patients who visit a low number of multiple prescribers (two to five) appears to be justifiable. If the number of providers in a given period of time is used to determine if a patient should be challenged as being a "doctor shopper," cutoffs with high specificity (low false-positive rates) should be chosen. Further epidemiologic research is needed to determine the association of the number of prescribers and misuse and/or abuse of opioids.

Computerized progress notes for chronic pain patients receiving opioids; the Prescription Opioid Documentation System (PODS).

OBJECTIVE: We herein provide a description of a health information technology tool using computer-assisted survey instruments as a methodology for documentation during long-term opioid therapy. DESIGN: We report our experience using the Prescription Opioid Documentation and Surveillance (PODS) System, a medical informatics tool that utilizes validated questionnaires to automate the assessment of opioid prescribing for chronic nonmalignant pain. SETTING AND PATIENTS: Chronic pain patients answered questions that were presented on a computer terminal prior to each appointment in a Department of Veterans Affairs Pain Clinic. MEASURES: Pain levels, activities of daily living, and screening for common psychological disorders were sought at each visit. Results were tabulated with some information gathered sequentially permitting evaluation of progress. Following a face-to-face interview, the clinician added additional comments to the medical record. RESULTS: By deploying a systematic series of questions that are recalled by the computer, PODS assures a comprehensive assessment. CONCLUSIONS: The PODS fulfills medicolegal requirements for documentation and provides a systematic means of determining outcomes. This process facilitates the determination of the appropriate intervals between clinic visits by stratifying patients into high, moderate, and low risk.

Documenting and improving opioid treatment: the Prescription Opioid Documentation and Surveillance (PODS) System.

OBJECTIVE: To demonstrate that a computer-assisted survey instrument offers an efficient means of patient evaluation when initiating opioid therapy. Design. We report on our experience with the Prescription Opioid Documentation and Surveillance (PODS) System, a medical informatics tool that uses validated questionnaires to collect comprehensive clinical and behavioral information from patients with chronic pain. SETTING AND PATIENTS: Over a 39-month period, 1,400 patients entered data into PODS using a computer touch screen in a Veterans Administration Pain Clinic. MEASURES: Indices of pain intensity, function, mental health status, addiction history, and the potential for prescription opioid abuse were formatted for immediate inclusion into the medical record. RESULTS: The PODS system offers physicians a tool for systematic evaluation prior to prescribing opioids The system generates an opioid agreement between the patient and physician, and provides medicolegal documentation of the patient's condition. CONCLUSIONS: PODS should improve patient care, refine pain control, and reduce the incidence of opioid abuse. Research to determine how PODS affects clinical care is underway. Specially, the effectiveness and efficiency of providing care utilizing PODS will be evaluated in future studies.

A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain.

UNLABELLED: The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use "medical marijuana," and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses. PERSPECTIVE: This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain, and may be an alternative for patients who do not respond to, or cannot tolerate, other drugs. However, the use of marijuana as medicine may be limited by its method of administration (smoking) and modest acute cognitive effects, particularly at higher doses.

Chronic pain management in the emergency department: a survey of attitudes and beliefs.

OBJECTIVE: The emergency department (ED) can be a particularly challenging environment in which to offer care for chronic pain. This study tried to determine if beliefs held by patients and providers about noncancer-related chronic pain affect evaluation and management of pain in ED. INTERVENTION: We surveyed 103 patients presenting to the ED with chronic pain, 34 ED physicians, and 44 ED nurses to assess the influence of 15 possible barriers to managing chronic pain in the ED. RESULTS: Patients were significantly more likely than providers to believe that their pain had to have a diagnosed physical component to be treated. Providers were significantly more likely than patients to believe that patients came to the ED because they lacked a primary care physician. All agreed that chronic pain treatment was not a priority in the ED and the potential for addiction, dependence, diversion, and forged prescriptions was low. CONCLUSIONS: Patients in chronic pain may need to be reassured that their pain will be treated, even in the absence of objective signs or magnified symptoms. Providers may wrongly believe that lack of a primary care physician brings these patients to the ED. Providers and patients appear to believe that treating chronic pain in the ED has a low priority. Both groups may underestimate the problems inherent with prescribing opioids in this setting.

Psychological comorbidities predicting prescription opioid abuse among patients in chronic pain presenting to the emergency department.

OBJECTIVE: We attempted to identify psychological comorbidities that are associated with the propensity for prescription opioid abuse. INTERVENTIONS: Patients presenting to an emergency department seeking opioid refills for chronic pain were evaluated with five validated self-report instruments and structured clinical interviews. The potential for prescription opioid abuse was modeled with multiple regression analysis using depression, anxiety disorders, personality disorder, and addiction as independent variables. RESULTS: Of the 113 patients studied, 91 (81%) showed a propensity for prescription opioid abuse as determined by scores on the Screener and Opioid Assessment for Patients with Pain instrument. Depression, anxiety, and a history of substance were common and panic attacks, posttraumatic stress disorder, and personality disorders were also found, albeit less frequently. Panic attacks, trait anxiety, and the presence of a personality disorder accounted for 38% of the variance in the potential for prescription opioid abuse. CONCLUSIONS: Patients in chronic pain should be assessed for psychological and addiction disorders because they are at increased risk for abusing opioids. They should also be referred for psychosocial treatment as part of their care, where appropriate.

A qualitative study of the barriers to chronic pain management in the ED.

PURPOSE: This qualitative study sought to identify perceived barriers to diagnosing and treating patients with chronic pain in the emergency department (ED). BASIC PROCEDURE: Semistructured interviews were conducted with 24 ED physicians from 4 hospitals to elucidate their experiences of managing chronic pain in the ED. MAIN FINDINGS: Time limitations and a low triage priority were major barriers to caring for patients with chronic pain. But despite the inherent problems of treating a nonurgent condition in a time-limited setting, physicians were strong proponents for treating chronic pain in the ED. PRINCIPAL CONCLUSION: Acknowledging that pain can neither be verified nor disproved, physicians tend to err on the side of the patient, often providing an allotment of opioid medications. They also believe that the ED is not an optimal setting for treating patients in chronic pain but that it is often the last resort for many of these patients, thus, providing the rationale for serving them to the best of their ability.

Effect of Mobile Device-Supported Single-Patient Multi-crossover Trials on Treatment of Chronic Musculoskeletal Pain: A Randomized Clinical Trial.

Importance: Individually designed single-patient multi-crossover (n-of-1) trials can facilitate tailoring of treatments directed at various conditions, including chronic musculoskeletal pain (CMSP) but are potentially burdensome, which may limit uptake in research and practice. Objectives: To determine whether patients randomized to participate in an n-of-1 trial supported by a mobile health (mHealth) app would experience less pain and improved global health, adherence, satisfaction, and shared decision making compared with patients assigned to usual care. Design, Setting, and Participants: This randomized clinical trial compared participation in an individualized, mHealth-supported n-of-1 trial vs usual care. The participating 215 patients had CMSP for at least 6 weeks, had a smartphone or tablet with a data plan, were enrolled in northern California from July 2014 through July 2016, and were followed for up to 1 year by 48 clinicians in academic, community, Veterans Affairs, and military settings. Interventions: Intervention patients met with their clinicians and used a desktop interface to select treatments and trial parameters for an n-of-1 trial comparing 2 pain-management regimens. The mHealth app provided reminders to take designated treatments on assigned days and to upload responses to daily questions on pain and treatment-associated adverse effects. Control patients received care as usual. Main Outcomes and Measures: The primary outcome was change in the PROMIS (Patient-Reported Outcomes Measurement Information System) pain-related interference 8-item short-form scale (full scale range, 41-78) from baseline to 6 months. Secondary outcomes included patient-reported pain intensity, overall health, analgesic adherence, trust in clinician, satisfaction with care, medication-related shared decision making, and, for the n-of-1 group only, participant engagement and experience. Results: Among 215 patients (108 randomized to the n-of-1 intervention and 107 to control), 102 (47%) were women, and the mean (SD) age was 55.5 (11.1) years. At the 6-month follow-up, pain interference was reduced in both groups, though there was no difference between the intervention and control groups (-1.36 points; 95% CI, -2.91 to 0.19 points; P = .09). There were no advantages in secondary outcomes for intervention patients vs control patients except for higher medication-related shared decision making at 6 months (between-group difference, 11.9 points; 95% CI, 2.6-21.2 points; P = .01). Among patients assigned to the n-of-1 group, 88% (n = 86) affirmed that the mHealth app could help people like them manage their pain. Conclusions and Relevance: In this population of patients with CMSP, mHealth-supported n-of-1 trials were feasible and associated with a satisfactory user experience, but n-of-1 trial participation did not significantly improve pain interference at 6 months vs usual care. Trial Registration: ClinicalTrials.gov identifier: NCT02116621.

Maintenance of Blinding in Clinical Trials and the Implications for Studying Analgesia Using Cannabinoids.

The design of analgesic clinical trials invariably involves a comparison between placebo and active study medication. An assumption is made that treatment effects can be approximated by subtracting the response to placebo from that attained with the use of active study medication. However, the psychoactivity of cannabinoids may unmask their presence and lead to an expectation and/or conditioning of pain relief. For example, study participants biased toward the belief that cannabis is beneficial for their condition might be more inclined to report positive effects if they were to accurately identify the active treatment because of its psychoactivity. This may lead to incorrect assumptions regarding the efficacy of a cannabinoid. Methodologies designed to counteract unmasking need to be implemented in the design phase of a study. During the clinical trial, it is also important to query participants as to which treatment they believe they have received. Blinding can be considered to be preserved when the accuracy of treatment guesses is not considerably different than random guessing, which is estimated to be correct 50% of the time. After a study has been completed, the use of statistical methodologies such as regression and mediation analysis are worthy of consideration to see whether psychoactive effects biased the results.

An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease.

UNLABELLED: 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. PERSPECTIVE: 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.

A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis.

A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat.

The Medicinal Cannabis Treatment Agreement: Providing Information to Chronic Pain Patients Through a Written Document.

AIM: Pain practitioners would seem to have an obligation to understand and inform their patients on key issues of the evidence base on cannabinoid therapeutics. One way to fulfill this obligation might be to borrow from concepts developed in the prescription of opioids: the use of a written agreement to describe and minimize risks. Regrettably, the widespread adoption of opioids was undertaken while harmful effects were minimized; obviously, no one wants to repeat this misstep. OBJECTIVE: This article describes a method of educating patients in a manner analogous to other treatment agreements. BACKGROUND: Surveys have demonstrated that pain is the most common indication for medical use of cannabis. As more individuals gain access to this botanical product through state ballot initiatives and legislative mandate, the pain specialist is likely to be confronted by patients either seeking such treatment where permitted, or otherwise inquiring about its potential benefits and harms, and alternative pharmaceuticals containing cannabinoids. METHODS: PubMed searches were conducted using the following keywords: cannabis guidelines, harmful effects of cannabis, medical marijuana, medicinal cannabis, opioid cannabis interaction, cannabis dependence and cannabis abuse RESULTS: : The authors selected individual tenets a medicinal cannabis patient would be asked to review and acknowledge via signature. CONCLUSIONS: Undoubtedly, the knowledge base concerning risks will be an iterative process as we learn more about the long-term use of medicinal cannabis. But we should start the process now so that patients may be instructed about our current conception of what the use of medicinal cannabis entails.

Defining risk of prescription opioid overdose: pharmacy shopping and overlapping prescriptions among long-term opioid users in medicaid.

UNLABELLED: Use of multiple pharmacies concurrently (pharmacy shopping) and overlapping prescriptions may be indicators of potential misuse or abuse of prescription opioid medications. To evaluate strategies for identifying patients at high risk, we first compared different definitions of pharmacy shopping and then added the indicator of overlapping opioid prescriptions. We identified a cohort of 90,010 Medicaid enrollees who used ≥ 3 opioid prescriptions for ≥ 90 days during 2008 to 2010 from a multistate Medicaid claims database. We compared the diagnostic odds ratios for opioid overdose events of 9 pharmacy shopping definitions. Within a 90-day interval, a threshold of 4 pharmacies had the highest diagnostic odds ratio and was used to define pharmacy shopping. The overdose rate was higher in the subgroup with overlapping prescriptions (18.5 per 1,000 person-years [PYs]) than in the subgroup with pharmacy shopping as the sole indicator (10.7 per 1,000 PYs). Among the subgroup with both conditions, the overdose rate was 26.3 per 1,000 PYs, compared with 4.3 per 1,000 PYs for those with neither condition. Overlapping opioid prescriptions and pharmacy shopping measures had adjusted hazard ratios of 3.0 and 1.8, respectively, for opioid overdose. Using these measures will improve accurate identification of patients at highest risk of opioid overdose, the first step in implementing targeted prevention policies. PERSPECTIVE: Long-term prescription opioid use may lead to adverse events, including overdose. Both pharmacy shopping and overlapping opioid prescriptions are associated with adverse outcomes. This study demonstrates that using both indicators will better identify those at high risk of overdose.

Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data.

UNLABELLED: Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%. PERSPECTIVE: This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment.

The PREEMPT study - evaluating smartphone-assisted n-of-1 trials in patients with chronic pain: study protocol for a randomized controlled trial.

BACKGROUND: Chronic pain is prevalent, costly, and clinically vexatious. Clinicians typically use a trial-and-error approach to treatment selection. Repeated crossover trials in a single patient (n-of-1 trials) may provide greater therapeutic precision. N-of-1 trials are the most direct way to estimate individual treatment effects and are useful in comparing the effectiveness and toxicity of different analgesic regimens. The goal of the PREEMPT study is to test the 'Trialist' mobile health smartphone app, which has been developed to make n-of-1 trials easier to accomplish, and to provide patients and clinicians with tools for individualizing treatments for chronic pain. METHODS/DESIGN: A randomized controlled trial is being conducted to test the feasibility and effectiveness of the Trialist app. A total of 244 participants will be randomized to either the Trialist app intervention group (122 patients) or a usual care control group (122 patients). Patients assigned to the Trialist app will work with their clinicians to set up an n-of-1 trial comparing two pain regimens, selected from a menu of flexible options. The Trialist app provides treatment reminders and collects data entered daily by the patient on pain levels and treatment side effects. Upon completion of the n-of-1 trial, patients review results with their clinicians and develop a long-term treatment plan. The primary study outcome (comparing Trialist to usual care patients) is pain-related interference with daily functioning at 26 weeks. DISCUSSION: Trialist will allow patients and clinicians to conduct personalized n-of-1 trials. In prior studies, n-of-1 trials have been shown to encourage greater patient involvement with care, which has in turn been associated with better health outcomes. mHealth technology implemented using smartphones may offer an efficient means of facilitating n-of-1 trials so that more patients can benefit from this approach. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02116621 , first registered 15 April 2014.