Effect of Pharmacist Email Alerts on Concurrent Prescribing of Opioids and Benzodiazepines by Prescribers and Primary Care Managers: A Randomized Clinical Trial.

Importance: Policy makers have sought to discourage concurrent prescribing of opioids and benzodiazepines (coprescribing) because it is associated with overdose. Email alerts sent by pharmacists may reduce coprescribing, but this intervention lacks randomized evidence. Objective: To investigate whether pharmacist emails to practitioners caring for patients who recently received opioids and benzodiazepines reduce coprescribing of these medications. Design, Setting, and Participants: Randomized clinical trial (intention to treat) conducted in 2019-2021 of patients and their practitioners (prescribers and primary care managers) in the National Capital Region of the Military Health System. Participants were 2237 patients who were recently coprescribed opioids and benzodiazepines. These patients had 789 practitioners eligible for emails. Interventions: Patients were randomized to email alerts to their practitioners or as-usual care. Clinical pharmacists sent the email alert. Messages were standardized and designed to facilitate coordination between practitioners, increase awareness of guidelines, and provide action steps and resources. Main Outcomes and Measures: The primary outcomes were patients' days received of opioids, benzodiazepines, and concurrent opioids and benzodiazepines during the 90 days following enrollment evaluated using 1-sided hypothesis tests. Secondary outcomes included total prescribing of opioids and benzodiazepines by patients' practitioners, including to patients outside the study, to test for broader outcomes on their prescribing. Results: Of 2237 patients, 1187 were assigned to treatment and 1050 to control; 1275 (57%) were women. Patients received a mean (SD) of 31 (44) days of opioids and 33 (34) days of benzodiazepines in the 90 days before enrollment. There were no detected differences in the primary end points, including patients' receipt of opioids (adjusted difference, 1.1 days; 95% CI, -∞ to 3.0; P = .81), benzodiazepines (adjusted difference, -0.6 days; 95% CI, -∞ to 1.4; P = .30), and opioids and benzodiazepines together (adjusted difference, -0.1 days; 95% CI, -∞ to 0.7; P = .41). Of 789 practitioners, 429 were considered the treatment group, 325 were considered controls, and 35 were excluded. There were no detected differences in practitioners' total prescribing of opioids, benzodiazepines, or both drug classes together. Conclusions and Relevance: In this randomized clinical trial of pharmacist emails to practitioners, email alerts failed to detectably reduce coprescribing, highlighting the value of alternative approaches. Combining randomization with quality improvement activities may help stakeholders seeking evidence-based interventions to encourage guideline-concordant care. Trial Registration: ClinicalTrials.gov Identifier: NCT03887247.

Compounded Topical Pain Creams to Treat Localized Chronic Pain: A Randomized Controlled Trial.

Background: The use of compounded topical pain creams has increased dramatically, yet their effectiveness has not been well evaluated. Objective: To determine the efficacy of compounded creams for chronic pain. Design: Randomized controlled trials of 3 interventions. (ClinicalTrials.gov: NCT02497066). Setting: Military treatment facility. Participants: 399 patients with localized pain classified by each patient's treating physician as neuropathic (n = 133), nociceptive (n = 133), or mixed (n = 133). Intervention: Pain creams compounded for neuropathic pain (ketamine, gabapentin, clonidine, and lidocaine), nociceptive pain (ketoprofen, baclofen, cyclobenzaprine, and lidocaine), or mixed pain (ketamine, gabapentin, diclofenac, baclofen, cyclobenzaprine, and lidocaine), or placebo. Measurements: The primary outcome measure was average pain score 1 month after treatment. A positive categorical response was a reduction in pain score of 2 or more points coupled with a score above 3 on a 5-point satisfaction scale. Secondary outcomes included Short Form-36 Health Survey scores, satisfaction, and categorical response. Participants with a positive outcome were followed through 3 months. Results: For the primary outcome, no differences were found in the mean reduction in average pain scores between the treatment and control groups for patients with neuropathic pain (-0.1 points [95% CI, -0.8 to 0.5 points]), nociceptive pain (-0.3 points [CI, -0.9 to 0.2 points]), or mixed pain (-0.3 points [CI, -0.9 to 0.2 points]), or for all patients (-0.3 points [CI, -0.6 to 0.1 points]). At 1 month, 72 participants (36%) in the treatment groups and 54 (28%) in the control group had a positive outcome (risk difference, 8% [CI, -1% to 17%]). Limitations: Generalizability is limited by heterogeneity among pain conditions and formulations of the study interventions. Randomized follow-up was only 1 month. Conclusion: Compounded pain creams were not better than placebo creams, and their higher costs compared with approved compounds should curtail routine use. Primary Funding Source: Centers for Rehabilitation Sciences Research, Defense Health Agency, U.S. Department of Defense.

Evaluation of the Reinforcing Effect of Quetiapine, Alone and in Combination with Cocaine, in Rhesus Monkeys.

There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003-0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self-administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003-0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored.

Effects of quetiapine treatment on cocaine self-administration and behavioral indices of sleep in adult rhesus monkeys.

RATIONALE: Clinical literature suggests a link between substance abuse and sleep disturbances. Quetiapine, an atypical antipsychotic, has shown efficacy in treating sleep disturbances, with clinical studies showing promise for quetiapine as a treatment for cocaine abuse. OBJECTIVE: The goal of this study was to examine the effects of quetiapine on cocaine self-administration and behavioral indices of sleep in monkeys. METHODS: Seven adult male rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a choice paradigm of food (1.0-g pellets) and cocaine (0.003-0.3 mg/kg per injection) presentation. First, monkeys received acute pretreatment (45 min) with quetiapine (25-75 mg, p.o.) prior to choice sessions; three cocaine doses were studied in combination with quetiapine. Next, the effect of chronic (14-16 days) quetiapine treatment (25-250 mg, p.o., BID) was examined in combination with the lowest preferred cocaine dose (≥80 % cocaine choice). Behavioral indices of sleep, based on activity measures obtained during lights-out, were recorded throughout the study. RESULTS: Acute quetiapine decreased cocaine choice in four of the seven monkeys. Chronic quetiapine treatment resulted in initial decreases in cocaine choice, but tolerance developed to these effects. Acute doses of quetiapine did not improve sleep efficiency the following night nor did chronic quetiapine. The first night after discontinuing quetiapine treatment resulted in significant decreases in sleep efficiency and increases in nighttime activity. CONCLUSIONS: These findings do not offer support for the use of quetiapine as a monotherapy for treatment of cocaine abuse nor as an adjunct therapy to treat sleep disturbances associated with stimulant abuse.

The relationship between cocaine self-administration and actigraphy-based measures of sleep in adult rhesus monkeys.

RATIONALE: Clinical trials show that chronic cocaine users suffer from sleep disturbances and preclinical research has shown that acute sleep deprivation increases the rate of cocaine self-administration in rats. OBJECTIVE: This study examined the effect of cocaine self-administration on behavioral indices of sleep and alternatively the effect of sleep disruption on cocaine-maintained responding by rhesus monkeys. METHODS: Seven adult rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a concurrent choice paradigm with food (three 1.0-g pellets) and cocaine (0.003-0.3 mg/kg) or saline presentation. For each monkey, the lowest preferred dose of cocaine (>80% cocaine choice) was determined. Activity data were analyzed during lights out (2000-0600) to determine sleep efficiency, sleep latency, and total activity counts. Subsequently, the monkeys' sleep was disrupted (every hour during lights-out period) the night prior to food-cocaine choice sessions. RESULTS: Self-administration of the preferred dose of cocaine resulted in a significant decrease in sleep efficiency, with a significant increase in total lights-out activity. Sleep disruption significantly altered behavioral indices of sleep, similar to those seen following cocaine self-administration. However, sleep disruption did not affect cocaine self-administration under concurrent choice conditions. CONCLUSIONS: Based on these findings, cocaine self-administration does appear to disrupt behavioral indices of sleep, although it remains to be determined if treatments that improve sleep measures can affect future cocaine taking.

Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced rhabdomyolysis with alpha1- plus beta3-adrenoreceptor antagonists.

1. Studies were designed to examine the effects of alpha(1) (alpha(1)AR)- plus beta(3)-adrenoreceptor (beta(3)AR) antagonists on 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced hyperthermia and measures of rhabdomyolysis (creatine kinase (CK)) and renal function (blood urea nitrogen (BUN) and serum creatinine (sCr)) in male Sprague-Dawley rats. 2. MDMA (40 mg x kg(-1), s.c.) induced a rapid and robust increase in rectal temperature, which was significantly attenuated by pretreatment with the alpha(1)AR antagonist prazosin (100 microg x kg(-1), i.p.) plus the beta(3)AR antagonist SR59230A (5 mg x kg(-1), i.p.). 3. CK levels significantly increased (peaking at 4 h) after MDMA treatment and were blocked by the combination of prazosin plus SR59230A. 4. At 4 h after MDMA treatment, BUN and sCr levels were also significantly increased and could be prevented by this combination of alpha(1)AR- plus beta(3)AR-antagonists. 5. The results from this study suggest that alpha(1)AR and beta(3)AR play a critical role in the etiology of MDMA-mediated hyperthermia and subsequent rhabdomyolysis.