Efficacy and tolerability of brivaracetam monotherapy in childhood and juvenile absence epilepsy: An innovative adaptive trial design.

OBJECTIVE: Despite introduction of several antiseizure medications over the past two decades, treatment options for childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) remain limited. We report the innovative adaptive design of an ongoing phase 2/3 trial to evaluate efficacy, safety, and tolerability of brivaracetam (BRV) monotherapy in patients 2-25 years of age with CAE or JAE. METHODS: N01269 (ClinicalTrials.gov: NCT04666610; start: July 2021; expected completion: 2024) is a randomized, dose-finding and confirmatory, double-blind, placebo-controlled, parallel-group, multicenter trial. The trial consists of a dose-selection and assessment for futility stage, followed by an optimal-dose stage after interim analysis. Both stages include an up to 2-week screening period, a 2-week placebo-controlled period, and an 11-week active treatment period (10 weeks of initial treatment followed by a 24-hour electroencephalogram [EEG] and an additional week of active treatment for 24-hour EEG assessment). Patients who are absence seizure-free will enter an up to 4-week randomized withdrawal period. Efficacy assessments will be based on 24-hour EEG and seizure diaries. SIGNIFICANCE: This two-stage adaptive trial design allows investigation of two potentially efficacious BRV doses, where one dose is dropped in favor of the other dose with a better benefit-risk profile. This allows for a combined phase 2 dose-finding and phase 3 confirmatory efficacy trial, which reduces the number of patients needed to be recruited and reduces trial duration. A randomized withdrawal period is included to evaluate sustainability of treatment effect over time and to allow for placebo control while minimizing placebo exposure. Use of EEG capture in addition to seizure diaries offers a robust mechanism of detecting seizure activity and measuring treatment effect. Positive efficacy and safety/tolerability data may support the use of BRV as monotherapy for CAE or JAE, providing another treatment option and representing long-delayed progress in the treatment of absence seizures in these populations.

Long-term safety, efficacy, and quality of life during adjunctive brivaracetam treatment in patients with uncontrolled epilepsy: An open-label follow-up trial.

OBJECTIVES: The primary objective of this long-term follow-up (LTFU) trial was to evaluate the long-term safety and tolerability of brivaracetam (BRV). The secondary objective was to evaluate the maintenance of efficacy of BRV (including quality of life) over time. METHODS: This open-label, multicenter, flexible-dose trial (N01379 [NCT01339559]) was conducted in adults (≥16 years) with focal or generalized-onset seizures, who had participated in a placebo (PBO)-controlled trial of adjunctive BRV (N01258: NCT01405508 or N01358: NCT01261325). RESULTS: Seven hundred and sixty-six patients received BRV in this LTFU trial (753 had focal seizures and 13 had generalized-onset seizures). Kaplan-Meier-estimated retention was 71.9% at 12 months, and 53.7% at 36 months. Treatment-emergent adverse events (TEAEs) were reported by 643 (83.9%) patients, most commonly headache (104 [13.6%] patients) and dizziness (100 [13.1%] patients). Two hundred and fifty-seven (33.6%) patients had drug-related TEAEs, most commonly somnolence (49 [6.4%] patients) and dizziness (41 [5.4%] patients). Permanent discontinuation of BRV due to TEAEs occurred in 91 (11.9%) patients. Patients with focal seizures had a median percentage reduction in focal seizure frequency of 52.0% and 51.7% were 50% responders (sustained over time); 26.0% were seizurefree for 6 months, and 17.9% were seizurefree for 12 months. 42.4% of patients at 12 months and 46.8% at 24 months had clinically meaningful improvements in Patient Weighted Quality of Life in Epilepsy Questionnaire 31 total score. CONCLUSIONS: In this select group of patients who entered the LTFU trial, BRV was generally safe and well tolerated. Results indicate the long-term efficacy of BRV in patients with focal seizures.

Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease: An open-label, long-term follow-up trial.

This long-term open-label extension (OLE) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses in patients with epilepsy and focal (partial-onset) or generalized onset seizures, or Unverricht-Lundborg disease (ULD). A secondary objective was to evaluate efficacy of BRV in the subgroups of patients with focal or generalized onset seizures. Patients with epilepsy were eligible to enroll in this OLE (N01125; NCT00175916) and were analyzed if they had completed a previous double-blind BRV trial (N01114 [NCT00175929], N01252 [NCT00490035], N01254 [NCT00504881], N01187 [NCT00357669], and N01236 [NCT00368251]), and were expected to obtain a reasonable benefit from long-term BRV treatment. Patients entered the OLE at the BRV dose recommended at the end of the previous trial, with dose adjustments of BRV and concomitant antiseizure medications permitted. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables in patients with focal seizures were percent reduction in focal seizure frequency, 50 % responder rates, and 6- and 12-month seizure-freedom. Eight hundred and fifty-three patients (729 [85.5 %] with focal seizures, 30 [3.5 %] with generalized onset seizures, and 94 [11.0 %] with ULD) were enrolled and included in the Safety Set. Overall, 619 (72.6 %) patients discontinued the trial, mainly due to lack of efficacy (354 [41.5 %]), adverse events (100 [11.7 %]), and patient choice (98 [11.5 %]). During the OLE, 588 (68.9 %) patients received BRV for ≥12 months, 403 (47.2 %) for ≥36 months, and 223 (26.1 %) for ≥96 months. The most common modal dose of BRV was 150 mg/day (415 [48.7 %] patients). In the ULD subgroup, the most common modal BRV dose was 100 mg/day (44/94 [46.8 %] patients), and 37/94 (39.4 %) patients had ≥96 months of BRV exposure. Overall, 720/853 (84.4 %) patients reported TEAEs, 451 (52.9 %) had a drug-related TEAE, and 95 (11.1 %) discontinued BRV due to a TEAE. In the ULD subgroup, 87/94 (92.6 %) patients reported TEAEs, 60 (63.8 %) had a drug-related TEAE, and 16 (17.0 %) discontinued due to a TEAE. In patients with focal seizures, the median reduction in focal seizure frequency from Baseline was 43.1 % (n = 728), the 50 % responder rate was 43.6 % (n = 729), and 6- and 12-month seizure freedom rates were 22.2 % and 15.8 %, respectively (n = 595). Overall, BRV was well-tolerated as long-term adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease, with improvements in focal seizure frequency maintained over time.

Safety and efficacy of midazolam nasal spray for the treatment of intermittent bouts of increased seizure activity in the epilepsy monitoring unit: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Midazolam nasal spray (MDZ-NS) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern, in patients 12 years of age and older with epilepsy. This trial evaluated safety and efficacy of MDZ-NS in patients with epilepsy who were admitted to the epilepsy monitoring unit for seizure characterization/presurgical evaluation. METHODS: In this randomized, double-blind, placebo-controlled phase 3 trial (P261-301; NCT01999777), eligible patients with ≥2 seizures in the 6-hour window preceding trial medication administration for whom treatment was appropriate based on investigator's judgment were randomized (1:1) to MDZ-NS 5 mg or placebo. Efficacy outcomes were proportion of patients seizure-free for 6 hours after treatment and time to first seizure within 6 hours. Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs). RESULTS: Sixty-two patients were randomized (MDZ-NS n = 31; placebo n = 31), received trial medication, and completed the trial. A higher proportion of patients on MDZ-NS than placebo were seizure-free for 6 hours following treatment (54.8% vs 38.7%); however, the 16.1% difference was not statistically significant (P = .1972). The Kaplan-Meier curve of time to first seizure showed separation of both groups in favor of MDZ-NS from ~1.5 hours post-dose and throughout the 6-hour Treatment phase. Median time to first seizure was not estimable for MDZ-NS (>50% of patients had no seizure) and 3.9 hours for placebo (P = .1388). TEAEs with MDZ-NS were generally comparable to those with placebo. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. SIGNIFICANCE: Although the observed treatment difference may be clinically meaningful, statistical significance was not demonstrated. Results suggest that MDZ-NS 5 mg may provide improvement over placebo, with efficacy maintained for ≥6 hours post-dose. MDZ-NS was well tolerated in this population.

The Recurrence of Digital Ulcers in Patients with Systemic Sclerosis after Discontinuation of Oral Treprostinil.

OBJECTIVE: Prior studies investigating the efficacy of oral treprostinil to treat digital ulcers (DU) in systemic sclerosis (SSc)-associated Raynaud phenomenon have yielded conflicting results. In this investigation, we examined whether DU burden increased after patients withdrew from oral treprostinil that was administered during an open-label extension study. METHODS: A multicenter, retrospective study was conducted to determine DU burden in the year after withdrawal from oral treprostinil. DU burden 3-6 months (Time A) and > 6-12 months (Time B) after drug withdrawal was compared with DU burden at baseline, defined as the last day receiving drug in the open-label extension study, by a paired Student t test. Changes in DU burden while receiving drug in the open-label study were compared with changes in DU burden at Time B by a paired Student t test. RESULTS: Fifty-one patients from 9 clinical sites were included for analysis. DU burden increased significantly from baseline (mean 0.47) to Time A (mean 2.1, p = 0.002, n = 23) and Time B (mean 1.45, p = 0.013, n = 30). Total DU burden decreased during oral treprostinil exposure (mean change -0.6) and then increased by Time B (mean change 1.05, p = 0.0027 for comparison, n = 30). In the year after drug withdrawal, many patients required vasodilator therapy and pain medications. Three patients were hospitalized for complications from DU, and 4 patients required surgery for DU. CONCLUSION: Total DU burden increased significantly after discontinuation of oral treprostinil. These data provide supportive evidence of a beneficial effect of oral treprostinil for the vascular complications of SSc and suggest that further study is warranted.

Effect of Age on Phenotype and Outcomes in Pulmonary Arterial Hypertension Trials.

BACKGROUND: In recent years, the population of patients with pulmonary arterial hypertension (PAH) has changed dramatically, including more advanced age at diagnosis. We hypothesized that older patients have a distinct clinical profile with different disease characteristics and response to intervention. METHODS: All previously published treatment studies for PAH conducted by United Therapeutics including seven randomized, placebo-controlled trials and one extension study were included and analyzed to assess the association of age with various demographic, functional, hemodynamic, and outcome variables. RESULTS: A total of 2,627 patients across three age groups were included: ≤ 50 (n = 1,438, 54.7%), 51 to 64 (n = 780, 29.7%), and ≥ 65 years (n = 409, 15.6%). In comparison with the youngest group, the oldest age group had higher proportions of connective tissue disease-associated etiology (range across the studies, 27%-49% vs 13%-21%), higher proportions of New York Heart Association Functional classes III and IV (74%-91% vs 57%-84%), shorter baseline 6-min walk distance (6MWD) (261-316 vs 335-371 m), better hemodynamic measurements including lower baseline mean pulmonary artery pressure (48-51 vs 58-63 mmHg), and smaller changes in 6MWD from baseline to endpoint (-5.6 to 24 vs 14-43 m). Age remained associated with change in 6MWD when adjusting for covariates in multivariate analyses. CONCLUSIONS: For the first time, using data from large randomized controlled trials, this study characterizes the different phenotype and outcomes of older patients with PAH, which includes different disease etiology, diminished functional status, and decreased response to intervention. This may have significant implications for the management of this patient population and design of future therapy trials.

Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide.

BACKGROUND: Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here. METHODS: Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography. RESULTS: Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h). CONCLUSIONS: Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.

Effectiveness and safety of morphine sulfate extended-release capsules in patients with chronic, moderate-to-severe pain in a primary care setting.

BACKGROUND: The purpose of this study was to determine the effectiveness and safety of morphine sulfate extended-release capsules among primary care patients with chronic, moderate-to-severe pain using a universal precautions approach that assessed and monitored risk for opioid misuse and abuse. METHODS: This open-label, uncontrolled, multicenter, prospective study was conducted in primary care centers (n = 281) and included opioid-naïve and opioid-experienced patients with either a pain score ≥4 (0 = no pain, 10 = pain as bad as you can imagine), or with unacceptable side effects while taking opioids. The patients were treated with morphine sulfate extendedrelease capsules for up to four months. Patient-rated pain intensity (worst, least, average) over the past 24 hours (0-10 scale), pain interference with seven activities of daily living (0 = no interference, 10 = completely interferes), and adverse events were recorded. RESULTS: Of 1487 patients who filled at least one prescription, 561 (38%) completed the study. Patients were primarily white (87%) and female (57%); 92% had pain for more than one year; and 79% were opioid-experienced. Median age was 52 years. Decreases in mean (± standard deviation) average pain scores (baseline 6.2 ± 2.3) were -0.8 ± 2.2 at visit 2 (5-14 days later), and -1.6 ± 2.3 and -1.7 ± 2.2 at visits 3 and 4 (spaced 3-4 weeks apart), respectively, and -1.1 ± 2.4 at visit 5 (included patients withdrawn from the study who were no longer taking the study drug). A similar trend was observed for worst pain and least pain scores and for pain interference with activities. Fifty-one percent of the safety population patients and 81% in the completer population reported being satisfied or very satisfied with the study treatment. Most common adverse events were typical of opioids, ie, constipation (14%), nausea (11%), vomiting (5%), and somnolence (5%). CONCLUSION: The results suggest that pain outcomes improved in patients with chronic, moderate-to-severe pain receiving morphine sulfate extended-release capsules within the context of a structured universal precautions approach in the primary care setting.

Opioid titration and conversion in patients receiving morphine sulfate and naltrexone hydrochloride extended release capsules.

OBJECTIVE: To determine the number of steps and identify characteristics associated with attaining a stable dose of morphine sulfate and sequestered naltrexone extended release capsules (MS-sNT). PATIENTS AND METHODS: Data from an open-label, long-term multicenter study designed to assess the safety of MS-sNT for managing chronic (≥ 3 m), moderate-to-severe pain were analyzed post hoc. Initial MS-sNT dose was 20 mg twice daily (BID) for opioid-naïve patients and 50% to 75% of current daily opioid dose for opioid-experienced patients. Dose adjustments upward/downward were allowed throughout the study with ≥ 3 days between increases; opioid-experienced patients could increase ≥ 24 hours after initial drug dispensing. Nonopioid analgesics were permitted as rescue medication. Stable dose was defined post hoc as one maintained for 2 consecutive study visits. RESULTS: Overall, 69% of patients (n = 319/465) achieved a stable dose; 85% (n = 272) achieved a stable dose in ≤ 2 titration dose adjustments or "steps," and 96% (n = 305) achieved a stable dose in ≤ 4 steps. The mean time to stable dose was 28.9 days (standard deviation [SD], 34.1 days); the median was 12 days. A stable dose was achieved in 70% (118/168) of opioid-naïve patients (mean, 24.2 days [SD, 33.4 days]; median, 8 days) and 68% (201/297) of opioid-experienced patients (mean, 31.7 days [SD, 34.3 days]; median, 25 days). A stable dose was achieved by 79% (19/24) of patients who previously used morphine, 64% (27/42) who used oxycodone, 59% (47/79) who used hydrocodone, and 71% (83/117) who used multiple opioids. Baseline pain scores were similar between patients who did and did not achieve a stable dose. At the time of stable dose achievement, average, least, worst, and current pain were all decreased from baseline. CONCLUSIONS: The study provides information about anticipated rates of achieving stable opioid dose in patients who received MS-sNT for up to 1 year to manage chronic, moderate-to-severe pain. Both opioid-naïve and opioid-experienced patients achieved a stable dose of MS-sNT, generally in ≤ 2 steps. Opioid experience and previous opioid use may influence ability to achieve a stable dose and number of steps required. More studies are needed on the anticipated experience of opioid titration/conversion to help physicians and patients set expectations for initiation of and conversion between opioid therapies.

Clinical outcomes during opioid titration following initiation with or conversion to Remoxy®, an extended-release formulation of oxycodone.

Intra- and interpatient variability in opioid response usually necessitates opioid therapy titration to optimally balance analgesia and side effects, whether initiating therapy or converting from another opioid. Remoxy® (King Pharmaceuticals, Inc., Bristol, TN, which was acquired by Pfizer Inc in March 2011) is an extended-release formulation of oxycodone designed to maintain its rate-controlling mechanism following physical and chemical manipulation. A recent phase 3 trial, which required dose titration following initiation or conversion to Remoxy, demonstrated the long-term safety and efficacy of Remoxy in relieving moderate to severe chronic pain. In this study, opioid-naïve patients were to be initiated on Remoxy 5 mg twice daily (10 mg total daily oxycodone dose) and opioid-experienced patients were to be converted to Remoxy at a dose equivalent to their previous opioid daily dose, determined from a conversion chart. A post-hoc analysis of study data provided clinically relevant information regarding initiation of or conversion to Remoxy. The intent-to-treat population (N=823) consisted of 429 opioid-experienced patients (52%) and 394 opioid-naïve patients (48%). A stable Remoxy dose (defined as the first dose administered on 2 consecutive visits, whereby on the first of these visits, further dose titration was deemed unnecessary) was achieved by 325 opioid-experienced patients (76%; mean, 2.2 titration steps), of whom 278 (86%) successfully converted to Remoxy according to the prospectively determined post-hoc definition (≤4 titration steps). Of opioid-naïve patients, 300 (76%) reached a stable dose of Remoxy (mean, 2.2 titration steps), 253 (84%) of whom successfully initiated on Remoxy. Pain intensity decreased from baseline to study completion by approximately 35% for both opioid-experienced and opioid-naïve patients and adverse events were similar to those typically reported for opioids, with a higher incidence rate reported during titration (pre-stable dose period). These data provide important clinical information when initiating opioid-naïve patients on or converting opioid-experienced patients to Remoxy.

The abuse potential of Remoxy(®), an extended-release formulation of oxycodone, compared with immediate- and extended-release oxycodone.

OBJECTIVES: Remoxy(®) is a water-insoluble, highly viscous oral formulation of oxycodone extended release (ER) currently in development. The primary objective was to determine the abuse potential of Remoxy under fed conditions relative to oxycodone ER and immediate release (IR) under fasted conditions and compared with placebo (treatment group X). A secondary objective was to evaluate abuse potential under reversed fed/fasted conditions (treatment group Y). DESIGN: Phase I randomized double-blind triple-dummy placebo- and active-controlled 6-way crossover study. Setting. A single US site. PATIENTS. Healthy men and women aged 18-50 years who were nondependent, recreational opioid users. Interventions. Remoxy 40 mg whole and chewed, oxycodone ER 40 mg whole and crushed, oxycodone IR 40 mg crushed, and placebo. OUTCOME MEASURES: The primary endpoint was the drug liking subscale of the drug effects questionnaire assessed by various pharmacodynamic parameters. Secondary endpoints included additional pharmacodynamic measures, chewing duration, and safety measures. RESULTS: In treatment group X, Remoxy whole (fed) and chewed (fed) had a significantly lower abuse potential compared with oxycodone ER (crushed, fasted) and IR (fasted) based on the majority of pharmacodynamic parameters of interest for the primary endpoint (drug liking subscale) as well as secondary endpoints. Treatment group Y showed generally similar results. CONCLUSIONS: The abuse potential of Remoxy when taken whole or chewed was significantly lower than two comparators with known abuse potential, including oxycodone IR and crushed oxycodone ER, under the fed/fasted conditions tested. Remoxy may be associated with a reduced risk potential for abuse.

Societal costs of prescription opioid abuse, dependence, and misuse in the United States.

OBJECTIVES: The objective of this study was to estimate the societal costs of prescription opioid abuse, dependence, and misuse in the United States. METHODS: Costs were grouped into three categories: health care, workplace, and criminal justice. Costs were estimated by 1) quantity method, which multiplies the number of opioid abuse patients by cost per opioid abuse patient; and 2) apportionment method, which begins with overall costs of drug abuse per component and apportions the share associated with prescription opioid abuse based on relative prevalence of prescription opioid to overall drug abuse. Excess health care costs per patient were based on claims data analysis of privately insured and Medicaid beneficiaries. Other data/information were derived from publicly available survey and other secondary sources. RESULTS: Total US societal costs of prescription opioid abuse were estimated at $55.7 billion in 2007 (USD in 2009). Workplace costs accounted for $25.6 billion (46%), health care costs accounted for $25.0 billion (45%), and criminal justice costs accounted for $5.1 billion (9%). Workplace costs were driven by lost earnings from premature death ($11.2 billion) and reduced compensation/lost employment ($7.9 billion). Health care costs consisted primarily of excess medical and prescription costs ($23.7 billion). Criminal justice costs were largely comprised of correctional facility ($2.3 billion) and police costs ($1.5 billion). CONCLUSIONS: The costs of prescription opioid abuse represent a substantial and growing economic burden for the society. The increasing prevalence of abuse suggests an even greater societal burden in the future.

Assessment, stratification, and monitoring of the risk for prescription opioid misuse and abuse in the primary care setting.

OBJECTIVES: To evaluate potential for and incidence of aberrant drug-related behaviors among patients with chronic, moderate-to-severe pain in a primary care setting and to determine investigator compliance with universal precautions (UP) approach to pain management. DESIGN: Open label, multicenter. SETTING: Primary care centers (N = 281) across the United States. PATIENTS: Opioid naïve and opioid experienced with chronic, moderate-to-severe pain (N = 1,487). INTERVENTIONS: Morphine sulfate extended-release capsules for < or = 4 months. Tools comprising UP approach were treatment agreement, card for obtaining/tracking prescriptions, Screener and Opioid Assessment for Patients with Pain-Revised questionnaire, pill counts, pain-patient follow-up tool, investigator assessment/plan, and urine drug screens (UDSs). OUTCOME MEASURES: Proportion of patients at low, moderate, and high risk of opioid misuse/abuse based on prespecified criteria and investigator judgment, proportion of patients with aberrant drug-related behaviors, and proportion of investigators compliant with UP approach. RESULTS: Patients were primarily white (87 percent), women (57 percent); mean age, 53 years (range, 21-92years). At baseline, 47 percent were considered low risk for opioid misuse/abuse, 52 percent moderate, and 1 percent high. UDSs were positive for illicit/nonprescribed drugs in a proportion of patients throughout the study. Overall, 64 percent of investigators were compliant with major components of UP approach in > or = 75 percent of their patients. However, there was a tendency for investigators to assign risk levels for opioid misuse/abuse as lower than protocol specified. CONCLUSIONS: Most patients in these primary care study centers were categorized as at least moderate risk for opioid misuse/abuse at baseline. Most primary care investigators complied with the UP approach to pain management and risk assessment. The completion of the brief training and clinical use of the tools during the study led to retained behavior change, but there was a tendency for investigators to assign lower risk levels than those that were protocol-specified, suggesting a need for better understanding of factors influencing investigator decisions.