Opioid use in cancer patients compared with noncancer pain patients in a veteran population.

BACKGROUND: Opioid safety initiatives may secondarily impact opioid prescribing and pain outcomes for cancer care. METHODS: We reviewed electronic health record data at a tertiary Veterans Affairs system (VA Palo Alto) for all patients from 2015 to 2021. We collected outpatient Schedule II opioid prescriptions data and calculated morphine milligram equivalents (MMEs) using Centers for Disease Control and Prevention conversion formulas. To determine the clinical impact of changes in opioid prescription, we used the highest level of pain reported by each patient on the 0-to-10 Numeric Rating Scale in each year, categorized into mild (0-3), moderate (4-6), and severe (7 and above). RESULTS: Among 89 569 patients, 9073 had a cancer diagnosis. Cancer patients were almost twice as likely to have an opioid prescription compared with noncancer patients (69.0% vs 36.7%, respectively). The proportion of patients who received an opioid prescription decreased from 27.1% to 18.1% (trend P < .01) in cancer patients and from 17.0% to 10.2% in noncancer patients (trend P < .01). Cancer and noncancer patients had similar declines of MMEs per year between 2015 and 2019, but the decline was more rapid for cancer patients (1462.5 to 946.4, 35.3%) compared with noncancer patients (1315.6 to 927.7, 29.5%) from 2019 to 2021. During the study period, the proportion of noncancer patients who experienced severe pain was almost unchanged, whereas it increased among cancer patients, reaching a significantly higher rate than among noncancer patients in 2021 (31.9% vs 27.4%, P < .01). CONCLUSIONS: Our findings suggest potential unintended consequences for cancer care because of efforts to manage opioid-related risks.

Smallest Clinically Meaningful Improvement in Amputation-Related Pain and Brief Pain Inventory Scores as Defined by Patient Reports of Global Improvement After Cryoneurolysis: a Retrospective Analysis of a Randomized, Controlled Clinical Trial.

BACKGROUND: The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis. METHODS: In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC. RESULTS: The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667. CONCLUSIONS: Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

National review of acute pain service utilization, models of care, and clinical practices within the Veterans Health Administration.

INTRODUCTION: The Veterans Health Administration (VHA) is the largest healthcare network in the USA and has been a national leader in opioid safety for acute pain management. However, detailed information on the availability and characteristics of acute pain services within its facilities is lacking. We designed this project to assess the current state of acute pain services within the VHA. METHODS: A 50-question electronic survey developed by the VHA national acute pain medicine committee was emailed to anesthesiology service chiefs at 140 VHA surgical facilities within the USA. Data collected were analyzed by facility complexity level and service characteristics. RESULTS: Of the 140 VHA surgical facilities contacted, 84 (60%) completed the survey. Thirty-nine (46%) responding facilities had an acute pain service. The presence of an acute pain service was associated with higher facility complexity level designation. The most common staffing model was 2.0 full-time equivalents, which typically included at least one physician. Services performed most by formal acute pain programs included peripheral nerve catheters, inpatient consult services, and ward ketamine infusions. CONCLUSIONS: Despite widespread efforts to promote opioid safety and improve pain management, the availability of dedicated acute pain services within the VHA is not universal. Higher complexity programs are more likely to have acute pain services, which may reflect differential resource distribution, but the barriers to implementation have not yet been fully explored.

Association of Patient Race and Hospital with Utilization of Regional Anesthesia for Treatment of Postoperative Pain in Total Knee Arthroplasty: A Retrospective Analysis Using Medicare Claims.

BACKGROUND: Regional anesthesia for total knee arthroplasty has been deemed high priority by national and international societies, and its use can serve as a measure of healthcare equity. The association between utilization of regional anesthesia for postoperative pain and (1) race and (2) hospital in patients undergoing total knee arthroplasty was estimated. The hypothesis was that Black patients would be less likely than White patients to receive regional anesthesia, and that variability in regional anesthesia would more likely be attributable to the hospital where surgery occurred than race. METHODS: This study used Medicare fee-for-service claims for patients aged 65 yr or older who underwent primary total knee arthroplasty between January 1, 2011, and December 31, 2016. The primary outcome was administration of regional anesthesia for postoperative pain, defined as any peripheral (femoral, lumbar plexus, or other) or neuraxial (spinal or epidural) block. The primary exposure was self-reported race (Black, White, or Other). Clinical significance was defined as a relative difference of 10% in regional anesthesia administration. RESULTS: Data from 733,406 cases across 2,507 hospitals were analyzed: 90.7% of patients were identified as White, 4.7% as Black, and 4.6% as Other. Median hospital-level prevalence of use of regional anesthesia was 51% (interquartile range, 18 to 79%). Black patients did not have a statistically different probability of receiving a regional anesthetic compared to White patients (adjusted estimates: Black, 53.3% [95% CI, 52.5 to 54.1%]; White, 52.7% [95% CI, 52.4 to 54.1%]; P = 0.132). Findings were robust to alternate specifications of the exposure and outcome. Analysis of variance revealed that 42.0% of the variation in block administration was attributable to hospital, compared to less than 0.01% to race, after adjusting for other patient-level confounders. CONCLUSIONS: Race was not associated with administration of regional anesthesia in Medicare patients undergoing primary total knee arthroplasty. Variation in the use of regional anesthesia was primarily associated with the hospital where surgery occurred.

Standardizing nomenclature in regional anesthesia: an ASRA-ESRA Delphi consensus study of upper and lower limb nerve blocks.

BACKGROUND: Inconsistent nomenclature and anatomical descriptions of regional anesthetic techniques hinder scientific communication and engender confusion; this in turn has implications for research, education and clinical implementation of regional anesthesia. Having produced standardized nomenclature for abdominal wall, paraspinal and chest wall regional anesthetic techniques, we aimed to similarly do so for upper and lower limb peripheral nerve blocks. METHODS: We performed a three-round Delphi international consensus study to generate standardized names and anatomical descriptions of upper and lower limb regional anesthetic techniques. A long list of names and anatomical description of blocks of upper and lower extremities was produced by the members of the steering committee. Subsequently, two rounds of anonymized voting and commenting were followed by a third virtual round table to secure consensus for items that remained outstanding after the first and second rounds. As with previous methodology, strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. RESULTS: A total of 94, 91 and 65 collaborators participated in the first, second and third rounds, respectively. We achieved strong consensus for 38 names and 33 anatomical descriptions, and weak consensus for five anatomical descriptions. We agreed on a template for naming peripheral nerve blocks based on the name of the nerve and the anatomical location of the blockade and identified several areas for future research. CONCLUSIONS: We achieved consensus on nomenclature and anatomical descriptions of regional anesthetic techniques for upper and lower limb nerve blocks, and recommend using this framework in clinical and academic practice. This should improve research, teaching and learning of regional anesthesia to eventually improve patient care.

Barriers to Implementation of Telehealth Pre-anesthesia Evaluation Visits in the Department of Veterans Affairs.

Background: Evaluations are conducted days or weeks before a scheduled surgical or invasive procedure involving anesthesia to assess patients' preprocedure condition and risk, optimize status, and prepare them for their procedure. The traditional pre-anesthesia evaluation is conducted in person, although telehealth modalities have been used for several years and have accelerated since the advent of the COVID-19 pandemic. Methods: We surveyed 109 anesthesiology services to understand the barriers and facilitators to the adoption of telephone- and video-based pre-anesthesia evaluation visits within the US Department of Veterans Affairs (VA). Results: The analysis included 55 responses from 50 facilities. Twenty-two facilities reported using both telephone and video, 11 telephone only, 5 video only, and 12 none of these modalities. For telehealth users, the ability to obtain a history of present illness, the ability to assess for comorbidities, and assess for health habits were rated highest while assessing nutritional status was lowest. Among nonusers of telehealth modalities, barriers to adoption included the inability to perform a physical examination and the inability to obtain vital signs. Respondents not using telephone cited concerns about safety, while respondents not using video also cited lack of information technology and staff support and patient-level barriers. Conclusions: We found no significant perceived advantages of video over telephone in the ability to conduct routine pre-anesthesia evaluations except for the perceived ability to assess nutritional status. Clinicians with no telehealth experience cited the inability to perform a physical examination and obtain vital signs as the most significant barriers to implementation. Future work should focus on delineating the most appropriate and valuable uses of telehealth for pre-anesthesia evaluation and/or optimization.

More Than a Perioperative Surgical Home: An Opportunity for Anesthesiologists to Advance Public Health.

Public health and the medical specialty of anesthesiology have been closely intertwined throughout history, dating back to the 1800s when Dr. John Snow used contact tracing methods to identify the Broad Street Pump as the source of a cholera outbreak in London. During the COVID-19 pandemic, leaders in anesthesiology and anesthesia patient safety came forward to develop swift recommendations in the face of rapidly changing evidence to help protect patients and healthcare workers. While these high-profile examples may seem like uncommon events, there are many common modern-day public health issues that regularly intersect with anesthesiology and surgery. These include, but are not limited to, smoking; chronic opioid use and opioid use disorder; and obstructive sleep apnea. As an evolving medical specialty that encompasses pre- and postoperative care and acute and chronic pain management, anesthesiologists are uniquely positioned to improve patient care and outcomes and promote long-lasting behavioral changes to improve overall health. In this article, we make the case for advancing the role of the anesthesiologist beyond the original perioperative surgical home model into promoting public health initiatives within the perioperative period.

How large language models can augment perioperative medicine: a daring discourse.

Interest in natural language processing, specifically large language models, for clinical applications has exploded in a matter of several months since the introduction of ChatGPT. Large language models are powerful and impressive. It is important that we understand the strengths and limitations of this rapidly evolving technology so that we can brainstorm its future potential in perioperative medicine. In this daring discourse, we discuss the issues with these large language models and how we should proactively think about how to leverage these models into practice to improve patient care, rather than worry that it may take over clinical decision-making. We review three potential major areas in which it may be used to benefit perioperative medicine: (1) clinical decision support and surveillance tools, (2) improved aggregation and analysis of research data related to large retrospective studies and application in predictive modeling, and (3) optimized documentation for quality measurement, monitoring and billing compliance. These large language models are here to stay and, as perioperative providers, we can either adapt to this technology or be curtailed by those who learn to use it well.

Addition of dexamethasone to prolong peripheral nerve blocks: a ChatGPT-created narrative review.

Chat Generative Pre-trained Transformer (ChatGPT), an artificial intelligence chatbot, produces detailed responses and human-like coherent answers, and has been used in the clinical and academic medicine. To evaluate its accuracy in regional anesthesia topics, we produced a ChatGPT review on the addition of dexamethasone to prolong peripheral nerve blocks. A group of experts in regional anesthesia and pain medicine were invited to help shape the topic to be studied, refine the questions entered in to the ChatGPT program, vet the manuscript for accuracy, and create a commentary on the article. Although ChatGPT produced an adequate summary of the topic for a general medical or lay audience, the review that were created appeared to be inadequate for a subspecialty audience as the expert authors. Major concerns raised by the authors included the poor search methodology, poor organization/lack of flow, inaccuracies/omissions of text or references, and lack of novelty. At this time, we do not believe ChatGPT is able to replace human experts and is extremely limited in providing original, creative solutions/ideas and interpreting data for a subspecialty medical review article.

An exploratory analysis of pediatric anesthesia activity on Twitter using the #pedsanes hashtag.

BACKGROUND: The use of social media within the medical field has rapidly evolved over the past two decades, with Twitter being one of the most common platforms of engagement. The use of hashtags such as #pedsanes has been reported as a community builder around the subject of pediatric anesthesia. Understanding the use of #pedsanes can inform dissemination of pediatric anesthesia content and discourse. We aimed to describe the distribution and patterns of tweets and contributors using #pedsanes across the globe. METHODS: Using Tweetbinder (https://www.tweetbinder.com) and the R package "academictwitteR," we extracted tweets that included the hashtag "#pedsanes" from March 14, 2016 to March 10, 2022. Tweets were analyzed for frequency, type, unique users, impact and reach, language, content, and the most common themes. RESULTS: A total of 58 724 tweets were retrieved; 22 071 (38.8%) were original tweets including 3247 replies, while 35 971 (61.2%) were retweets all generated by over 5946 contributors located in at least 122 countries. The frequency distribution of tweets gradually increased over time with peaks in activity corresponding to major pediatric anesthesia societal meetings and during the early phases of the COVID-19 pandemic. The most retweeted and most liked posts included images. DISCUSSION: We report the widespread and increasing use of social media and the "#pedsanes" hashtag within the pediatric anesthesia and medical community over time. It remains unknown the extent to which Twitter hashtag activity translates to changes in clinical practice. However, the #pedsanes hashtag appears to play a key role in disseminating pediatric anesthesia information globally.

Rate of occurrence of respiratory complications in patients who undergo shoulder arthroplasty with a continuous interscalene brachial plexus block and associated risk factors.

INTRODUCTION: Continuous interscalene nerve block techniques are an effective form of targeted non-opioid postoperative analgesia for shoulder arthroplasty patients. One of the limiting risks, however, is potential phrenic nerve blockade with resulting hemidiaphragmatic paresis and respiratory compromise. While studies have focused on block-related technical aspects to limit the incidence of phrenic nerve palsy, little is known about other factors associated with increased risk of clinical respiratory complications in this population. METHODS: A single-institution retrospective cohort study was conducted using electronic health records from adult patients who underwent elective shoulder arthroplasty with continuous interscalene brachial plexus blocks (CISB). Data collected included patient, nerve block, and surgery characteristics. Respiratory complications were categorized into four groups (none, mild, moderate, and severe). Univariate and multivariable analyses were conducted. RESULTS: Among 1025 adult shoulder arthroplasty cases, 351 (34%) experienced any respiratory complication. These 351 were subdivided into 279 (27%) mild, 61 (6%) moderate, and 11 (1%) severe respiratory complications. In an adjusted analysis, patient-related factors were associated with an increased likelihood of respiratory complication: ASA Physical Status III (OR 1.69, 95% CI 1.21 to 2.36); asthma (OR 1.59, 95% CI 1.07 to 2.37); congestive heart failure (OR 1.99, 95% CI 1.19 to 3.33); body mass index (OR 1.06, 95% CI 1.03 to 1.09); age (OR 1.02, 95% CI 1.00 to 1.04); and preoperative oxygen saturation (SpO2). For every 1% decrease in preoperative SpO2, there was an associated 32% higher likelihood of a respiratory complication (OR 1.32, 95% CI 1.20 to 1.46, p<0.001). CONCLUSIONS: Patient-related factors that can be measured preoperatively are associated with increased likelihood of respiratory complications after elective shoulder arthroplasty with CISB.

Multiorganizational consensus to define guiding principles for perioperative pain management in patients with chronic pain, preoperative opioid tolerance, or substance use disorder.

Significant knowledge gaps exist in the perioperative pain management of patients with a history of chronic pain, substance use disorder, and/or opioid tolerance as highlighted in the US Health and Human Services Pain Management Best Practices Inter-Agency Task Force 2019 report. The report emphasized the challenges of caring for these populations and the need for multidisciplinary care and a comprehensive approach. Such care requires stakeholder alignment across multiple specialties and care settings. With the intention of codifying this alignment into a reliable and efficient processes, a consortium of 15 professional healthcare societies was convened in a year-long modified Delphi consensus process and summit. This process produced seven guiding principles for the perioperative care of patients with chronic pain, substance use disorder, and/or preoperative opioid tolerance. These principles provide a framework and direction for future improvement in the optimization and care of 'complex' patients as they undergo surgical procedures.

Knee Injury and Osteoarthritis Outcome Score Trajectories After Primary Total Knee Arthroplasty in United States Veterans.

INTRODUCTION: The volume of total knee arthroplasty (TKA) procedures continues to increase, including among United States (US) veterans, but there is little data characterizing recovery using validated knee-related questionnaires. METHODS: In this prospective cohort study, we sought to establish the feasibility of longitudinal characterization of recovery after TKA using the validated Knee Injury and Osteoarthritis Outcome Score (KOOS), specifically focusing on two of the KOOS subscales (pain and quality of life (QOL)). We solicited participants who agreed to fill out these knee-related questionnaires preoperatively and 3, 6, and 12 months after discharge following unilateral TKA within the Durham Veterans Affairs Health Care System. We examined rates of prospective completion of the KOOS and face validity of scores at each study time point. We transformed and reported scores on the 0-100 scale, with zero representing significant knee pain or poor QOL and 100 representing no knee pain or good QOL. RESULTS: Of 200 US veterans presenting between May 2017 and 2018, 21 (10.5%) agreed to participate by filling out the KOOS questionnaire longitudinally from before surgery until one year after discharge. All 21 (100%) participants were male and completed the two KOOS subscale questions (pain and QOL) preoperatively. Of those, 16 (76.2%) also completed KOOS at 3 months, 16 (76.2%) at 6 months, and seven (33.3%) at 12 months. Compared to mean preoperative values (pain: 33.47 + 6.78, QOL: 11.91 + 4.99), the KOOS subscale scores had significantly improved by 6 months after TKA (pain: 74.41 + 10.72, QOL: 49.61 + 13.25) but plateaued at 12 months (pain: 74.60 + 20.80, QOL: 50.89 + 20.61). The magnitude of improvement in absolute scores, pain and QOL, was similar and significant at 12 months compared to preoperative values with an increase of 41.13 (p=0.007) and 38.98 (p=0.009), respectively. CONCLUSION: Primary TKA in US veterans with advanced osteoarthritis may lead to improved patient-reported KOOS pain and QOL subscale measures at 12 months compared to preoperative scores, with the majority of improvement occurring by 6 months. Only one in ten US veterans approached preoperatively agreed to complete the validated knee-related outcomes questionnaire prior to undergoing TKA. About three-quarters of those veterans also completed it both three and six months after discharge. Collected KOOS subscale scores demonstrated face validity and showed substantial improvement in pain and QOL over the six-month postoperative period. Only one in three veterans who completed the KOOS questionnaire preoperatively also completed it at 12 months, but this does not support the feasibility of follow-up assessments beyond 6 months. To better understand longitudinal pain and QOL trajectories in US veterans undergoing primary TKA for advanced osteoarthritis and to improve study participation, additional research using the KOOS questionnaire may add further insights into this underreported population.

Perioperative and anesthetic considerations for the management of neuromodulation systems.

The use of neuromodulation systems is increasing for the treatment of various pathologies ranging from movement disorders to urinary incontinence to chronic pain syndromes. While the type of neuromodulation devices varies, they are largely categorized as intracranial (eg, deep brain stimulation), neuraxial (eg, spinal cord stimulation, dorsal root ganglion stimulation, and intrathecal drug delivery systems), or peripheral (eg, sacral nerve stimulation and peripheral nerve stimulation) systems. Given the increasing prevalence of these systems in the overall population, it is important for anesthesiologists, surgeons, and the perioperative healthcare team to familiarize themselves with these systems and their unique perioperative considerations. In this review, we explore and highlight the various neuromodulation systems, their general perioperative considerations, and notable special circumstances for perioperative management.

Patient-centered results from a multicenter study of continuous peripheral nerve blocks and postamputation phantom and residual limb pain: secondary outcomes from a randomized, clinical trial.

INTRODUCTION: We previously reported that a 6-day continuous peripheral nerve block reduces established postamputation phantom pain. To provide patients and providers with the information to best inform treatment decisions, here we reanalyze the data and present the results in a more patient-centered format. We also provide information on patient-defined clinically relevant benefits to facilitate evaluation of available studies and guide future trial design. METHODS: The original trial enrolled participants with a limb amputation and phantom pain who were randomized to receive a 6-day continuous peripheral nerve block(s) of either ropivacaine (n=71) or saline (n=73) in a double-masked fashion. Here we calculate the percentage of each treatment group that experienced a clinically relevant improvement as defined by previous studies as well as present what the participants of our study defined as small, medium, and large analgesic improvements using the 7-point ordinal Patient Global Impression of Change scale. RESULTS: Among patients who were given a 6-day ropivacaine infusion, 57% experienced at least a 2-point improvement on the 11-point numeric rating scale in their average and worst phantom pain 4 weeks postbaseline as compared with 26% (p<0.001) for average and 25% (p<0.001) for worst pain in patients given a placebo infusion. At 4 weeks, the percentage of participants rating their pain as improved was 53% for the active vs 30% for the placebo groups (95% CI 1.7 (1.1, 2.7), p=0.008). For all patients combined, the median (IQR) phantom pain Numeric Rating Scale improvements at 4 weeks considered small, medium, and large were 2 (0-2), 3 (2-5), and 5 (3-7), respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with small, medium, and large analgesic changes were 8 (1-18), 22 (14-31), and 39 (26-47). CONCLUSIONS: Among patients with postamputation phantom pain, a continuous peripheral nerve block more than doubles the chance of a clinically relevant improvement in pain intensity. Amputees with phantom and/or residual limb pain rate analgesic improvements as clinically relevant similarly to other chronic pain etiologies, although their smallest relevant improvement in the Brief Pain Inventory was significantly larger than previously published values. TRIAL REGISTRATION NUMBER: NCT01824082.

Acute pain service reduces barriers to buprenorphine/naloxone initiation by using regional anesthesia techniques.

BACKGROUND: Medications for opioid use disorder (MOUD) are a life-saving intervention; thus, it is important to address barriers to successful initiation. Spasticity affects many patients with spinal cord injury and can be painful and physically debilitating. Chronic painful conditions can lead to the illicit use of non-prescribed opioids, but fear of pain is a barrier to the initiation of MOUD. In this case report, we describe the novel use of botulinum toxin A injections to treat abdominal spasticity and facilitate Acute Pain Service-led buprenorphine/naloxone initiation in a patient with opioid use disorder and severe abdominal spasticity due to spinal cord injury. CASE PRESENTATION: A patient with C4 incomplete tetraplegia and opioid use disorder complicated by abdominal spasticity refractory to oral antispasmodics and self-treating with intravenous heroin was referred to the Acute Pain Service for inpatient buprenorphine/naloxone initiation. The patient began to fail initiation of buprenorphine/naloxone secondary to increased pain from abdominal spasms. The patient was offered ultrasound-guided abdominal muscle chemodenervation with botulinum toxin A, which resulted in the resolution of abdominal spasticity and facilitated successful buprenorphine/naloxone initiation. At 6 months post-initiation, the patient remained abstinent from non-prescribed opioids and compliant with buprenorphine/naloxone 8 mg/2 mg three times a day. CONCLUSIONS: This case report demonstrates that inpatient buprenorphine/naloxone initiation by an Acute Pain Service can improve the success of treatment by addressing barriers to initiation. Acute Pain Service clinicians possess unique skills and knowledge, including ultrasound-guided interventions, that enable them to provide innovative and personalized approaches to care in the complex opioid use disorder population.