Prescription Drug Dispensing and Patient Costs After Implementation of a No Behavioral Health Cost-Sharing Law.

Importance: On January 1, 2022, New Mexico implemented a No Behavioral Cost-Sharing (NCS) law that eliminated cost-sharing for mental health and substance use disorder (MH/SUD) treatments in plans regulated by the state, potentially reducing a barrier to treatment for MH/SUDs among the commercially insured; however, the outcomes of the law are unknown. Objective: To assess the association of implementation of the NCS with out-of-pocket spending for prescription for drugs primarily used to treat MH/SUDs and monthly volume of dispensed drugs. Design, Settings, and Participants: This retrospective cohort study used a difference-in-differences research design to examine trends in outcomes for New Mexico state employees, a population affected by the NCS, compared with federal employees in New Mexico who were unaffected by NCS. Data were collected on prescription drugs for MH/SUDs dispensed per month between January 2021 and June 2022 for New Mexico patients with a New Mexico state employee health plan and New Mexico patients with a federal employee health plan. Data analysis occurred from December 2022 to January 2024. Exposure: Enrollment in a state employee health plan or federal health plan. Main Outcomes and Measures: The primary outcomes were mean patient out-of-pocket spending per dispensed MH/SUD prescription and the monthly volume of dispensed MH/SUD prescriptions per 1000 employees. A difference-in-differences estimation approach was used. Results: The implementation of the NCS law was associated with a mean (SE) $6.37 ($0.30) reduction (corresponding to an 85.6% decrease) in mean out-of-pocket spending per dispensed MH/SUD medication (95% CI, -$7.00 to -$5.75). The association of implementation of NCS with the volume of prescriptions dispensed was not statistically significant. Conclusions and Relevance: These findings suggest that the implementation of the New Mexico NCS law was successful in lowering out-of-pocket spending on prescription medications for MH/SUDs, but that there was no association of NCS with the volume of medications dispensed in the first 6 months after implementation. A key challenge is to identify policies that protect from high out-of-pocket spending while also promoting access to needed care.

Targeting the cytoskeleton as a therapeutic approach to substance use disorders.

Substance use disorders (SUD) are chronic relapsing disorders governed by continually shifting cycles of positive drug reward experiences and drug withdrawal-induced negative experiences. A large body of research points to plasticity within systems regulating emotional, motivational, and cognitive processes as drivers of continued compulsive pursuit and consumption of substances despite negative consequences. This plasticity is observed at all levels of analysis from molecules to networks, providing multiple avenues for intervention in SUD. The cytoskeleton and its regulatory proteins within neurons and glia are fundamental to the structural and functional integrity of brain processes and are potentially the major drivers of the morphological and behavioral plasticity associated with substance use. In this review, we discuss preclinical studies that provide support for targeting the brain cytoskeleton as a therapeutic approach to SUD. We focus on the interplay between actin cytoskeleton dynamics and exposure to cocaine, methamphetamine, alcohol, opioids, and nicotine and highlight preclinical studies pointing to a wide range of potential therapeutic targets, such as nonmuscle myosin II, Rac1, cofilin, prosapip 1, and drebrin. These studies broaden our understanding of substance-induced plasticity driving behaviors associated with SUD and provide new research directions for the development of SUD therapeutics.

Substance use disorder of equimolar oxygen-nitrous oxide mixture in French sickle-cell patients: results of the PHEDRE study.

BACKGROUND: In many countries, nitrous oxide is used in a gas mixture (EMONO) for short-term analgesia. Cases of addiction, with significant misuse, have been reported in hospitalized patients. Patients suffering from sickle cell disease (SCD) could represent a high-risk population for substance use disorder (SUD) due to their significant pain crisis and repeated use of EMONO. The objective of the PHEDRE study was to assess the prevalence of SUD for EMONO in French SCD patients. RESULTS: A total of 993 patients were included. Among 339 EMONO consumers, only 38 (11%) had a SUD, with very few criteria, corresponding mainly to a mild SUD due to a use higher than expected (in quantity or duration) and relational tensions with the care teams. Almost all patients (99.7%) were looking for an analgesic effect, but 68% of patients were also looking for other effects. The independent risks factors associated with at least one SUD criterion were: the feeling of effects different from the expected therapeutic effects of EMONO, at least one hospitalization for vaso occlusive crisis in the past 12 months and the presence of a SUD for at least one other analgesic drug. CONCLUSIONS: The use of EMONO was not problematic for the majority of patients. Manifestations of SUD that led to tensions with healthcare teams should alert and lead to an evaluation, to distinguish a true addiction from a pseudoaddiction which may be linked to an insufficient analgesic treatment related to an underestimation of pain in SCD patients. TRIAL REGISTRATION: Clinical Trials, NCT02580565. Registered 16 October 2015, https://clinicaltrials.gov/.

Food preference-based screening method for identification of effectors of substance use disorders using Caenorhabditis elegans.

Substance use disorder (SUD) affects over 48 million Americans aged 12 and over. Thus, identifying novel chemicals contributing to SUD will be critical for developing efficient prevention and mitigation strategies. Considering the complexity of the actions and effects of these substances on human behavior, a high-throughput platform using a living organism is ideal. We developed a quick and easy screening assay using Caenorhabditis elegans. C. elegans prefers high-quality food (Escherichia coli HB101) over low-quality food (Bacillus megaterium), with a food preference index of approximately 0.2, defined as the difference in the number of worms at E. coli HB101 and B. megaterium over the total worm number. The food preference index was significantly increased by loperamide, a µ-opioid receptor (MOPR) agonist, and decreased by naloxone, a MOPR antagonist. These changes depended on npr-17, a C. elegans homolog of opioid receptors. In addition, the food preference index was significantly increased by arachidonyl-2'-chloroethylamide, a cannabinoid 1 receptor (CB1R) agonist, and decreased by rimonabant, a CB1R inverse agonist. These changes depended on npr-19, a homolog of CB1R. These results suggest that the conserved opioid and endocannabinoid systems modulate the food preference behaviors of C. elegans. Finally, the humanoid C. elegans strains where npr-17 was replaced with human MOPR and where npr-19 was replaced with human CB1R phenocopied the changes in food preference by the drug treatment. Together, the current results show that this method can be used to rapidly screen the potential effectors of MOPR and CB1R to yield results highly translatable to humans.

Modafinil, an atypical CNS stimulant?

Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an "atypical" CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders.

Prescribed safer opioid supply: A scoping review of the evidence.

BACKGROUND: Safer opioid supply programs provide prescription pharmaceutical opioids, often with supportive services, to people at high risk of experiencing harms related to substance use. However, questions regarding the effectiveness and safety of this practice remain. We conducted a scoping review of literature describing client outcomes from formal opioid supply programs providing prescriptions for pharmaceutical opioids, and the perceptions of involved clients/providers. METHODS: We performed a scoping review of peer-reviewed studies and grey literature published between January 1, 2012, to September 12, 2023. We included articles reporting either safer opioid supply client outcomes or clients/providers perspectives. Extracted data included study objectives, substance use patterns, client outcomes, client/provider perspectives, and estimates of effectiveness and/or harm. RESULTS: Our search yielded 1,597 articles. Following removal of duplicates and application of exclusion criteria, 24 publications comprising 17 peer-reviewed and seven grey literature publications were included in our study. We generated eight themes summarizing topics in the available literature: opioid-related toxicities, infectious complications, other clinical outcomes, client-reported outcomes, program access barriers, diversion, program retention, and costs to the healthcare system. Specific findings included low rates of opioid toxicities, improved physical and mental health, and improved quality of life among clients. A lack of access to adequate opioid doses and the limited range of opioid options offered within safer opioid supply programs was described by clients and providers as a potential reason for diversion and a barrier to program access. CONCLUSIONS: Generally, evidence suggests that safer opioid supply programs are beneficial to clients through measurable outcomes. However, the available literature has important limitations, including limited inferences about the effectiveness, safety, and potential for diversion within safer opioid supply programs. Further research is needed to support the ongoing evaluation of safer opioid supply programs as one component of a multifactorial response to escalating rates of substance-related harms.

Associations between cannabis policies and state-level specialty cannabis use disorder treatment in the United States, 2004-2019.

BACKGROUND: Cannabis use disorder (CUD) treatment prevalence decreased in the US between 2002 and 2019, yet structural mechanisms for this decrease are poorly understood. We tested associations between cannabis laws becoming effective and self-reported CUD treatment. METHODS: Restricted-use 2004-2019 National Surveys on Drug Use and Health included people ages 12+ classified as needing CUD treatment (i.e., past-year DSM-5-proxy CUD or last/current specialty treatment for cannabis). Time-varying indicators of medical cannabis laws (MCL) with/without cannabis dispensary provisions differentiated state-years before/after laws using effective dates. Multi-level logistic regressions with random state intercepts estimated individual- and state-adjusted CUD treatment odds by MCLs and model-based changes in specialty CUD treatment state-level prevalence. Secondary analyses tested associations between CUD treatment and MCL or recreational cannabis laws (RCL). RESULTS: Using a broad treatment need sample definition in 2004-2014, specialty CUD treatment prevalence decreased by 1.35 (95 % CI = -2.51, -0.18) points after MCL without dispensaries and by 2.15 points (95 % CI = -3.29, -1.00) after MCL with dispensaries provisions became effective, compared to before MCL. Among people with CUD in 2004-2014, specialty treatment decreased only in MCL states with dispensary provisions (aPD = -0.91, 95 % CI = -1.68, -0.13). MCL were not associated with CUD treatment use in 2015-2019. RCL were associated with lower CUD treatment among people classified as needing CUD treatment, but not among people with past-year CUD. CONCLUSIONS: Policy-related reductions in specialty CUD treatment were concentrated in states with cannabis dispensary provisions in 2004-2014, but not 2015-2019, and partly driven by reductions among people without past-year CUD. Other mechanisms (e.g., CUD symptom identification, criminal-legal referrals) could contribute to decreasing treatment trends.

Feeling safer: effectiveness, feasibility, and acceptability of continuous pulse oximetry for people who smoke opioids at overdose prevention services in British Columbia, Canada.

BACKGROUND: Smoking is the most common mode of unregulated opioid consumption overall and implicated in fatal overdoses in British Columbia (BC). In part, perception of decreased risk (e.g., fewer who smoke carry naloxone kits) and limited smoking-specific harm reduction services contribute to overdose deaths. Overdose prevention services (OPS) offer supervised settings for drug use. Continuous pulse oximetry, common in acute care, allows real-time, remote oxygen monitoring. We evaluated the effectiveness of a novel continuous pulse oximetry protocol aimed at allowing physical distancing (as required by COVID-19, secluded spaces, and to avoid staff exposure to vaporized opioids), its feasibility, and acceptability at OPS for people who smoke opioids. METHODS: This was a mixed methods survey study. We developed a continuous pulse oximetry protocol in collaboration with clinical experts and people with lived/living experience of substance use. We implemented our protocol from March to August 2021 at four OPS in BC permitting smoking. We included adults (≥ 18 years) presenting to OPS to smoke opioids. Peer researchers collected demographic, health, and substance use information, and conducted structured observations. OPS clients participating in our study, OPS staff, and peer researchers completed post-monitoring surveys. We analyzed responses using a thematic inductive approach and validated themes with peer researchers. RESULTS: We included 599 smoking events. OPS clients participating in our study had a mean age of 38.5 years; 73% were male. Most (98%) reported using "down", heroin, or fentanyl; 48% concurrently used other substances (32% of whom reported stimulants); 76% reported smoking alone in the last 3 days; and 36% reported an overdose while smoking. Respondents reported that the protocol facilitated physical distancing, was easy to use, high satisfaction, improved confidence, improved sense of safety, and that they would use it again. CONCLUSIONS: Continuous pulse oximetry allowed safe physical distancing, was feasible, and acceptable in monitoring people who smoke opioids at OPS.

Naloxone access in perinatal substance use disorder.

BACKGROUND: Risk of fatal drug overdose is higher in pregnant and postpartum people with substance use disorder (SUD) than for nonpregnant women of reproductive age. It is recommended that naloxone is prescribed for pregnancies complicated by opioid or stimulant use disorder. OBJECTIVE: The purpose of this study was to assess the rates of naloxone coprescribing with buprenorphine in a perinatal SUD (PSUD) specialty clinic and identify opportunities for pharmacist-led interventions to improve communication and documentation surrounding naloxone access to achieve a rate of 100% coprescribing of naloxone with buprenorphine. PRACTICE DESCRIPTION: A clinical pharmacist practitioner is embedded on the Project CARA (Care that Advocates Respect/Resilience/Recovery for All) team, which provides outpatient SUD care integrated with perinatal care in Western North Carolina. PRACTICE INNOVATION: The clinical pharmacist practitioner assessed baseline rates of naloxone coprescribing with medications for opioid use disorder. Interventions to improve rates of coprescribing include provider education, electronic health record (EHR) documentation templates, and direct patient outreach. EVALUATION METHODS: Baseline rates of naloxone coprescribing were assessed and then re-evaluated after different interventions to measure pharmacist impact. RESULTS: Each intervention improved rates of naloxone coprescribing in a PSUD clinic. EHR documentation templates had the largest impact on baseline efforts, although the long-term benefits derived from these efforts have not yet been demonstrated. Substantial time investment from the pharmacist was required to address patients' barriers to obtaining naloxone after their visits. CONCLUSION: Further process improvement should address barriers to naloxone access for both patients and providers. This may include proactive identification of patients in need of naloxone and a "meds-to-beds" pilot to assist patients in navigating logistical challenges.

IUPHAR Review: New strategies for medications to treat substance use disorders.

Substance use disorders (SUDs) and drug overdose are a public health emergency and safe and effective treatments are urgently needed. Developing new medications to treat them is expensive, time-consuming, and the probability of a compound progressing to clinical trials and obtaining FDA-approval is low. The small number of FDA-approved medications for SUDs reflects the low interest of pharmaceutical companies to invest in this area due to market forces, characteristics of the population (e.g., stigma, and socio-economic and legal disadvantages), and the high bar regulatory agencies set for new medication approval. In consequence, most research on medications is funded by government agencies, such as the National Institute on Drug Abuse (NIDA). Multiple scientific opportunities are emerging that can accelerate the discovery and development of new medications for SUDs. These include fast and efficient tools to screen new molecules, discover new medication targets, use of big data to explore large clinical data sets and artificial intelligence (AI) applications to make predictions, and precision medicine tools to individualize and optimize treatments. This review provides a general description of these new research strategies for the development of medications to treat SUDs with emphasis on the gaps and scientific opportunities. It includes a brief overview of the rising public health toll of SUDs; the justification, challenges, and opportunities to develop new medications; and a discussion of medications and treatment endpoints that are being evaluated with support from NIDA.

Availability of Long-Acting Injectable Buprenorphine at Substance Use Treatment Facilities in 2021.

This study assesses the proportion of US substance use and mental health care facilities that offered any medications for opioid use disorder and, specifically, long-acting injectable buprenorphine in 2021.

Treatment of Posttraumatic Stress Disorder: A State-of-the-art Review.

This narrative state-of-the-art review paper describes the progress in the understanding and treatment of Posttraumatic Stress Disorder (PTSD). Over the last four decades, the scientific landscape has matured, with many interdisciplinary contributions to understanding its diagnosis, etiology, and epidemiology. Advances in genetics, neurobiology, stress pathophysiology, and brain imaging have made it apparent that chronic PTSD is a systemic disorder with high allostatic load. The current state of PTSD treatment includes a wide variety of pharmacological and psychotherapeutic approaches, of which many are evidence-based. However, the myriad challenges inherent in the disorder, such as individual and systemic barriers to good treatment outcome, comorbidity, emotional dysregulation, suicidality, dissociation, substance use, and trauma-related guilt and shame, often render treatment response suboptimal. These challenges are discussed as drivers for emerging novel treatment approaches, including early interventions in the Golden Hours, pharmacological and psychotherapeutic interventions, medication augmentation interventions, the use of psychedelics, as well as interventions targeting the brain and nervous system. All of this aims to improve symptom relief and clinical outcomes. Finally, a phase orientation to treatment is recognized as a tool to strategize treatment of the disorder, and position interventions in step with the progression of the pathophysiology. Revisions to guidelines and systems of care will be needed to incorporate innovative treatments as evidence emerges and they become mainstream. This generation is well-positioned to address the devastating and often chronic disabling impact of traumatic stress events through holistic, cutting-edge clinical efforts and interdisciplinary research.

Drug dependence in cancer is exploitable by optimally constructed treatment holidays.

Cancers with acquired resistance to targeted therapy can become simultaneously dependent on the presence of the targeted therapy drug for survival, suggesting that intermittent therapy may slow resistance. However, relatively little is known about which tumours are likely to become dependent and how to schedule intermittent therapy optimally. Here we characterized drug dependence across a panel of over 75 MAPK-inhibitor-resistant BRAFV600E mutant melanoma models at the population and single-clone levels. Melanocytic differentiated models exhibited a much greater tendency to give rise to drug-dependent progeny than their dedifferentiated counterparts. Mechanistically, acquired loss of microphthalmia-associated transcription factor in differentiated melanoma models drives ERK-JunB-p21 signalling to enforce drug dependence. We identified the optimal scheduling of 'drug holidays' using simple mathematical models that we validated across short and long timescales. Without detailed knowledge of tumour characteristics, we found that a simple adaptive therapy protocol can produce near-optimal outcomes using only measurements of total population size. Finally, a spatial agent-based model showed that optimal schedules derived from exponentially growing cells in culture remain nearly optimal in the context of tumour cell turnover and limited environmental carrying capacity. These findings may guide the implementation of improved evolution-inspired treatment strategies for drug-dependent cancers.

Factors associated with daily use of benzodiazepines/tranquilizers and opioids among people who use drugs.

BACKGROUND: Co-use of benzodiazepines and opioids significantly increases fatal overdose risk, yet few studies have examined co-use of these drugs when obtained both with and without a prescription. We examined associations of daily co-use of prescribed benzodiazepines/tranquilizers (BZD/TRQ) and prescribed and nonprescribed opioids among people who use street opioids (PWUO). METHODS: PWUO (N = 417) were recruited from Baltimore City and neighboring Anne Arundel County, Maryland, and surveyed on sociodemographic characteristics, structural vulnerabilities, healthcare access and utilization, substance use, and overdose experiences. Multivariable logistic regression was used to identify factors associated with self-reported co-use. RESULTS: Participants were 46 years old on average, and predominantly Black (74%) males (62%). Daily co-use was reported by 22%. In multivariable analyses, odds of co-use were significantly higher among participants who did not have a high school degree/GED (adjusted odds ratio [aOR]: 1.71, 95% confidence interval [CI]: 1.02-2.88), endorsed receiving mental health treatment in the past 6 months (aOR: 2.13, 95% CI: 1.28-3.56), reported daily use of powdered cocaine (aOR: 3.57, 95% CI: 1.98-6.45), and synthetic cannabinoids (aOR: 3.11, 95% CI: 1.40-6.93). Odds of co-use were significantly lower among Black participants compared to white participants (aOR: 0.39, 95% CI: 0.19-0.82). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Clinicians working with PWUO or who prescribe BZDs or opioids should screen patients who use cocaine or synthetic cannabinoids, have low level of educational attainment, or recently accessed mental health services, as these patients may be at higher risk for daily co-use of BZD/TRQ and opioids, and therefore lethal overdose.

Examining Adult Patients' Success with Discontinuing Long-term Benzodiazepine Use: a Qualitative Study.

BACKGROUND: Little is known about patients' experiences with benzodiazepine (BZD) discontinuation, which is thought to be challenging given the physiological and psychological dependence and accompanying potential for significant withdrawal symptoms. The marked decline in BZD prescribing over the past decade in the US Department of Veterans Affairs healthcare system presents an important opportunity to examine the experience of BZD discontinuation among long-term users. OBJECTIVE: Examine the experience of BZD discontinuation among individuals prescribed long-term BZD treatment to identify factors that contributed to successful discontinuation. DESIGN: Descriptive qualitative analysis of semi-structured interviews conducted between April and December of 2020. PARTICIPANTS: A total of 21 Veterans who had been prescribed long-term BZD pharmacotherapy (i.e., > 120 days of exposure in a 12-month period) and had their BZD discontinued. APPROACH: We conducted semi-structured interviews with Veteran participants to learn about their BZD use and the process of discontinuation, with interviews recorded and transcribed verbatim. Data were deductively and inductively coded and coded text entered into a matrix to identify factors that contributed to successful BZD discontinuation. KEY RESULTS: The mean age of interview participants was 63.0 years (standard deviation 3.9); 94.2% were male and 76.2% were white. Of 21 participants, only 1 had resumed BZD treatment (prescribed by a non-VA clinician). Three main factors influenced success with discontinuation: (1) participants' attitudes toward BZDs (e.g., risks of long-term use, perceived lack of efficacy, potential for dependence); (2) limited withdrawal symptoms; and (3) effective alternatives, either from their clinician (e.g., medication, psychotherapy) or identified by participants. CONCLUSIONS: BZD discontinuation after long-term use is relatively well tolerated, and participants appreciated reducing their medication exposure, particularly to one associated with physical dependence. These findings may help reduce both patient and clinician anxiety related to BZD discontinuation.

Prescription psychostimulants for the treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of randomized placebo-controlled trials.

BACKGROUND AND AIMS: There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD. METHODS: Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables. RESULTS: Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD  -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention. CONCLUSIONS: Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.