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Introduction: Mu opioid receptor gene (OPRM1) variant rs1799971 introduces a CpG site, which may influence DNA methylation (DNAm) and opioid/pain outcomes. Objectives: In this nested analysis, we investigated both OPRM1 A118G genotype and promoter/immediate downstream blood DNAm sequencing data for associations with opioid effects and chronic postsurgical pain (CPSP) in a surgical cohort. Methods: Prospectively recruited opioid naïve patients undergoing Nuss procedure or spinal fusion with rs1799971 genotypes (Illumina arrays), DNAm (next generation enzymatic methylation sequencing at Chr6:154,039,209-154,039,803) and outcomes—opioid analgesia (integrated opioid use 1 pain over postoperative days 0 and 1 normalized to surgery type), safety—respiratory depression (RD) in high opioid use groups, and CPSP (Numerical Rating Scale .3/10 2-12 months postsurgery)—were included. Linear and logistic regression were performed to test genetic and epigenetic associations, adjusted for sociodemographics, cell types, and analgesics. Results: In this cohort (N 5 112; 15.3 6 2.0 years, 50% female, 83% White, 55% had CPSP, 13% had RD), DNAm at Chr6: 154039216-154039217 was associated with CPSP (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.00-1.57; P 5 0.03), Chr6: 154039661-154039662 with acute integrated pain (b 5 220.9, 95% CI, 240.70 to 21.10, P 5 0.04), Chr6:154039520-154039521 (OR, 1.49; 95% CI, 1.09-2.03; P 5 0.01), and Chr6:154039571-154039572 (OR, 1.47; 95% CI, 1.08-2.01; P 5 0.02) with RD. Significant CpG sites were located in Repressed Polycomb chromatin states. Genotype was not associated with DNAm or outcomes. Conclusion: Our analyses support OPRM1 DNAm as predictors of acute and chronic pain/opioid outcomes in children after painful surgery. Study limitations included absent GG genotype, low sequencing coverage, and lack of correction for multiple testing.

Introduction: Coronavirus 2019 (COVID-19) has had a devastating impact on mental health and access to addiction treatment in the United States, including in California, which resulted in the highest rates of emergency department visits (ED) for opioid poisoning in 2020. As California slowly returns to pre-pandemic normalcy, it remains uncertain whether the rates of opioid-related events have slowed down over time. We hypothesized that the number of opioid-related ED visits were exacerbated after the period of the COVID-19 pandemic and continue at a high rate in the present.Methods: In this analysis we searched the University of California (UC) Health Data Warehouse—a database of electronic health records from six UC health centers—for opioid-related ED visits, identifiying using the following International Classification of Diseases, 10th Ed, Clinical Modification codes: F11 codes, and T40.0*, T40.1*, T40.2*, T40.3*, T40.4*, T40.6*. Opioid overdose-associated visits were classified by types of opioids involved: heroin (T40.1*); prescription opioids (T40.2* or T40.3*); and synthetic opioids (T40.4*). We performed interrupted time analysis to estimate the immediate (level) change and change-in-time trend (trend change), from before (January 2018–October 2019) and during the pandemic (April 2020–December 2022). Monthly visit rates were evaluated with negative binomial regression adjusted for first-order autoregression and using all-cause ED counts as the offset. We present effect sizes as rate ratios (RR) and 95% confidence intervals (CI), tested at α = .05.Results: Before COVID-19, a steadily increasing trend in ED visit rates was observed for all outcomes (P < 0.05) except synthetic opioids. Total opioid-related ED visit rates increased by 15% (RR 1.15, 95%CI 1.02–1.29, P = 0.20) immediately after March 2020 before decreasing by 0.5% every month, albeit without statistical significance (RR .995, 95% CI .991–1.00, P = 0.06). Similar trends were observed with prescription opioid overdoses, with a step increase of 44% (RR 1.44, 95% CI 1.10–1.89, P = .008) before plateauing after March 2020 (RR 1.01, 95% CI .998–1.02, P = 0.12). After March 2020, ED visit rates for synthetic opioid overdoses were increasing steadily by 4% every month (RR 1.04, 95% CI 1.02–1.06, P = .001), unlike with heroin, which was observed with an 8% monthly reduction (RR .92, 95% CI .90–.93, P < .001). No immediate increase in visit rates was observed for either opioid.Conclusion: While opioid-related ED admissions among the UC health centers showed an overall decrease, prescription and synthetic opioid overdoses remained significantly higher than pre-pandemic trends as of December 2022. A multilevel approach to improve awareness of new opioid health policies could ameliorate these alarming rises in the post-pandemic era.

PurposeWe aimed to estimate health state utility values (HSUVs) for the key health states found in opioid use disorder (OUD) cost-effectiveness models in the published literature.MethodsData obtained from six trials representing 1,777 individuals with OUD. We implemented mapping algorithms to harmonize data from different measures of quality of life (the SF-12 Versions 1 and 2 and the EQ-5D-3 L). We performed a regression analysis to quantify the relationship between HSUVs and the following variables: days of extra-medical opioid use in the past 30 days, injecting behaviors, treatment with medications for OUD, HIV status, and age. A secondary analysis explored the impact of opioid withdrawal symptoms.ResultsThere were statistically significant reductions in HSUVs associated with extra-medical opioid use (-0.002 (95% CI [-0.003,-0.0001]) to -0.003 (95% CI [-0.005,-0.002]) per additional day of heroin or other opiate use, respectively), drug injecting compared to not injecting (-0.043 (95% CI [-0.079,-0.006])), HIV-positive diagnosis compared to no diagnosis (-0.074 (95% CI [-0.143,-0.005])), and age (-0.001 per year (95% CI [-0.003,-0.0002])). Parameters associated with medications for OUD treatment were not statistically significant after controlling for extra-medical opioid use (0.0131 (95% CI [-0.0479,0.0769])), in line with prior studies. The secondary analysis revealed that withdrawal symptoms are a fundamental driver of HSUVs, with predictions of 0.817 (95% CI [0.768, 0.858]), 0.705 (95% CI [0.607, 0.786]), and 0.367 (95% CI [0.180, 0.575]) for moderate, severe, and worst level of symptoms, respectively.ConclusionWe observed HSUVs for OUD that were higher than those from previous studies that had been conducted without input from people living with the condition.

Converging lines of preclinical and clinical research indicate that females, in stark contrast to males, display an increased prevalence of chronic pain. Females also demonstrate weaker analgesic efficacy in response to opioid therapies when compared with males. These sex-specific differences may be driven by dimorphic endogenous opioidergic responses. In rodent models, analgesia exhibited in males but not females was reversed by inhibiting endogenous opioidergic reception. In humans, the sex-specific endogenous system(s) supporting the direct attenuation of evoked pain has not been identified. To determine whether opioidergic blockade reverses self-regulated analgesia in males as compared to females, the present study combined two operationally analogous clinical trials (n = 98; 51 females and 47 males). In a double-blinded, counterbalanced study involving healthy (n = 39) and chronic low back pain (n = 59) populations, a high-dose naloxone (μ-, κ-, δ-opioid antagonist) vs. placebo-saline cross-over design (15 mg/kg bolus +0.1 mg/kg/h) tested the hypothesis that endogenous opioids mediate analgesia in males but not females. An 11-point visual analog scale (VAS) (0 = no pain; 10 = worst pain imaginable) evaluated pain ratings in response to noxious heat stimulation (49 °C; calf). After baseline pain testing, participants were randomized to a validated four-session mindfulness meditation or sham mindfulness meditation training intervention. Participants practiced their respective meditation during noxious heat, intravenous high-dose naloxone, and placebo saline, respectively. In males and females, meditation significantly lowered evoked pain during saline infusion. Intravenous naloxone inhibited analgesia in males, but pain relief was well preserved in females. The present findings indicate that endogenous opioids mediate self-regulated analgesia in males but not females and underscore the need to establish sex-specific pain therapeutics.

Neuropeptides are ubiquitous in the nervous system. Research into neuropeptides has been limited by a lack of experimental tools that allow for the precise dissection of their complex and diverse dynamics in a circuit-specific manner. Opioid peptides modulate pain, reward and aversion and as such have high clinical relevance. To illuminate the spatiotemporal dynamics of endogenous opioid signaling in the brain, we developed a class of genetically encoded fluorescence sensors based on kappa, delta and mu opioid receptors: κLight, δLight and µLight, respectively. We characterized the pharmacological profiles of these sensors in mammalian cells and in dissociated neurons. We used κLight to identify electrical stimulation parameters that trigger endogenous opioid release and the spatiotemporal scale of dynorphin volume transmission in brain slices. Using in vivo fiber photometry in mice, we demonstrated the utility of these sensors in detecting optogenetically driven opioid release and observed differential opioid release dynamics in response to fearful and rewarding conditions.

BackgroundPostoperative nausea and vomiting occur frequently following thyroid and parathyroid surgery and are associated with worse patient outcomes. We hypothesised that opioid-free propofol anaesthesia would reduce the incidence of postoperative nausea and vomiting compared with opioid-inclusive propofol anaesthesia in patients undergoing these procedures.MethodsWe conducted a randomised, double-blinded controlled trial in adult patients scheduled to undergo thyroid and parathyroid surgery at two medical centres in mainland China. Patients were allocated randomly (1:1, stratified by sex and trial site) to an opioid-free anaesthesia group (esketamine, lidocaine, dexmedetomidine and propofol) or an opioid-inclusive group (sufentanil and propofol). Propofol infusions were titrated to bispectral index 45-55. Patients received prophylaxis for nausea and vomiting using dexamethasone and ondansetron and multimodal analgesia with paracetamol and flurbiprofen axetil. The primary outcome was the incidence of postoperative nausea and vomiting in the first 48 h after surgery.ResultsWe assessed 557 patients for eligibility and 394 completed this trial. The incidence of postoperative nausea and vomiting in the first postoperative 48 h was lower in the opioid-free anaesthesia group (10/197, 5%) compared with opioid-inclusive group (47/197, 24%) (OR (95%CI) 0.17 (0.08-0.35), p

The intensifying global opioid crisis, majorly attributed to fentanyl (FT) and its analogs, has necessitated the development of rapid and ultrasensitive remote/on-site FT sensing modalities. However, current approaches for tracking FT exposure through wastewater-based epidemiology (WBE) are unadaptable, time-consuming, and require trained professionals. Toward developing an extended in situ wastewater opioid monitoring system, we have developed a screen-printed electrochemical FT sensor and integrated it with a customized submersible remote sensing probe. The sensor composition and design have been optimized to address the challenges for extended in situ FT monitoring. Specifically, ZIF-8 metal-organic framework (MOF)-derived mesoporous carbon (MPC) nanoparticles (NPs) are incorporated in the screen-printed carbon electrode (SPCE) transducer to improve FT accumulation and its electrocatalytic oxidation. A rapid (10 s) and sensitive square wave voltammetric (SWV) FT detection down to 9.9 µgL-1 is thus achieved in aqueous buffer solution. A protective mixed-matrix membrane (MMM) has been optimized as the anti-fouling sensor coating to mitigate electrode passivation by FT oxidation products and enable long-term, intermittent FT monitoring. The unique MMM, comprising an insulating polyvinyl chloride (PVC) matrix and carboxyl-functionalized multi-walled carbon nanotubes (CNT-COOH) as semiconductive fillers, yielded highly stable FT sensor operation (> 95% normalized response) up to 10 h in domestic wastewater, and up to 4 h in untreated river water. This sensing platform enables wireless data acquisition on a smartphone via Bluetooth. Such effective remote operation of submersible opioid sensing probes could enable stricter surveillance of community water systems toward timely alerts, countermeasures, and legal enforcement.

BackgroundYoung adult (18-30 years) people who inject drugs (PWID) face high hepatitis C virus (HCV) prevalence. In San Francisco, where >60% of PWID lack stable housing, barriers hinder HCV treatment access. We assessed progress towards the World Health Organization's (WHO) HCV elimination goal of an 80% reduction in incidence over 2015-2030, focusing on young (YPWID) and unstably housed PWID in San Francisco.MethodsWe developed a dynamic HCV transmission model among PWID, parameterized and calibrated using bio-behavioural survey datasets from San Francisco. This included 2018 estimates for the antibody-prevalence among PWID (77%) and care cascade estimates for HCV for YPWID (72% aware of their status and 33% ever initiating treatment). Based on programmatic data, we assumed a 53.8% reduction in testing and 40.7% decrease in treatment from 2020 due to the COVID-19 pandemic, which partially rebounded from April 2021 with testing rates then being 31.1% lower than pre-pandemic rates and treatment numbers being 19.5% lower. We simulated different scenarios of how services changed after the pandemic to project whether elimination goals would be met.ResultsContinuing post-pandemic rates of testing and treatment, the model projects an 83.3% (95% credibility interval [95% CrI]:60.6-96.9%) decrease in incidence among PWID over 2015-2030 to 1.5/100pyrs (95% CrI:0.3-4.4) in 2030. The probability of achieving the elimination goal by 2030 is 62.0%. Among YPWID and unstably housed PWID, the probability of achieving the elimination goal by 2030 is 54.8 and 67.6%, respectively. Importantly, further increasing testing and treatment rates to pre-pandemic levels by 2025 only results in a small increase in the probability (67.5%) of the elimination goal being achieved among all PWID by 2030, while increased coverage of medication for opioid use disorder among YPWID and/or housing interventions results in the probability of achieving elimination increasing to over 75%.ConclusionThe COVID-19 pandemic impeded progress toward achieving HCV elimination. Our findings indicate that existing partial rebounds in HCV testing and treatment may achieve the elimination goal by 2030, with an additional scale-up of interventions aimed at YPWID or unstably housed PWID ensuring San Francisco is likely to achieve elimination by 2030.

INTRODUCTION: Across specialties, surgeons over-prescribe opioids to patients after surgery. We aimed to develop and implement an evidence-based calculator to inform post-discharge opioid prescription size for gynecologic oncology patients after laparotomy. METHODS: In 2021, open surgical gynecologic oncology patients were called 2-4 weeks after surgery to ask about their home opioid use. This data was used to develop a calculator for post-discharge opioid prescription size using two factors: 1) age of the patient, 2) oral morphine equivalents (OME) used by patients the day before hospital discharge. The calculator was implemented on the inpatient service from 8/21/22 and patients were contacted 2-4 weeks after surgery to again assess their opioid use at home. RESULTS: Data from 95 surveys were used to develop the opioid prescription size calculator and are compared to 95 post-intervention surveys. There was no difference pre- to post-intervention in demographic data, surgical procedure, or immediate postoperative recovery. The median opioid prescription size decreased from 150 to 37.5 OME (p

Introduction: People who use drugs in community settings are at risk of a fatal overdose, which can be mitigated by naloxone administered via bystanders. In this study we sought to investigate methods of estimating and tracking opioid overdose reversals by community members with take-home naloxone (THN) to coalesce possible ways of characterizing THN reach with a metric that is useful for guiding both distribution of naloxone and advocacy of its benefits.Methods: We conducted a scoping review of published literature on PubMed on August 15, 2022, using PRISMA-ScR protocol, for articles discussing methods to estimate THN reversals in the community. The following search terms were used: naloxone AND (“take home” OR kit OR “community distribution” OR “naloxone distribution”). We used backwards citation searching to potentially find additional studies. Overdose education and naloxone distribution program-based studies that analyzed only single programs were excluded.Results: The database search captured 614 studies, of which 14 studies were relevant. Backwards citation searching of 765 references did not reveal additional relevant studies. Of the 14 relevant studies, 11 were mathematical models. Ten used Markov models, and one used a system dynamics model. Of the remaining three articles, one was a meta-analysis, and two used spatial analysis. Studies ranged in year of publication from 2013–2022 with mathematical modeling increasing in use over time. Only spatial analysis was used with a focus on characterizing local naloxone use at the level of a specific city.Conclusion: Of existing methods to estimate bystander administration of THN, mathematical models are most common, particularly Markov models. System dynamics modeling, meta-analysis, and spatial analysis have also been used. All methods are heavily dependent upon overdose education and naloxone distribution program data published in the literature or available as ongoing surveillance data. Overall, there is a paucity of literature describing methods of estimation and even fewer with methods applied to a local focus that would allow for more targeted distribution of naloxone.

Introduction: The opioid epidemic is a major cause of morbidity and mortality in the United States. Prior work has shown that emergency department (ED) opioid prescribing can increase the incidence of opioid use disorder in a dose-dependent manner, and systemic changes that decrease default quantity of discharge opioid tablets in the electronic health record (EHR) can impact prescribing practices. However, ED leadership may be interested in the impact of communication around the intervention as well as whether the intervention may differentially impact different types of clinicians (physicians, physician assistants [PA], and nurse practitioners). We implemented and evaluated a quality improvement intervention of an announced decrease in EHR default quantities of commonly prescribed opioids at a large, academic, urban, tertiary-care ED.Methods: We gathered EHR data on all ED discharges with opioid prescriptions from January 1, 2019–December 6, 2021, including chief complaint, clinician, and opioid prescription details. Data was captured and analyzed on a monthly basis throughout this time period. On March 29, 2021, we implemented an announced decrease in EHR default dispense quantities from 20 tablets to 12 tablets for commonly prescribed opioids. We measured pre- and post-intervention quantities of opioid tablets prescribed per discharge receiving opioids, distribution by patient demographics, and inter-clinician variability in prescribing behavior.Results: The EHR change was associated with a 14% decrease in quantity of opioid tablets per discharge receiving opioids, from 14 to 12 tablets (P =

Opioid receptors are therapeutically important G protein-coupled receptors (GPCRs) with diverse neuromodulatory effects. The functional consequences of opioid receptor activation are known to depend on receptor location in the plasma membrane, but mechanisms mediating selective localization of receptors to any particular membrane domain remain elusive. Here, we demonstrate the targeting of the mu opioid receptor (MOR) to the primary cilium, a discrete microdomain of the somatic plasma membrane, both in vivo and in cultured cells. We further show that ciliary targeting is specific to MORs, requires a 17-residue sequence unique to the MOR cytoplasmic tail, and additionally requires the Tubby-like protein 3 (TULP3) ciliary adaptor protein. Our results reveal the potential for opioid receptors to undergo selective localization to the primary cilium. We propose that ciliary targeting is mediated through an elaboration of the recycling pathway, directed by a specific C-terminal recycling sequence in cis and requiring TULP3 in trans.

BACKGROUND: Buprenorphine is an effective treatment for opioid use disorder (OUD); however, buprenorphine initiation can be complicated by withdrawal symptoms including precipitated withdrawal. There has been increasing interest in using low dose initiation (LDI) strategies to reduce this withdrawal risk. As there are limited data on withdrawal symptoms during LDI, we characterize withdrawal symptoms in people with daily fentanyl use who underwent initiation using these strategies as outpatients. METHODS: We conducted a retrospective chart review of patients with OUD using daily fentanyl who were prescribed 7-day or 4-day LDI at 2 substance use disorder treatment clinics in San Francisco. Two addiction medicine experts assessed extracted chart documentation for withdrawal severity and precipitated withdrawal, defined as acute worsening of withdrawal symptoms immediately after taking buprenorphine. A third expert adjudicated disagreements. Data were analyzed using descriptive statistics. RESULTS: There were 175 initiations in 126 patients. The mean age was 37 (SD 10 years). 71% were men, 26% women, and 2% non-binary. 21% identified as Black, 16% Latine, and 52% white. 60% were unstably housed and 75% had Medicaid insurance. Substance co-use included 74% who used amphetamines, 29% cocaine, 22% benzodiazepines, and 19% alcohol. Follow up was available for 118 (67%) initiations. There was deviation from protocol instructions in 22% of these initiations with follow up. 31% had any withdrawal, including 21% with mild symptoms, 8% moderate and 2% severe. Precipitated withdrawal occurred in 10 cases, or 8% of initiations with follow up. Of these, 7 had deviation from protocol instructions; thus, there were 3 cases with follow up (3%) in which precipitated withdrawal occurred without protocol deviation. CONCLUSIONS: Withdrawal was relatively common in our cohort but was mostly mild, and precipitated withdrawal was rare. Deviation from instructions, structural barriers, and varying fentanyl use characteristics may contribute to withdrawal. Clinicians should counsel patients who use fentanyl that mild withdrawal symptoms are likely during LDI, and there is still a low risk for precipitated withdrawal. Future studies should compare withdrawal across initiation types, seek ways to support patients in initiating buprenorphine, and qualitatively elicit patients withdrawal experiences.

Introduction: Bystander provision of naloxone is a key modality to reduce opioid overdose-related death. Naloxone training courses are available, but no standardized program exists. As part of a bystander empowerment course, we created and evaluated a brief naloxone training module.Methods: This was a retrospective evaluation of a naloxone training course, which was paired with Stop the Bleed training for hemorrhage control and was offered to administrative staff in an office building. Participants worked in an organization related to healthcare, but none were clinicians. The curriculum included the following topics: 1) background about the opioid epidemic; 2) how to recognize the signs of an opioid overdose; 3) actions not to take when encountering an overdose victim; 4) the correct steps to take when encountering an overdose victim; 5) an overview of naloxone products; and 6) Good Samaritan protection laws. The 20-minute didactic section was followed by a hands-on session with nasal naloxone kits and a simulation mannequin. The course was evaluated with the Opioid Overdose Knowledge (OOKS) and Opioid Overdose Attitudes (OOAS) scales for take-home naloxone training evaluation. We used the paired Wilcoxon signed-rank test to compare scores pre- and post-course.Results: Twenty-eight participants completed the course. The OOKS, measuring objective knowledge about opioid overdose and naloxone, had improved scores from a median of 73.2% (interquartile range [IQR] 68.3%–79.9%) to 91.5% (IQR 85.4%–95.1%), P < 0.001. The three domains on the OOAS score also showed statistically significant results. Competency to manage an overdose improved on a five-point scale from a median of 2.5 (IQR 2.4–2.9) to a median of 3.7 (IQR 3.5–4.1), P < 0.001. Concerns about managing an overdose decreased (improved) from a median of 2.3 (IQR 1.9–2.6) to median 1.8 (IQR 1.5–2.1), P < 0.001. Readiness to intervene in an opioid overdose improved from a median of 4 (IQR 3.8–4.2) to a median of 4.2 (IQR 4–4.2), P < 0.001.Conclusion: A brief course designed to teach bystanders about opioid overdose and naloxone was feasible and effective. We encourage hospitals and other organizations to use and promulgate this model. Furthermore, we suggest the convening of a national consortium to achieve consensus on program content and delivery.

RationaleUse of electronic drug delivery systems (EDDS, "e-cigarettes") to ingest nicotine and Δ9-tetrahydrocannabinol (THC) has surged in adolescents in the USA; five times as many high-school seniors vape nicotine daily using tobacco. At the same time, 19.5% of seniors use cannabis at least monthly, with 12% using EDDS to deliver it.ObjectivesThis study was conducted to examine the impact of repeated adolescent vapor inhalation of nicotine and THC in rats.MethodsFemale Sprague-Dawley rats were exposed to 30-min sessions of vapor inhalation, twice daily, from post-natal day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle, nicotine (60 mg/mL in the PG), THC (100 mg/mL in the PG), or the combination of nicotine (60 mg/mL) and THC (100 mg/mL). Rats were assessed on wheel activity, heroin anti-nociception and nicotine and heroin vapor volitional exposure during adulthood.ResultsNicotine-exposed rats exhibited few differences as adults, but were less sensitive to anti-nociceptive effects of heroin (1 mg/kg, s.c.). THC- and THC + nicotine-exposed rats were less spontaneously active, and obtained fewer nicotine vapor deliveries as adults. In contrast, THC-exposed rats obtained volitional heroin vapor at rates indistinguishable from the non-THC-exposed groups. Repeated THC exposure also caused tolerance to temperature-disrupting effects of THC (5 mg/kg, i.p.).ConclusionsThese studies further confirm that the effects of repeated vapor exposure to THC in adolescence last into early to middle adulthood, including decreased volitional consumption of nicotine. Effects of repeated nicotine in adolescence were comparatively minor.

The harmful side effects of opioid drugs such as respiratory depression, tolerance, dependence, and abuse potential have limited the therapeutic utility of opioids for their entire clinical history. However, no previous attempt to develop effective pain drugs that substantially ameliorate these effects has succeeded, and the current opioid epidemic affirms that they are a greater hindrance to the field of pain management than ever. Recent attempts at new opioid development have sought to reduce these side effects by minimizing engagement of the regulatory protein arrestin-3 at the mu-opioid receptor, but there is significant controversy around this approach. Here, we discuss the ongoing effort to develop safer opioids and its relevant historical context. We propose a new model that reconciles results previously assumed to be in direct conflict to explain how different signaling profiles at the mu-opioid receptor contribute to opioid tolerance and dependence. Our goal is for this framework to inform the search for a new generation of lower liability opioid analgesics.

IntroductionDeaths from drug overdoses are rising dramatically in the United States. Treatment for opioid use disorders may include behavioral treatments as well as medications for opioid use disorders (MOUD). Buprenorphine can be prescribed by physicians, nurse practitioners (NPs), other advanced practice registered nurses (APRNs), and physician assistants (PAs) and required a training and a federal waiver until recently. The number of NP MOUD prescribers grew steadily over the past decade, but research has identified state-level scope of practice regulations as a barrier to NP MOUD prescribing. This article explores the contributions of, and remaining barriers faced by NP and other APRN MOUD prescribers. We describe qualitative findings from a study of NPs and other key stakeholders involved in MOUD treatment in four states with two differing levels of regulatory structure.MethodsIn this qualitative study, we conducted site visits and semi-structured interviews with NPs and other APRNs, physicians, clinic managers, and regulators in four states including New Mexico and West Virginia (full practice authority for NPs), and Ohio and Michigan (which require physician supervision). Interview notes were entered into a qualitative software package and coded and reviewed by two members of the research team. Data were grouped into key themes.ResultsA total of 76 participants participated in individual or small group interviews in the four states. We found key themes and several subthemes that describe NP practice in MOUD. Participants described key contributions of NP engagement in MOUD, including increasing access, serving rural areas, the unique role of psychiatric NPs, and the value of the nursing model of care in working with people with substance use disorders (SUD). Participants also identified barriers including scope of practice regulations, other regulatory barriers, stigma, and lack of supportive services to address psychosocial needs.ConclusionsThe waiver requirements were eliminated at the end of 2022 in federal budget legislation. Other barriers for NP and other APRN prescribers remain and should be addressed in practice, and in state and federal regulations. Research needs to explore the impact of the waiver elimination on MOUD prescribing and access to services.

BackgroundIncarceration is associated with drug-related harms among people who inject drugs (PWID). We trained >1800 police officers in Tijuana, Mexico on occupational safety and HIV/HCV, harm reduction, and decriminalization reforms (Proyecto Escudo). We evaluated its effect on incarceration, population impact and cost-effectiveness on HIV and fatal overdose among PWID.MethodsWe assessed self-reported recent incarceration in a longitudinal cohort of PWID before and after Escudo. Segmented regression was used to compare linear trends in log risk of incarceration among PWID pre-Escudo (2012-2015) and post-Escudo (2016-2018). We estimated population impact using a dynamic model of HIV transmission and fatal overdose among PWID, with incarceration associated with syringe sharing and fatal overdose. The model was calibrated to HIV and incarceration patterns in Tijuana. We compared a scenario with Escudo (observed incarceration declines for 2 years post-Escudo among PWID from the segmented regression) compared to a counterfactual of no Escudo (continuation of stable pre-Escudo trends), assessing cost-effectiveness from a societal perspective. Using a 2-year intervention effect and 50-year time horizon, we determined the incremental cost-effectiveness ratio (ICER, in 2022 USD per disability-adjusted life years [DALYs] averted).FindingsCompared to stable incarceration pre-Escudo, for every three-month interval in the post-Escudo period, recent incarceration among PWID declined by 21% (adjusted relative risk = 0.79, 95% CI: 0.68-0.91). Based on these declines, we estimated 1.7% [95% interval: 0.7%-3.5%] of new HIV cases and 12.2% [4.5%-26.6%] of fatal overdoses among PWID were averted in the 2 years post-Escudo, compared to a counterfactual without Escudo. Escudo was cost-effective (ICER USD 3746/DALY averted compared to a willingness-to-pay threshold of $4842-$13,557).InterpretationEscudo is a cost-effective structural intervention that aligned policing practices and human-rights-based public health practices, which could serve as a model for other settings where policing constitutes structural HIV and overdose risk among PWID.FundingNational Institute on Drug Abuse, UC MEXUS CONACyT, and the San Diego Center for AIDS Research (SD CFAR).

BACKGROUND: The overdose crisis driven by synthetic opioids continues to escalate in the USA. We evaluated the efficacy of multiple manufacturing lots of a fentanyl test strip (FTS) to detect fentanyl and fentanyl analogs and assessed cross-reactivity with possible interferences. METHODS: Drug standards were dissolved in water in a laboratory setting and serially diluted. Drug dilutions were tested using five different manufacturing lots of BTNX Rapid Response (20 ng/mL cutoff) lateral flow chromatographic immunoassay strips to assess lot-to-lot variability for FTS sensitivity and cross-reactivity for the analytes of interest. RESULTS: All five manufacturing lots cross-reacted with fentanyl and eleven fentanyl analogs. Diphenhydramine, lidocaine, MDMA, and methamphetamine were found to cause false positives with the strips. There was notable lot-to-lot variability in the sensitivity of the strips for fentanyl, fentanyl analogs, and known interferences. DISCUSSION: FTS remains an important overdose prevention tool, but lot-to-lot variability in performance complicates robust instructions that balance the prevention of false positives and false negatives. Continued lot-to-lot performance assessment is recommended to ensure health education for FTS remains accurate. More sophisticated drug checking technologies and services are needed in the community landscape to augment personal FTS use to facilitate informed consumption and overdose risk mitigation.

INTRODUCTION: The opioid overdose crisis in the United States has become a significant national emergency. Buprenorphine, a primary medication for individuals coping with opioid use disorder (OUD), presents promising pharmacokinetic properties for use in primary care settings, and is often delivered as a take-home therapy. The COVID-19 pandemic exacerbated the scarcity of access to buprenorphine, leading to dire consequences for those with OUD. Most existing studies, primarily focused on the immediate aftermath of the COVID-19 outbreak, highlight the challenges in accessing medications for opioid use disorder (MOUDs), particularly buprenorphine. However, these studies only cover a relatively short timeframe. METHODS: To bridge this research gap, in our study, we utilized 33 months of Californias prescription drug monitoring program (PDMP) data to provide insights into real-world buprenorphine dispensing trends since the onset of the pandemic from 2018 to 2021, focusing on outcomes such as patient counts, prescription volumes, prescriber involvement, days supply, and dosage. Statistical analysis employed interrupted time series analysis to measure changes in trends before and during the pandemic. RESULTS: We found no significant impact on patient counts or prescription volumes during the pandemic, although it impeded the upward trajectory of prescriber numbers that was evident prior to the onset of the pandemic. An immediate increase in days supply per prescription was observed post-pandemic. CONCLUSION: Our findings differ in comparison to previous data regarding the raw monthly count of patients and prescriptions. The analysis encompassed uninsured patients, offering a comprehensive perspective on buprenorphine prescribing in California. Our studys insights contribute to understanding the impact of COVID-19 on buprenorphine access, emphasizing the need for policy adjustments.

In 2020, three crises coalesced to transform the clinical care landscape of addiction medicine in the United States (US). The opioid overdose crisis (crisis #1), which had been contributing to excess US mortality for over two decades, worsened during the COVID-19 pandemic (crisis #2). The racial reckoning (crisis #3) spurred by the murder of George Floyd at the hands of police impacted clinical care, especially in safety net clinical settings where the majority of people targeted by police violence, and other forms of structural violence, receive healthcare to mend both physical and psychological wounds. Collectively, the three crises changed how providers and patients viewed their experiences of clinical surveillance and altered their relationships to the violence of US healthcare. Drawing from two different research studies conducted during the years preceding and during the COVID-19 pandemic (2017-2022) with low income, safety net patients at risk for opioid overdose and their care providers, I analyze the relationship between surveillance and violence in light of changes wrought by these three intersecting health and social crises. I suggest that shifting perceptions about surveillance and violence contributed to clinical care innovations that offer greater patient autonomy and transform critical components of addiction medicine care practice.

BackgroundThe growing availability of big data spontaneously generated by social media platforms allows us to leverage natural language processing (NLP) methods as valuable tools to understand the opioid crisis.ObjectiveWe aimed to understand how NLP has been applied to Reddit (Reddit Inc) data to study opioid use.MethodsWe systematically searched for peer-reviewed studies and conference abstracts in PubMed, Scopus, PsycINFO, ACL Anthology, IEEE Xplore, and Association for Computing Machinery data repositories up to July 19, 2022. Inclusion criteria were studies investigating opioid use, using NLP techniques to analyze the textual corpora, and using Reddit as the social media data source. We were specifically interested in mapping studies' overarching goals and findings, methodologies and software used, and main limitations.ResultsIn total, 30 studies were included, which were classified into 4 nonmutually exclusive overarching goal categories: methodological (n=6, 20% studies), infodemiology (n=22, 73% studies), infoveillance (n=7, 23% studies), and pharmacovigilance (n=3, 10% studies). NLP methods were used to identify content relevant to opioid use among vast quantities of textual data, to establish potential relationships between opioid use patterns or profiles and contextual factors or comorbidities, and to anticipate individuals' transitions between different opioid-related subreddits, likely revealing progression through opioid use stages. Most studies used an embedding technique (12/30, 40%), prediction or classification approach (12/30, 40%), topic modeling (9/30, 30%), and sentiment analysis (6/30, 20%). The most frequently used programming languages were Python (20/30, 67%) and R (2/30, 7%). Among the studies that reported limitations (20/30, 67%), the most cited was the uncertainty regarding whether redditors participating in these forums were representative of people who use opioids (8/20, 40%). The papers were very recent (28/30, 93%), from 2019 to 2022, with authors from a range of disciplines.ConclusionsThis scoping review identified a wide variety of NLP techniques and applications used to support surveillance and social media interventions addressing the opioid crisis. Despite the clear potential of these methods to enable the identification of opioid-relevant content in Reddit and its analysis, there are limits to the degree of interpretive meaning that they can provide. Moreover, we identified the need for standardized ethical guidelines to govern the use of Reddit data to safeguard the anonymity and privacy of people using these forums.

IntroductionOpioid overdose deaths are increasing rapidly in the United States. Medications for opioid use disorder (MOUD) are effective and can be delivered in primary care, but uptake has been limited in rural communities. Referral to and coordination with an external telemedicine (TM) vendor by rural primary care clinics for MOUD (TM-MOUD) may increase MOUD access for rural patients, but we know little about perspectives on this model among key stakeholders. As part of a TM-MOUD feasibility study, we explored TM-MOUD acceptability and feasibility among personnel and patients from seven rural primary care clinics and a TM-MOUD vendor.MethodsWe conducted virtual interviews or focus groups with clinic administrators (n = 7 interviews), clinic primary care and behavioral health providers (8 groups, n = 30), other clinic staff (9 groups, n = 37), patients receiving MOUD (n = 16 interviews), TM-MOUD vendor staff (n = 4 interviews), and vendor-affiliated behavioral health and prescribing providers (n = 17 interviews). We asked about experiences with and acceptability of MOUD (primarily buprenorphine) and telemedicine (TM) and a TM-MOUD referral and coordination model. We conducted content analysis to identify themes and participants quantitatively rated acceptability of TM-MOUD elements on a 4-item scale.ResultsPerceived benefits of vendor-based TM-MOUD included reduced logistical barriers, more privacy and less stigma, and access to services not available locally (e.g., counseling, pain management). Barriers included lack of internet or poor connectivity in patients' homes, limited communication and trust between TM-MOUD and clinic providers, and questions about the value to the clinic of TM-MOUD referral to external vendor. Acceptability ratings for TM-MOUD were generally high; they were lowest among frontline staff.ConclusionsRural primary care clinic personnel, TM-MOUD vendor personnel, and patients generally perceived referral from primary care to a TM-MOUD vendor to hold potential for increasing access to MOUD in rural communities. Increasing TM-MOUD uptake requires buy-in and understanding among staff of the TM-MOUD workflow, TM services offered, requirements for patients, advantages over clinic-based or TM services from clinic providers, and identification of appropriate patients. Poverty, along with patient hesitation to initiate treatment, creates substantial barriers to MOUD treatment generally; insufficient internet availability creates a substantial barrier to TM-MOUD.

BackgroundThis study evaluated the real-world impact of acupuncture on analgesics and healthcare resource utilization among breast cancer survivors.MethodsFrom a United States (US) commercial claims database (25% random sample of IQVIA PharMetrics® Plus for Academics), we selected 18-63 years old malignant breast cancer survivors experiencing pain and ≥ 1 year removed from cancer diagnosis. Using the difference-in-difference technique, annualized changes in analgesics [prevalence, rates of short-term (

BackgroundXylazine is an increasingly common adulterant in the North American unregulated drug supply that is associated with adverse health outcomes (e.g., skin infections, overdose). However, there are significant knowledge gaps regarding how xylazine was initially identified and how syringe services program (SSP) staff and clients (people who use drugs) responded to its emergence.MethodsFrom June-July 2023, we conducted qualitative interviews with medical (e.g., clinicians) and frontline SSP staff (e.g., outreach workers) and adult clients with a history of injection drug use at a Miami-based SSP. Inductive memos identified emergent codes; thematic analysis involving team consensus established final themes.ResultsFrom interviews with SSP staff (n = 8) and clients (n = 17), xylazine emergence was identified at different times, in various ways. Initially, during summer 2022, clients identified a "tranquilizer-like substance" that worsened sedation and withdrawal and caused wounds. SSP medical staff later identified this adulterant as xylazine by treating new medical cases and through diverse information-sharing networks that included professional societies and news sources; however, frontline SSP staff and clients needed additional educational resources about xylazine and its side effects. With limited guidance on how to reduce harm from xylazine, SSP clients altered their drug consumption routes, reduced drug use, and relied on peers' experiences with the drug supply to protect themselves. Some individuals also reported preferring xylazine-adulterated opioids and increasing their drug use, including the use of stimulants to avoid over sedation.ConclusionsXylazine's emergence characterizes the current era of unprecedented shifts in the unregulated drug supply. We found that xylazine spurred important behavioral changes among people who use drugs (e.g., transitioning from injecting to smoking). Incorporating these experiences into early drug warning surveillance systems and scaling up drug-checking services and safer smoking supply distribution could help mitigate significant health harms caused by xylazine and other emergent adulterants.

BACKGROUND: Anatomical location-dependent differences in transdermal opioid penetration are well described in human patients. Although this has been investigated in horses with fentanyl, there is no literature available on location-dependent plasma buprenorphine concentrations when administered as a transdermal matrix-type patch. OBJECTIVE: This study aims to compare the plasma concentrations achieved from the matrix-type transdermal buprenorphine patches placed at different anatomical sites (metacarpus, gaskin, and ventral tail base) in healthy adult horses. STUDY DESIGN: This is a randomized experimental study with a Latin square design. METHODS: Six adult horses were given each of three treatments with a minimum 10-day washout period. For each treatment, two 20 μg h-1 matrix-type buprenorphine patches were applied to the ventral aspect of the tail base (TailTDP), metacarpus region (MetacarpusTDP), or gaskin region (GaskinTDP). Whole blood samples (for determination of buprenorphine concentration) and physiological variables were collected before (0 h) and at 0.5, 2, 4, 6, 8, 10, 12, 16, 24, 32, 48, 56, 72, 96 and 120 h after patches were applied. The patches were removed 96 h following placement and were analyzed for residual buprenorphine content. Buprenorphine concentrations were measured in plasma by LC-MS/MS. A mixed-effects model was used to analyze the physiological variables. RESULTS: Between the three treatment groups, there was no change in physiological variables across timepoints as compared to baseline and when compared to each other in a single horse and between horses (p > 0.3). When comparing all three locations, the buprenorphine uptake was observed to be more consistent with respect to measurable plasma concentrations >0.1 ng ml-1 when applied to the ventral aspect of the tail base. In the TailTDP group, the mean plasma buprenorphine concentrations were >0.1 ng ml-1 from 2 to 32 h. The highest group mean was 0.25 ng ml-1 noted at 4 h. CONCLUSIONS: The metacarpal and gaskin regions presented more erratic and inconsistent buprenorphine uptake and plasma concentrations as compared to the ventral aspect of the tail base. Further research must be directed at investigating the optimal dose, achievable duration of analgesia, change in measurable plasma concentrations, and behavioral and systemic effects.

INTRODUCTION: An increased incidence of maternal opioid use disorder (OUD) and neonatal abstinence syndrome (NAS) has prompted recommendations supporting a dyadic approach to care for birthing persons and their infants. However, there are no consensus guidelines outlining how the dyad is clinically defined. METHODS: To examine how the opioid-exposed birthing person-infant dyad has been defined for purposes of data collection and research, a literature review applying the RAND/UCLA Appropriateness Method was conducted. RESULTS: The search yielded 320 abstracts, with 110 articles identified as having a dyadic focus. While no articles included a specific definition for the dyad, 33 (30%) contained a descriptive reference to the birthing person-infant dyad. Thematic analysis revealed eight recurring elements characteristic of the dyad: (1) engagement, (2) communication, (3) bonding, (4) attachment, (5) mutual responsiveness, (6) reciprocity, (7) synchrony, and (8) attunement. Integrating these elements revealed the interactional relationship between the opioid-exposed birthing person and infant as the foundational principle that defines the dyad. DISCUSSION: This definition shifts the focus of the opioid-exposed dyad from two individual patient populations to an interactional relationship that has broad applicability for clinical use, public health data collection, and research considerations.

ObjectiveMany persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood.Method and participantsStudy participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time.ResultsHPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14.ConclusionsWorsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation.

BackgroundMortality related to opioid overdose in the U.S. has risen sharply in the past decade. In California, opioid overdose death rates more than tripled from 2018 to 2021, and deaths from synthetic opioids such as fentanyl increased more than seven times in those three years alone. Heightened attention to this crisis has attracted funding and programming opportunities for prevention and harm reduction interventions. Drug checking services offer people who use drugs the opportunity to test the chemical content of their own supply, but are not widely used in North America. We report on qualitative data from providers and clients of harm reduction and drug checking services, to explore how these services are used, experienced, and considered.MethodsWe conducted in-depth semi-structured key informant interviews across two samples of drug checking stakeholders: "clients" (individuals who use drugs and receive harm reduction services) and "providers" (subject matter experts and those providing clinical and harm reduction services to people who use drugs). Provider interviews were conducted via Zoom from June-November, 2022. Client interviews were conducted in person in San Francisco over a one-week period in November 2022. Data were analyzed following the tenets of thematic analysis.ResultsWe found that the value of drug checking includes but extends well beyond overdose prevention. Participants discussed ways that drug checking can fill a regulatory vacuum, serve as a tool of informal market regulation at the community level, and empower public health surveillance systems and clinical response. We present our findings within three key themes: (1) the role of drug checking in overdose prevention; (2) benefits to the overall agency, health, and wellbeing of people who use drugs; and (3) impacts of drug checking services at the community and systems levels.ConclusionThis study contributes to growing evidence of the effectiveness of drug checking services in mitigating risks associated with substance use, including overdose, through enabling people who use and sell drugs to test their own supply. It further contributes to discussions around the utility of drug checking and harm reduction, in order to inform legislation and funding allocation.

BACKGROUND: Matrix type transdermal buprenorphine patches have not been investigated in horses and may provide an effective means of providing continuous pain control for extended period and eliminating venous catheterization. OBJECTIVE: Assessment of the physiological variables (heart rate, respiratory rate, body temperature) and thermal nociceptive threshold testing, and describing the pharmacokinetic profile of transdermal buprenorphine matrix-type patch (20 μg h-1 and 40 μg h-1 dosing) in healthy adult horses. STUDY DESIGN: Randomised experimental study with a Latin-square design. METHODS: Six adult healthy horses received each of the three treatments with a minimum 10 day washout period. BUP0 horses did not receive a patch (control). BUP20 horses received one patch (20 μg h-1) applied on the ventral aspect of the tail base resulting in a dose of 0.03-0.04 μg kg-1 h-1. BUP40 horses received two patches placed alongside each other (40 μg h-1) on the tail base resulting in a dose of 0.07-0.09 μg kg-1 h-1. Whole blood samples (for determination of buprenorphine concentration), physiological variables and thermal threshold testing were performed before (0 h) and at 2, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, and 96 h after patch application. The patches were removed 72 h following placement and were analyzed for residual buprenorphine content. RESULTS: Between the three groups, there was no change in physiological variables across timepoints as compared to baseline (p > 0.1). With the higher dose, there was a significant increase in thermal thresholds from baseline values from 2 h until 48 h and these values were significantly higher than the group receiving the lower patch dose for multiple timepoints up to 40 h. 40 μg h-1 patch led to consistent measurable plasma concentrations starting at 2 h up to 96 h, with the mean plasma concentrations of > 0.1 ng/ml from 4 h to 40 h. CONCLUSIONS: 20 μg h-1 and 40 μg h-1 patch doses were well tolerated by all horses. At higher dose, plasma buprenorphine concentrations were more consistently measurable and blunted thermal thresholds for 48 h vs. 32 h with 20 μg h-1 dosing as compared to control.

BackgroundPersons with opioid use disorders who inject drugs (PWID) in the United States (US) face multiple and intertwining health risks. These include interference with consistent access, linkage, and retention to health care including medication for opioid use disorder (MOUD), HIV prevention using pre-exposure prophylaxis (PrEP), and testing and treatment for sexually transmitted infections (STIs). Most services, when available, including those that address substance misuse, HIV prevention, and STIs, are often provided in multiple locations that may be difficult to access, which further challenges sustained health for PWID. HPTN 094 (INTEGRA) is a study designed to test the efficacy of an integrated, "whole-person" strategy that provides integrated HIV prevention including antiretroviral therapy (ART), PrEP, MOUD, and STI testing and treatment from a mobile health delivery unit ("mobile unit") with peer navigation compared to peer navigation alone to access these services at brick and mortar locations.MethodsHPTN 094 (INTEGRA) is a two-arm, randomized controlled trial in 5 US cities where approximately 400 PWID without HIV are assigned either to an experimental condition that delivers 26 weeks of "one-stop" integrated health services combined with peer navigation and delivered in a mobile unit or to an active control condition using peer navigation only for 26 weeks to the same set of services delivered in community settings. The primary outcomes include being alive and retained in MOUD and PrEP at 26 weeks post-randomization. Secondary outcomes measure the durability of intervention effects at 52 weeks following randomization.DiscussionThis trial responds to a need for evidence on using a "whole-person" strategy for delivering integrated HIV prevention and substance use treatment, while testing the use of a mobile unit that meets out-of-treatment PWID wherever they might be and links them to care systems and/or harm reduction services. Findings will be important in guiding policy for engaging PWID in HIV prevention or care, substance use treatment, and STI testing and treatment by addressing the intertwined epidemics of addiction and HIV among those who have many physical and geographic barriers to access care.Trial registrationClinicalTrials.gov NCT04804072 . Registered on 18 March 2021.

OBJECTIVE: To examine variables associated with engagement in (1) integrative health and medicine (IHM) and (2) nonpharmacologic modalities rather than opioids among United States adults with chronic pain. METHODS: Using the 2019 National Health Interview Survey, we examined sociodemographic, pain, and mental health predictors of (1) the sum of IHM modalities (ie, chiropractic care, yoga/Tai Chi, massage, or meditation/guided imagery) used to manage pain and (2) exclusive engagement in nonpharmacologic pain management modalities (ie, IHM, a chronic pain self-management program, support groups, or physical, rehabilitative, occupational, or talk therapy) or opioids in the past 3 months. RESULTS: Metropolitan residency, higher family income, higher education levels, increased number of pain locations, and increased frequency of pain limiting life/work activities were associated with increased odds of IHM engagement. Older age, male sex, non-Hispanic Black/African American race/ethnicity, and daily opioid use were associated with decreased odds of IHM engagement. Older age, male sex, and increased depressive symptoms were associated with decreases in the count of IHM modalities used to manage pain. Metropolitan residency, higher family income, and higher education levels were associated with increased odds of exclusive nonpharmacologic modality engagement. Older age and increasing frequency of pain limiting life/work activities were associated with decreased odds of exclusive nonpharmacologic modality engagement. CONCLUSIONS: We identified several contrasts between factors prevalent among individuals with chronic pain and factors associated with engagement in nonpharmacologic and IHM modalities. These results support efforts to address barriers to accessing these modalities among subpopulations of adults with chronic pain (eg, older adults, individuals identifying as Black/African American, rural residents, and those with lower levels of education and income).

ObjectivesThe purpose of this study was to evaluate the impact of pharmacist-driven naloxone training of resident physicians as part of discharge prescribing from an inpatient psychiatric unit.MethodsThis is a prospective pilot study in which psychiatric resident physicians (N = 21) were educated on naloxone administration, prescribing, and counseling. A ten-question survey was designed and delivered immediately pre- and post-training to assess resident knowledge of and comfort with naloxone prescribing. Respondents were asked to rate ten statements on a scale from 1 to 5, with 1 corresponding to "strongly disagree" and 5 corresponding to "strongly agree." The primary objective was to evaluate the impact of training on prescriber knowledge and attitudes using the designed questionnaire. The secondary objective was to assess the difference in naloxone prescribing pre- and post-training implementation. Descriptive statistics and paired t-tests were conducted to assess statistical significance.ResultsPrior to training, 11 resident physicians (approximately 50%) agreed or strongly agreed that they felt knowledgeable about naloxone and approximately 70% (n = 15) felt confident identifying patients who would benefit from naloxone at discharge. Only 10% of resident physicians (n = 2) felt comfortable counseling patients on and administering naloxone during an overdose pre-training compared to 100% after training. Thirty-seven patients were discharged and counseled on naloxone use during the study period.ConclusionPharmacist-driven naloxone training significantly increased physician knowledge and comfort prescribing naloxone and resulted in an increase in naloxone prescriptions upon discharge from an inpatient psychiatric unit.

Background: As the opioid epidemic continues to have a major negative impact across the US, community pharmacies have come under scrutiny from legal systems attempting to hold them accountable for their role in over dispensing and lack of patient intervention. While the most available tool for monitoring patients' opioid use is Prescription Drug Monitoring Programs (PDMP), these do not provide pharmacists with actionable information and decision support. Our study addresses this gap through three objectives: [1] incorporate validated opioid risk metric thresholds into a PDMP platform to create the Opioid Risk Reduction Clinical Decision Support (ORRCDS) tool; [2] assess ORRCDS' ability to reduce patient opioid risk; [3] assess ORRCDS' sustainability and viability for broader dissemination in community pharmacy. Methods: For objective 1, our team is partnering with leadership from the largest US PDMP organization and a top-five pharmacy chain to implement ORRCDS into the pharmacy chain's workflow following the Guideline Implementation with Decision Support (GUIDES) framework. For objective 2, our team will conduct a type-1 implementation mixed methods study using a 2-arm parallel group clustered randomized design. We anticipate enrolling ~ 6,600 patients with moderate and high opioid use risk during the 6-month enrollment phase across 80 pharmacies. This sample size will provide 96.3% power to detect a 5% or greater difference in responder rate between the intervention and control arm. Responders are patients with moderate-risk at baseline who reduce to low-risk or those with high-risk at baseline who reduce to moderate or low-risk at 180 days post last intervention. To accomplish objective 3, we will use the Consolidated Framework for Implementation Research (CFIR) to develop and execute cross-sectional qualitative interviews with pharmacists (n = 15), pharmacy leaders (n = 15), and PDMP leaders (n = 15) regarding long term adoption and sustainability of the ORRCDS tool. Conclusions: A PDMP tool that addresses moderate- and high-risk opioid use is not available in community pharmacy. This study will implement ORRCDS in a large retail pharmacy chain that will include additional screening and guidance to pharmacy staff to address risky opioid medication use. Our results will make critical advancements for protecting patient health and addressing the opioid epidemic. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Given the high prevalence of both mental health and acute pain conditions during pregnancy, use of antidepressants and analgesic opioids in this period is widespread. Whether single and combined use of these medications is associated with spontaneous preterm birth (sPTB) remains unclear.To investigate the association between maternal prescription opioid and antidepressant medication exposures for co‐occurring mental health and acute pain management, either alone or in combination, and sPTB.We used Tennessee Medicaid data (2007–2019) linked to birth certificates to conduct a nested case–control study among 15‐ to 44‐year‐old pregnant patients with singleton live births. Cases were identified as spontaneous live births between 24 and <37 gestational weeks using a validated birth certificate‐based algorithm. We selected up to 10 controls per case, matched on estimated pregnancy start date and other factors. We identified analgesic opioid and antidepressant pharmacy fills to define medication exposures in the 60 days before index date (case delivery date) and categorised them as unexposed, opioid‐only, antidepressant‐only and combined exposure. We estimated odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression, adjusting for confounders. We assessed the additive interaction between opioids and antidepressants by estimating relative excess risk due to interaction.We identified 25,406 eligible cases of sPTB and 225,771 matched controls. Opioid‐only and combined exposures were associated with higher odds of sPTB relative to unexposed (adjusted OR 1.29, 95% CI 1.23, 1.35 and 1.22, 95% CI 1.06, 1.40, respectively), while antidepressant‐only exposure was not (1.04, 95% CI 0.96, 1.12). No additive interaction was identified for combined exposure.Exposure to prescription opioids during pregnancy, but not antidepressants, was associated with increased relative odds of sPTB. Co‐exposure to opioids and antidepressants did not elevate the odds of sPTB above what we observed for opioid‐only exposure. [ABSTRACT FROM AUTHOR]

Background: In clinical practice, family medication history is not routinely assessed as part of a patient's family health history (FHH). The information is self-reported and can depend on the individual's subjective perception. To illustrate how pharmacogenetic (PGx) testing results could be used to validate self-reported family medication history on drug-related problems (DRP), as well as to inform medication-related decisions, we herein present a case involving ten members of the same family. Case Presentation: Prior to a planned surgery, a preemptive PGx panel test was performed for a nine-year-old girl due to self-reported family medication history. The PGx panel test was also performed for her three siblings, parents, and grandparents. The focus was directed to the paternal grandmother, as she reported DRP from the hypnotic agent propofol, and to the maternal grandmother, as she described DRP after the administration of codeine and tramadol. A commercial PGx panel test of 100 variations in 30 different genes was conducted and analyzed focusing on genetic variants in cytochrome P450 enzyme 2B6 (CYP2B6), and CYP2D6 as they are involved in the biotransformation of propofol and the bioactivation of codeine and tramadol, respectively. The girl was identified as (1) CYP2B6 intermediate metabolizer (IM) with reduced enzyme activity and (2) CYP2D6 poor metabolizer (PM) with no enzyme activity. Regarding the planned surgery, it was recommended (1) to carefully titrate propofol dosage with increased monitoring of potential DRP and (2) to avoid opioids whose activation is mediated by CYP2D6 (e.g. codeine and tramadol). Further PGx testing revealed (1) the paternal grandmother as CYP2B6 normal metabolizer (NM) and (2) the maternal grandmother as CYP2D6 NM. Conclusion: The original trigger for PGx testing was the self-reported, conspicuous family medication history of DRP reported by the grandmothers. However, the girl's genotype predicted phenotypes of CYP2B6 IM and CYP2D6 PM, differed from the grandmothers'. With this exemplary case, we propose that hereditary concerns based on self-reported information on DRP should be verified by a PGx panel test, when the respective drug exhibits a PGx association. Also, the girl's PGx testing results provided important medication recommendations, which were considered perioperatively by the anesthetist suggesting to use PGx testing results preemptively to inform medication-related decisions. [ABSTRACT FROM AUTHOR]

Study Design. Prospective cohort using routinely collected health data. Objective. To compare opioid use based on surgery intensity (low or high). Summary of Background Data. Many factors influence an individual's experience of pain. The extent to which postsurgical opioid use is influenced by the severity of spine surgery is unknown. Methods. The participants were individuals undergoing spine surgery in a large military hospital. Procedures were categorized as low intensity (eg, microdiscectomy and laminectomy) and high intensity (eg, fusion and arthroplasty). The Surgical Scheduling System and Military Health System Data Repository were queried for healthcare utilization the 1 year before and after surgery. We compared opioid use after surgery between groups, adjusting for prior opioid use and surgical complications. Results. A total of 342 individuals met the inclusion criteria, with mean age 45.4 years (SD 10.9), and 33.0% were women. Of these, 221 (64.6%) underwent a low-intensity procedure and 121 (35.4%) underwent a high-intensity procedure. Mean postoperative opioid prescription fills were greater in the high- versus low-intensity group (9.0 vs. 5.7; P < 0.001), as were the mean total days' supply (158.9 vs. 81.8; P < 0.001). Median morphine milligram equivalents (MMEs) were not significantly different (40.2 vs. 42.7; P = 0.287). Of the cohort, 26.3% were chronic opioid users after surgery. Adjusted rates of long-term opioid use were not different between groups when only accounting for prior opioid use but significantly higher for the high-intensity group when adjusting for surgical complications (OR = 2.08; 95% CI 1.09-3.97). Of the entire cohort, 52.5% was still filling opioid prescriptions after 6 months. Conclusions. Higher-intensity procedures were associated with greater postoperative opioid use than lower-intensity procedures. Chronic opioid use was not significantly different between surgical intensity groups when considering only prior opioid use. Chronic opioid use was significantly higher among higher intensity procedures when accounting for surgical complications. The presence of surgical complications is a stronger predictor of postsurgical long-term opioid use in high-intensity surgeries than history of opioid use alone. Level of Evidence. Level III. [ABSTRACT FROM AUTHOR]

The prefrontal cortex is critical for decision-making across species, with its activity linked to choosing between options. Drift diffusion models (DDMs) are commonly employed to understand the neural computations underlying this behavior. Studies exploring the specific roles of regions of the rodent prefrontal cortex in controlling the decision process are limited. This study explored the role of the prelimbic cortex (PLC) in decision-making using a two-alternative forced-choice task. Rats first learned to report the location of a lateralized visual stimulus. The brightness of the stimulus indicated its reward value. Then, the rats learned to make choices between pairs of stimuli. Sex differences in learning were observed, with females responding faster and more selectively to high-value stimuli than males. DDM analysis found that males had decreased decision thresholds during initial learning, whereas females maintained a consistently higher drift rate. Pharmacological manipulations revealed that PLC inactivation reduced the decision threshold for all rats, indicating that less information was needed to make a choice in the absence of normal PLC processing. μ-Opioid receptor stimulation of the PLC had the opposite effect, raising the decision threshold and reducing bias in the decision process toward high-value stimuli. These effects were observed without any impact on the rats' choice preferences. Our findings suggest that PLC has an inhibitory role in the decision process and regulates the amount of evidence that is required tomake a choice. That is, PLC activity controls "when," but not "how," to act. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions This study evaluated the 10‐year consumption and economic patterns of classical analgesics, adjuvants and opioids in Portugal (2012‐2022), and conducted a comparative analysis between Portugal, Spain and Denmark to explore the consumption patterns among these countries for 2022.Data on sales and national health service (NHS) costs were obtained from the Portuguese National Authority of Medicines and Health Products. Sales data were converted to defined daily dose (DDD) per 1000 inhabitants per day according to the Anatomical Therapeutic Chemical (ATC) classification/DDD methodology, while comparisons between Spain and Denmark were evaluated with the chi‐square test, when appropriate.The findings reveal that classical analgesics use in Portugal remained stable during the period 2012‐2022, with ibuprofen being the most consumed. Adjuvants, specifically gabapentinoids, experienced an 84% increase in use, primarily attributed to pregabalin. Weak opioids, led by tramadol, witnessed a 117% rise in use, while strong opioid use, led by tapentadol, increased by 618%. Portugal presented the lowest overall opioid consumption when compared to Denmark and Spain in 2022. Economic trends indicated a heightened NHS expenditure on analgesics, primarily driven by increased opioid use. Notwithstanding, there was no significant burden on relative expenditure over the 10‐year period.Portugal presented a major increase in both weak and strong opioid prescriptions, aligning with the trends for Spain and Denmark. The development and approval of generic medicines and vigilant market monitoring are imperative strategies for managing the escalated costs resulting from heightened consumption, particularly concerning opioids. [ABSTRACT FROM AUTHOR]

Postoperative pain management has consistently been a critical topic in the medical field, with patient-controlled intravenous analgesia (PCIA) being one of the most commonly utilized methods for postoperative analgesia. Currently, opioids remain the primary choice for PCIA in clinical practice. However, in recent years, an increasing number of studies have explored analgesic strategies aimed at reducing or eliminating the use of opioids in PCIA to mitigate the associated side effects and dependence. This article systematically reviews the progress of research on opioid-free analgesic strategies in PCIA through a comprehensive analysis of relevant literature. [ABSTRACT FROM AUTHOR]

Background: With the broad recognition of increased U.S. opioid overdose (OOD) rates between 2020 and 2021, media, public health, and healthcare organizations have raised significant concerns over the emergence of a simultaneous COVID-19-opioid "twindemic." Research in this area has explored the possible relationships between negative externalities associated with the pandemic and/or COVID-19 public health interventions and increased risks for opioid use and overdose alongside diminished outcomes following OOD events. Methods: The study offers a summative content analysis of Emergency Medical Service (EMS) responses to opioid overdose (OOD) events before and after the institution of COVID-19 restrictions. Specifically, the study investigates three Texas counties to evaluate changing OOD rates, patient demographics, and OOD event features. The analysis uses a previously validated machine learning tool to identify OOD events and conducted a summative content analysis of identified events. Results: A total of 1170 OOD responses events were identified in the three-county dataset. This includes 874 in Travis County, 242 in El Paso County, and 54 in Williamson County. Each county experienced modest changes in EMS calls for OOD events between the pre-restriction and public health restriction time periods. Travis County's OOD event rate declined from 454 to 420. El Paso's increased from 103 to 139, and Williamson County's increased from 23 to 31. These changes were not significant as percentage of possible OOD events or based on by-month comparison. The notable differences between pre-restriction and public health restriction periods were significant decreases in documentation of patient race/ethnicity in Travis and Williamson Counties, significant decreases in housing insecurity and use alone in Travis County, and an increase in transport refusal after treatment in the field in Travis County. Conclusions: Ultimately the results presented here problematize prevailing analyses about the so-called opioid-COVID-19 "twindemic." The data further support emerging trends about substantial geographic variation and show some ways that COVID-19 mitigation measures may have improved conditions for some populations, particularly in terms of housing security. Additionally, the results presented here indicate that further attention should be paid to the effects of first responder stress on documentation quality. [ABSTRACT FROM AUTHOR]

Background: The U.S. opioid crisis, resulting in nearly 500,000 deaths from 1999 to 2019, has been exacerbated by persistent stigma, which hinders treatment and recovery efforts. This stigma, whether structural, social, or self-imposed, challenges overdose prevention and recovery. Our study aimed to assess and compare levels of stigma towards opioid users among rural law enforcement officers (LEOs) and community members in Tennessee, highlighting rural community-level attitudes. Methods: Methods involved surveying two groups: LEOs (N=48) and community members (N=393). Utilizing a Likert Scale based on prior research, the survey probed attitudes toward drug use across four stigma domains: dangerousness, blame, social distancing, and fatalism. Analysis employed standardized scoring and ANOVA for evaluating stigma differences by participant characteristics. Results: LEOs (75%) and community members (51.7%) predominantly identify drug users as white, with varied perceptions regarding socioeconomic status and employment. Despite similar perceptions, normalized stigma scores revealed statistical differences between groups across stigma domains. ANOVA found no significant impact of participant type or gender on stigma levels, though race/ethnicity and its interaction with gender suggested potential influences on overall stigma score. Conclusions: Both LEOs and community members in rural Tennessee hold measurable stigma against opioid users, spanning dangerousness, blame, social distancing, and fatalism domains. These insights highlight the need for further research into both professional and public attitudes toward individuals with opioid or other substance use disorders within shared communities. This research should aim to develop specific stigma-reducing interventions that target both providers and community members. Highlights: Explores rural drug-use stigma, comparing officer and community views. Urgency for anti-stigma interventions in rural areas with high overdose incidence. Both officers and the community in rural Tennessee show drug-use stigma across four domains: dangerousness, blame, social distance, and fatalism. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions To offer insights into various salient substance use and addictive behaviours related aspects as applicable to India.We synthesised the published literature on addictive disorders from India. While not a systematic review of all available literature, the synthesis captures relevant themes including salient epidemiological findings, issues related to the prevention and management services targeted at addictive disorders, key observations in the context of the state of addiction science in the country, the policy status and its implications for the country.In general, the prevalence of substance use in India seems to be lower compared with global averages. For opioids, the prevalence rate is higher than the global average. Addiction prevention and treatment options for persons with addictive disorders in India can be best described as ‘diverse’: there is a wide range of services available, which vary across settings. Some models, services and products aimed at prevention and treatment of addictive disorders have been developed in the country. The policy, regulatory framework and programs targeted at addictions are not entirely in sync with the science. India has a substantial body of addiction science research.The addiction landscape in India is complex and evolving. There is a heterogeneity not only across the different themes related to addiction, but also within the themes across different parts of the country. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ‐opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the Tac1 gene and is expressed in neurons regulating breathing, nociception, and locomotion. Tac1‐positive cells also express MORs in brainstem regions mediating opioid‐induced respiratory depression. We determined the role of Tac1‐positive cells in mediating the respiratory effects of opioid drugs.In situ hybridization was used to determine Oprm1 mRNA expression (gene encoding MORs) in Tac1‐positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in Tac1‐positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole‐body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl.Oprm1 mRNA was highly expressed (>80%) in subpopulations of Tac1‐positive cells in the preBötzinger Complex, nucleus tractus solitarius, and Kölliker–Fuse/lateral parabrachial region. Conditionally knocking out MORs in Tac1‐positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in Tac1‐positive cells, whereas locomotor effects induced by fentanyl were preserved.Our findings suggest that Tac1‐positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects. [ABSTRACT FROM AUTHOR]

Dynamic gain control of aversive signals enables adaptive behavioral responses. Although the role of amygdalar circuits in aversive processing is well established, the neural pathway for amplifying aversion remains elusive. Here, we show that the brainstem circuit linking the interpeduncular nucleus (IPN) with the nucleus incertus (NI) amplifies aversion and promotes avoidant behaviors. IPN GABA neurons are activated by aversive stimuli and their predicting cues, with their response intensity closely tracking aversive values. Activating these neurons does not trigger aversive behavior on its own but rather amplifies responses to aversive stimuli, whereas their ablation or inhibition suppresses such responses. Detailed circuit dissection revealed anatomically distinct subgroups within the IPN GABA neuron population, highlighting the NI-projecting subgroup as the modulator of aversiveness related to fear and opioid withdrawal. These findings unveil the IPN-NI circuit as an aversion amplifier and suggest potential targets for interventions against affective disorders and opioid relapse. • IPN GABA neurons encode aversive value • The activity of these neurons amplifies aversive responses • The IPN-NI pathway controls aversive evaluation and fear learning • This pathway strengthens the aversive response to opioid withdrawal Liang et al. demonstrate that the brainstem circuit from the interpeduncular nucleus (IPN) to the nucleus incertus (NI) is an aversion amplifier, offering potential therapeutic targets for affective disorders and opioid relapse prevention. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non‐steroidal anti‐inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma‐aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI‐related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti‐inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage‐gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery. [ABSTRACT FROM AUTHOR]

Background and Purpose: Despite the lack of proven efficacy, opioids historically have been used for the treatment of noncancer back pain. A variety of other effective therapeutic options for pain management are becoming more available over time. In 2016, Oregon implemented a unique and novel policy to improve evidence-based back pain care and promote safer and more effective opioid prescribing through the state's Medicaid program, the Oregon Health Plan. This article examines the ways providers adapted to providing care for patients with back pain in the context of COVID-19 and to better understand the challenges faced by and adaptations made by providers. Methods: We conducted focus groups with clinicians and physical pain treatment modality practitioners (PPTMPs). In total, 129 providers participated in one of six focus groups, including 74 clinicians (54%) and 55 PPTMPs (42%). Reflexive thematic analysis was used to construct themes or units of meaning across data. Results: Focus groups revealed concerns about PPE shortages, telemedicine challenges, communication barriers, and profession-specific responses to COVID-19, which hindered patient care and referrals. Focus groups also highlighted some advantages related to increased insight into patients' lives, which enhanced treatment. Care during COVID-19 has resulted in continued patient interest in telehealth and telemedicine. Conclusion: Optimizing use of these technologies for health conditions, such as back pain, adds to treatment options for patients and gives providers a more holistic understanding of patients' lives, the challenges they may face, and how that impacts their treatment. [ABSTRACT FROM AUTHOR]

One of the primary difficulties in treating burn patients lies in efficacious pain management. Pain arising from thermal injury is amalgamated with a multifaceted composition, encompassing acute, neuropathic, inflammatory, and nociceptive traits. Inadequate management of painful stimuli leads to reduced patients’ “compliance” and can prolong recovery times with a detrimental impact on the patient’s quality of life, given pain’s known association with negative perceptions such as fear and anxiety. Opioids are the preferred drug for treating extensive burns. However, administration must consider several crucial factors such as the patient’s consciousness state, pain perception, associated diseases and complications, and the surgical treatment plan or hospital stay length, which may exceed five months or longer. The efficiency of opioids significantly declines after repeated or constant administration during this period. In addition, administering opioids results in several adverse effects. Therefore, it is advisable to integrate them with additional drug regimens like ketamine, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, pregabalin, anxiolytics, as well as non-pharmacological methods such as psychological support, hypnosis, meditation, aromatherapy, virtual reality, and appropriate rehabilitation. Psychosocial family support plays a crucial role as well. [ABSTRACT FROM AUTHOR]