Gabapentinoids in Ireland 2010 to 2020: An observational study of trends in gabapentinoid prescribing, law enforcement drug seizures and postmortem toxicology.

AIMS: We explored trends in gabapentinoid prescribing, drug seizures and postmortem toxicology using a national pharmacy claims database, law enforcement drug seizures data and a population-based postmortem toxicology database. METHODS: Gabapentinoid prescribing rates per 100 000 eligible population (2010-2020), annual number of drug seizures involving gabapentinoids (2012-2020) and gabapentinoid detection (positive) rates per 100 postmortem toxicology case (2013-2020) were calculated. Negative binomial regression models were used to evaluate longitudinal trends for gabapentin and pregabalin separately. RESULTS: Gabapentin (adjusted rate ratio [RR] 1.06, 95% confidence interval [CI] 1.05-1.06, P < .001) and pregabalin (adjusted RR 1.08, 95% CI 1.08-1.09, P < .001) prescribing increased annually, with higher rates of pregabalin (vs. gabapentin) observed every year. Drug seizures involving pregabalin also increased over time (RR 1.54 95% CI 1.25-1.90, P < .0001). Of the 26 317 postmortem toxicology cases, 0.92% tested positive for gabapentin, and 6.37% for pregabalin. Detection rates increased for both gabapentin (RR 1.28, 95% CI 1.11-1.48, P < .001) and pregabalin (RR 1.13, 95% CI 1.11-1.48, P < .001) between 2013 and 2020. A total of 1901 cases (7.2%) tested positive for heroin/methadone; this sub-group had a higher detection rate for pregabalin (n = 528, 27.8%) and gabapentin (n = 41, 2.2%) over the study period, with a high burden of codetections for pregabalin with benzodiazepines (peaking at 37.3% in 2018), and pregabalin with prescription opioids (peaking at 28.9% in 2020). CONCLUSION: This study raises concerns regarding the wide availability of pregabalin in Ireland, including a growing illicit supply, and the potential for serious harm arising from poly drug use involving pregabalin among people who use heroin or methadone.

Prescription drugs with potential for misuse in Irish prisons: analysis of national prison prescribing trends, by gender and history of opioid use disorder, 2012 to 2020.

BACKGROUND: Pharmacotherapy is essential for the delivery of an equivalent standard of care in prison. Prescribing can be challenging due to the complex health needs of prisoners and the risk of misuse of prescription drugs. This study examines prescribing trends for drugs with potential for misuse (opioids, benzodiazepines, Z-drugs, and gabapentinoids) in Irish prisons and whether trends vary by gender and history of opioid use disorder (OUD). METHODS: A repeated cross-sectional study between 2012 and 2020 using electronic prescribing records from the Irish Prison Services, covering all prisons in the Republic of Ireland was carried out. Prescribing rates per 1,000 prison population were calculated. Negative binomial (presenting adjusted rate ratios (ARR) per year and 95% confidence intervals) and joinpoint regressions were used to estimate time trends adjusting for gender, and for gender specific analyses of prescribing trends over time by history of OUD. RESULTS: A total of 10,371 individuals were prescribed opioid agonist treatment (OAT), opioids, benzodiazepines, Z-drugs or gabapentinoids during study period. History of OUD was higher in women, with a median rate of 597 per 1,000 female prisoners, compared to 161 per 1,000 male prisoners. Prescribing time trends, adjusted for gender, showed prescribing rates decreased over time for prescription opioids (ARR 0.82, 95% CI 0.80-0.85), benzodiazepines (ARR 0.99, 95% CI 0.98-0.999), Z-drugs (ARR 0.90, 95% CI 0.88-0.92), but increased for gabapentinoids (ARR 1.07, 95% CI 1.05-1.08). However, prescribing rates declined for each drug class between 2019 and 2020. Women were significantly more likely to be prescribed benzodiazepines, Z-drugs and gabapentinoids relative to men. Gender-specific analyses found that men with OUD, relative to men without, were more likely to be prescribed benzodiazepines (ARR 1.49, 95% CI 1.41-1.58), Z-drugs (ARR 10.09, 95% CI 9.0-11.31), gabapentinoids (ARR 2.81, 95% CI 2.66-2.97). For women, history of OUD was associated with reduced gabapentinoid prescribing (ARR 0.33, 95% CI 0.28-0.39). CONCLUSIONS: While the observed reductions in prescription opioid, benzodiazepine and Z-drug prescribing is consistent with guidance for safe prescribing in prisons, the increase in gabapentinoid (primarily pregabalin) prescribing and the high level of prescribing to women is concerning. Our findings suggest targeted interventions may be needed to address prescribing in women, and men with a history of OUD.

Impact of changes to the delivery of opioid agonist treatment, introduced during the COVID-19 pandemic, on treatment access and dropout in Ireland: An interrupted time series analysis.

BACKGROUND: Following the emergence of COVID-19, Ireland introduced national contingency guidelines to ensure rapid and uninterrupted access to opioid agonist treatment (OAT). This study aims to assess the impact of changes introduced to the delivery of OAT on the number of people accessing treatment and treatment dropout. METHODS: The study conducted interrupted time series analyses, with separate segmented regression models (March 2019-February 2020) vs (April 2020-March 2021), for (A) total number of people accessing OAT, (B) the number initiating treatment, and (C) the number dropping out of treatment, using data from the National OAT treatment register. The study examined immediate (change in level or intercept: ß2) and long-term impacts (change in slope; i.e., the difference between the slope before and after the intervention: ß3). We performed total and stratified analyses by gender, age group (<40/≥40 years), and OAT drug (methadone or buprenorphine). RESULTS: A total of 10,251 people accessed OAT in Ireland in March 2019 (2 % buprenorphine, n = 178), increasing to 11,441 (4 % buprenorphine, n = 471) in March 2021. The study observed an immediate (ß2 = 504.3, p < 0.001) and continued (ß3 = 31.9, p < 0.001) increase of people accessing treatment following the introduction of the OAT contingency guidelines. In contrast, observed changes in level and slope were not significant for treatment initiation or dropout. The study did find, however, a modest reduction in dropout among those receiving buprenorphine (ß3 = -0.6, p = 0.036). CONCLUSIONS: Changes introduced to the delivery of OAT, under the COVID-19 contingency guidelines, are associated with increased access to OAT in Ireland, with no evidence of increase in treatment dropout. Whether these effects will be maintained over time remains to be seen.

Prescription drugs with potential for misuse: protocol for a multi-indicator analysis of supply, detection and the associated health burden in Ireland between 2010 and 2020.

INTRODUCTION: There is an increasing concern about the misuse of prescription drugs. Misuse refers to the intentional repurposing of prescribed drugs and/or the use of illicitly sourced prescription drugs, which may be counterfeit or contaminated. Drugs with the greatest potential for misuse are prescription opioids, gabapentinoids, benzodiazepines, Z-drugs and stimulants. OBJECTIVE: The aim of this study is to provide a comprehensive analysis of the supply, patterns of use and health burden associated with prescription drugs with potential for misuse (PDPM) in Ireland between 2010 and 2020. Three inter-related studies will be carried out. The first study will describe trends in supply of PDPM using law enforcement drug seizures data and national prescription records from national community and prison settings. The second study aims to estimate trends in the detection of PDPM across multiple early warning systems using national forensic toxicology data. The third study aims to quantify the health burden associated with PDPM nationally, using epidemiological indicators of drug-poisoning deaths, non-fatal intentional drug overdose presentations to hospitals and drug treatment demand. METHODS AND ANALYSIS: A retrospective observational study design, with repeated cross-sectional analyses, using negative binomial regression models or, where appropriate, joinpoint regression. ETHICS AND DISSEMINATION: The study has received approval from the RCSI Ethics Committee (REC202202020). Results will be disseminated in peer-reviewed journals, scientific and drug policy meetings and with key stakeholders via research briefs.

Consensus recommendations for opioid agonist treatment following the introduction of emergency clinical guidelines in Ireland during the COVID-19 pandemic: A national Delphi study.

BACKGROUND: Emergency contingency guidelines for opioid agonist treatment (OAT) were introduced in Ireland in March 2020, to ensure rapid and uninterrupted access to treatment while mitigating COVID-19 risk. The contingency guidelines deviated, across multiple clinical domains, from pre-pandemic clinical guidelines published in 2016. The objectives of this study are to (1) identify changes introduced to OAT clinical guidelines in Ireland during the pandemic; and (2) develop consensus on whether the new recommendations should be retained beyond the pandemic, using a national Delphi consensus methodology. METHODS: Clinical guidance recommendations ('statements') were generated by comparing the newly established contingency guidelines with the national 2016 Clinical Guidelines for OAT. Over two rounds of on-line Delphi testing, a panel of experts (people currently accessing OAT, psychiatrists, general practitioners, community pharmacists, a nurse, a psychologist and support/key workers) independently rated their agreement with each statement and provided comments. Statements with a median score of 4 or 5 and a lower quartile of ≥4 were classified as having reached consensus. RESULTS: Forty-eight panel members were recruited, with a high participation level at Round 2 (90%, n=43). Consensus was achieved for 12 of the 19 statements at Round 1. The 7 remaining statements were revised, with 2 new statements, resulting in 9 statements at Round 2. Four statements reached consensus at Round 2. The final list includes 16 clinical guidance statements; 9 relating to assessment, 3 to OAT drug choice and dosing, 1 to take-away doses, 2 to overdose prevention and 1 to the continuation of e-prescriptions. CONCLUSIONS: A wide range of stakeholders involved in the delivery and receipt of OAT agreed on 16 clinical guidance statements for inclusion in OAT clinical guidelines as we move beyond the pandemic, rather than reverting to pre-pandemic guidelines. The agreed statements relate to facilitating safe access to OAT with minimal waiting time, supporting patient-centred care to promote health and well-being, and preventing drug overdose. Notably, consensus was not achieved for OAT drug dosage and frequency of urine testing during the stabilisation and maintenance phase of care.

Factors associated with early and later dropout from methadone maintenance treatment in specialist addiction clinics: a six-year cohort study using proportional hazards frailty models for recurrent treatment episodes.

BACKGROUND: Retention in methadone maintenance treatment (MMT) is associated with reduced illicit drug use, criminal activity, and mortality; however, many clients move in and out of MMT. This study aims to identify determinants of time to dropout of MMT across multiple treatment episodes in specialist addiction services in Ireland. METHODS: Cohort study of persons attending specialist addiction clinics between 2010 and 2015. MMT episodes were periods of continuous treatment if there were no interruptions to treatment lasting > 7days. Proportional hazards frailty models were used to assess factors associated with time to dropout from recurrent MMT episodes at 3 (90 days) and 12 months (91-365 days). MMT episodes were right- censored at time of death, transfer to prison or primary care, and study end. RESULTS: A total of 2,035 individuals experienced 4,969 MMT episodes, with 2,724 dropout events during the six-year follow-up. Factors associated with dropout at 3 months included low dose methadone (<60 mg/day) (HR = 1.49, 95% CI 1.29-1.73) and previous dropout (HR = 1.65, 95% CI 1.41-1.92). Adherence was protective (HR = 0.91, 95% CI 0.90-0.92). Dropout at 12 months was associated with low dose methadone (HR = 1.44, 95% CI 1.23-1.68), previous dropout (HR = 1.37, 95% CI 1.16-1.61), males (HR 1.26, 95% CI 1.06-1.50), benzodiazepines (HR = 1.22, 95% CI 1.03-1.45) and number of comorbidities (HR = 1.12, 95% CI 1.05-1.20); adherence was protective (HR = 0.86, 95% CI 0.84-0.87). CONCLUSIONS: Clients with a previous history of treatment dropout and those on low dose methadone should be identified as high risk for both early and later dropout. Inversely, adherence to treatment, not missing methadone doses, is protective.

Retention of patients in opioid substitution treatment: A systematic review.

BACKGROUND: Retention in opioid substitution (OST) treatment is associated with substantial reductions in all cause and overdose mortality. This systematic review aims to identify both protective factors supporting retention in OST, and risk factors for treatment dropout. METHODS: A systematic search was performed using MEDLINE, Embase, PsycInfo, CINAHL and Web of Science (January 2001 to October 2019). Randomised controlled trials (RCTs) and observational cohort studies reporting on retention rates and factors associated with retention in OST were included. Factors associated with treatment retention and dropout were explored according to the Maudsley Addiction Profile. A narrative synthesis is provided. RESULTS: 67 studies were included in this review (4 RCTs and 63 observational cohort studies; N = 294,592), all assessing factors associated with retention in OST or treatment dropout. The median retention rate across observational studies was approximately 57% at 12 months, which fell to 38.4% at three years. Studies included were heterogeneous in nature with respect to treatment setting, type of OST, risk factor assessment, ascertainment of outcome and duration of follow-up. While the presence of such methodological heterogeneity makes it difficult to synthesise results, there is limited evidence to support the influence of a number of factors on retention, including age, substance use, OST drug dose, legal issues, and attitudes to OST. CONCLUSIONS: Younger age, substance use particularly cocaine and heroin use, lower doses of methadone, criminal activity/incarceration, and negative attitudes to MMT appear to be associated with reduced retention in OST. A consensus definition of retention is required to allow for comparability across future studies.

Effect of preservation solutions for static cold storage on kidney transplantation outcomes: A National Registry Study.

This study aimed to evaluate how 5 preservation solutions for static cold storage affected kidney transplant outcomes. It included all first single kidney transplants during 2010-2014 from donations after brain death in the French national transplant registry, excluding preemptive transplants and transplants of kidneys preserved with a hypothermic perfusion machine. The effects of each preservation solution on delayed graft function (DGF) and 1-year transplant failure were evaluated with hierarchical multivariable logistic regression models. The study finally included 7640 transplanted kidneys: 3473 (45.5%) preserved with Institut Georges Lopez-1 solution (IGL-1), 773 (10.1%) with University of Wisconsin solution, 731 (9.6%) with Solution de Conservation des Organes et Tissus (SCOT, organ and tissue preservation solution), 2215 (29.0%) with Celsior, and 448 (5.9%) with histidine-tryptophan-ketoglutarate. Primary nonfunction rates did not differ by solution. After adjustment for donor, recipient, and transplant characteristics, the DGF risk was significantly lower with IGL-1 than with all other solutions (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.48-0.64). Conversely, SCOT was associated with a DGF risk significantly higher than the other solutions (OR 2.69, 95% CI 2.21-3.27) and triple that of IGL-1 (OR 3.37, 95% CI 2.72-4.16). One year after transplantation, the transplant failure rate did not differ significantly by preservation solution. The difference between the groups for 1-year mean creatinine clearance was not clinically relevant.

Effect of Lung-Protective Ventilation in Organ Donors on Lung Procurement and Recipient Survival.

Rationale: Previous studies have shown that a lung-protective strategy, which aims at minimizing ventilator-induced lung injury (with low Vt/high positive end-expiratory pressure as the main pillars), in selected potential organ donors after brain death increased lung eligibility and procurement.Objectives: This prospective nationwide cohort study aimed to evaluate the impact of lung-protective ventilation (PV) in nonselected donors on lung procurement and recipient survival after lung transplantation.Methods: We included all reported donors aged 18-70 years after brain death without a lung recovery contraindication and with at least one organ recovered between January 2016 and December 2017. PV was defined as Vt ≤8 ml/kg predicted body weight and positive end-expiratory pressure ≥8 cm H2O. The association between PV at the time of lung proposal (T1) and lung procurement was determined by multivariable logistic regression stratified by propensity score quintile to account for PV and non-PV group differences in baseline characteristics. We studied 1-year survival of recipients from donors with or without PV at T1.Measurements and Main Results: Of 1,626 included lung donors, 1,109 (68%) had at least one lung proposed; 678 (61%) of these had at least one lung recovered. At T1, only 25.6% of donors with at least one lung proposed for lung transplantation were ventilated with a protective strategy. For donors with a lung proposal, the probability of lung procurement was increased with PV at T1 (odds ratio, 1.43; 95% confidence interval [CI], 1.03-1.98; P = 0.03). One-year survival did not differ between recipients of lungs from donors with and without PV (82.7%, 95% CI 76.0-87.8% vs. 82.3%, 95% CI 78.5-85.4%; P = 0.94).Conclusions: The use of lung PV in nonselected donors may increase lung procurement. One-year survival did not differ between recipients of lungs from donors with PV or from those without PV.

Do interruptions to the continuity of methadone maintenance treatment in specialist addiction settings increase the risk of drug-related poisoning deaths? A retrospective cohort study.

AIMS: To examine the risk of mortality associated with interruptions to the continuity of methadone maintenance treatment (MMT), including transfers between services, in opioid-dependent individuals attending specialist addiction services. DESIGN: Retrospective cohort study using addiction services and primary care dispensing records, the National Methadone Register and National Drug-Related Death Index (NDRDI). SETTING: Geographically defined population in Dublin, Ireland. PARTICIPANTS: A total of 2899 people prescribed and dispensed methadone in specialist addiction services between January 2010 and December 2015. There were five exposure groups: weeks 1-4 following transfer between treatment providers; weeks 1-4 out of treatment; weeks 5-52 out of treatment; weeks 1-4 of treatment initiation; and weeks 5+ of continuous treatment (reference category). MEASUREMENTS: Primary outcome: drug-related poisoning (DRP) deaths. Secondary outcome: all-cause mortality (ACM). Mortality rates calculated by dividing number of deaths (DRP; ACM) in exposure groups by person-years exposure. Unadjusted and adjusted Poisson regression (covariates age, sex, incarceration, methadone dose and comorbidities) estimated differences in mortality rates. FINDINGS: There were 154 ACM deaths, 55 (35.7%) identified as DRP deaths. No deaths were observed in the first month following transfer between treatment providers. The risk of DRP mortality was highest in weeks 1-4 out of treatment [adjusted relative risk (aRR = 4.04, 95% confidence interval (CI) = 1.43-11.43, P = 0.009] and weeks 1-4 of treatment initiation (ARR = 3.4, 95% CI = 1.2-9.64, P = 0.02). Similarly, risk of ACM was highest in weeks 1-4 out of treatment (ARR = 11.78, 95% CI = 7.73-17.94, P < 0.001), weeks 1-4 of treatment initiation (aRR = 5.11, 95% CI = 2.95-8.83, P < 0.001) and weeks 5-52 off treatment (aRR = 2.04, 95% CI = 1.2-3.47, P = 0.009). CONCLUSIONS: Interruptions to the continuity of methadone maintenance treatment by treatment provider do not appear to be periods of risk for drug-related poisoning or all-cause mortality deaths. Risk of drug related poisoning and all-cause mortality deaths appears to be greatest during the first 4 weeks of treatment initiation/re-initiation and after treatment cessation.

Brain-Dead Donors on Extracorporeal Membrane Oxygenation.

OBJECTIVES: To describe donors after brain death with ongoing extracorporeal membrane oxygenation and to analyze the outcome of organs transplanted from these donors. DESIGN: Retrospective analysis of the national information system run by the French Biomedicine Agency (CRISTAL database). SETTING: National registry data of all donors after brain death in France and their organ recipients between 2007 and 2013. PATIENTS: Donors after brain death and their organ recipients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, there were 22,270 brain-dead patients diagnosed in France, of whom 161 with extracorporeal membrane oxygenation. Among these patients, 64 donors on extracorporeal membrane oxygenation and 10,805 donors without extracorporeal membrane oxygenation had at least one organ retrieved. Donors on extracorporeal membrane oxygenation were significantly younger and had more severe intensive care medical conditions (hemodynamic, biological, renal, and liver insults) than donors without extracorporeal membrane oxygenation. One hundred nine kidneys, 37 livers, seven hearts, and one lung were successfully transplanted from donors on extracorporeal membrane oxygenation. We found no significant difference in 1-year kidney graft survival (p = 0.24) and function between recipients from donors on extracorporeal membrane oxygenation (92.7% [85.9-96.3%]) and matching recipients from donors without extracorporeal membrane oxygenation (95.4% [93.0-97.0%]). We also found no significant difference in 1-year liver recipient survival (p = 0.91): 86.5% (70.5-94.1) from donors on extracorporeal membrane oxygenation versus 80.7% (79.8-81.6) from donors without extracorporeal membrane oxygenation. CONCLUSIONS: Brain-dead patients with ongoing extracorporeal membrane oxygenation have more severe medical conditions than those without extracorporeal membrane oxygenation. However, kidney graft survival and function were no different than usual. Brain-dead patients with ongoing extracorporeal membrane oxygenation are suitable for organ procurement.