Pregabalin and gabapentin in non-opioid poisoning deaths.

Post-mortem findings of gabapentinoids have often been connected to drug abuse and especially opioid use. We aimed to investigate whether gabapentinoids have been implicated in the cause of death without the presence of opioids. In a three-year study period from 2016 to 2018, a total of 907 Finnish post-mortem cases positive for pregabalin or gabapentin were found. In nearly half of the pregabalin cases and in a third of the gabapentin cases, the blood concentration was above the typical therapeutic range of the drug. Of the cases in which pregabalin was detected, in 35% the drug was implicated in a fatal poisoning with or without other drugs or alcohol. For gabapentin, the percentage was 22%. In most of the fatal gabapentinoid poisonings, opioids or other central nervous system depressants were additionally detected in relevant concentrations. There were eight non-opioid gabapentinoid poisonings, in which no relevant other drugs were detected. Many of these cases were unintentional poisonings with a relatively high gabapentinoid concentration in the blood. In all but one, the manner of death was accidental, or the intent was undetermined. This study confirmed the previous findings that gabapentinoids are mostly implicated in fatal poisoning together with opioids. Half of the non-opioid cases were related to drug abuse but in the other half the death was presumably caused by overuse of a prescribed drug or suicide. While the use of gabapentinoids is a well-known problem among people who use drugs, it is important to note other groups of users who may be at risk of overdose by gabapentinoids.

Unintentional exposure to pregabalin in ≤6-year-old children: a nationwide French Poison Control Center study.

INTRODUCTION: In France, pregabalin is widely prescribed in adults but still not approved for children. We aimed to investigate the incidence of pregabalin exposure in ≤6-year-old children, to describe the characteristics and outcome of ingestions involving pregabalin alone, and to estimate a clinically relevant toxic dose in this population. METHODS: Retrospective analysis of pregabalin exposures in ≤6-year-old children, collected by the French Poison Control Centers in 2004-2019. The incidence was estimated using pregabalin prescription data from the Health Improvement Network database (the French version of THIN). The poison severity score (PSS) was used to grade severity. RESULTS: We found 313 unintentional immediate-release pregabalin ingestions in ≤6-year-old children. The number of cases per 100,000 pregabalin-treated adults increased over time (p < 0.001). One hundred twenty-six cases involving pregabalin alone (age, 2 years [1.6-3.0] (median [25th-75th percentiles]); median ingested dose 6.4 mg/kg [3.6-10.9]) were analyzed. No child presented an underlying neurological/cardiac disease and/or took concomitant medications. Most of the children (77%) remained asymptomatic (PSS0) while 21% and 2% developed minor (PSS1) or moderate (PSS2) neurological symptoms, respectively. No severe complications/fatalities were reported. All symptomatic children recovered within 24 h. The ingested pregabalin dose was positively correlated with PSS (p < 0.0001). Using a ROC curve approach (area under the curve, 0.85; p < 0.001), ingestion of ≥19.4 mg/kg pregabalin was appropriate to recommend hospital referral (sensitivity, 39% [95% confidence interval (95% CI), 24-56], specificity, 100% [95% CI, 96-100], predictive positive value, 100% [95% CI, 64-100], and negative predictive value, 85% [95% CI, 82-89]). Symptomatic children who ingested <19.4 mg/kg pregabalin developed minor symptoms. CONCLUSION: Despite increasing prescriptions in adults in France, unintentional pregabalin ingestions in ≤6-year-old children remain rare and cause minimal toxicity. Children with no underlying neurological/cardiac disease and concomitant medication ingesting <19.4 mg/kg immediate-release pregabalin alone can be safely observed at home.

Pregabalin poisoning and rising recreational use: a retrospective observational series.

AIMS: With rising use worldwide, pregabalin is increasingly implicated in poisoning deaths. We aimed to investigate the clinical effects and complications of pregabalin poisoning. METHODS: This is a retrospective review of patients presenting with pregabalin poisoning to two tertiary toxicology units from 1 July 2014 to 30 June 2019. Patients were identified from prospective databases maintained by both units and data were extracted from these in addition to medical records. RESULTS: There were 488 presentations in 413 patients (237 [57%] male) over the five-year period. The median age was 41 years (IQR 31-50 years). Deliberate self-poisonings accounted for 342 (70%) presentations, with 121 (25%) recreational exposures. Recreational exposures increased over the period from 2 (4%) in the first year to 54 (39%) presentations in the final year. The median dose of pregabalin was 1200 mg (IQR 600-3000 mg, range 75-16 800 mg). Co-ingestions occurred in 427 (88%) presentations, with sedating agents being co-ingested in 387 (79%)-most commonly opioids and benzodiazepines in 201 (41%) and 174 (36%) presentations respectively. Coma (GCS < 9) occurred in 89 (18%) cases, with 52 (11%) patients being intubated. Only one (0.2%) of these patients had not co-ingested a sedating agent. Hypotension occurred in 26 (5%) cases, all with co-ingestants. Seizures occurred in 11 (2%) cases, 3/59 (5%) in pregabalin-only overdoses. The median length of stay was 16.5 hours (IQR 10-25 hours). CONCLUSIONS: Pregabalin overdose does not cause severe toxicity, but rather mild sedation and, uncommonly, seizures. Coma is common in the presence of sedating co-ingestants. Recreational use is increasing.

[On the issue of the detection of pregabalin and lorazepam in the cases of their joint presence for the purpose of chemical toxicological studies]. / Izuchenie pregabalina i lorazepama pri sovmestnom prisutstvii dlia tselei khimiko-toksikologicheskogo issledovaniia.

Data on the detection of joint presence of pregabalin and lorazepam in the biological objects and material evidence. Aim of this study is to develop a method of the detection of pregabalin and lorazepam in urine. The proposed approach to sample preparation of a biological object and the detection of lorazepam and pregabalin allows the detection of toxicants in cases of their joint presence. It can be used in the analysis of urine in cases of acute poisoning for detoxification therapy or chemical toxicological analysis as a preliminary and confirmatory study for the presence of abuse of these drugs.

Pregabalin and Its Involvement in Coronial Cases.

Pregabalin is an anticonvulsant and analgesic designed to treat neuropathic pain and partial seizure disorders and has been available in Australia as a prescription medication since 2005. Studies have found high rates of polydrug use associated with pregabalin and it is reportedly used recreationally for its euphoric and relaxing effects as well as to self-manage opioid withdrawal symptoms. A robust analytical method for the analysis of pregabalin using protein precipitation and LC/MS/MS was developed, validated and employed in routine case work. In recent years a substantial increase in pregabalin detections in coronial case submissions had been noted. This study examines the case characteristics and outcomes of 332 coronial cases submitted to the laboratory and analyzed for pregabalin between 2015 and 2017. Pregabalin was identified in approximately 5% of all coronial cases submitted during this time. A high rate of concurrent drug use with pregabalin was evident with the predominant classes being opioids, benzodiazepines and anti-depressants. Post-mortem blood pregabalin concentrations ranged from <0.05 to 140 mg/kg (median 5.5 mg/kg); however, limited interpretation of levels could be achieved as the drug was rarely identified in the absence of other drugs. Cause of death (COD) was found to be drug related in 58% of all cases, with mixed drug toxicity specifically mentioned as related to COD in 40% of cases.

A repeated cross-sectional study of factors associated with pregabalin-positive poisoning deaths in Ireland.

BACKGROUND: The increasing use of pregabalin and the presence of pregabalin in poisoning deaths, particularly with opioids, highlight it as a potential drug of abuse. In this study we examined factors associated with pregabalin-positive poisoning deaths (PPPD) between 2013 and 2016 in Ireland. METHODS: Data were extracted from the National Drug-Related Deaths Index (NDRDI). Analysis included univariate and multivariate logistic regression to estimate unadjusted and adjusted odds ratios (OR) and 95 % confidence intervals (CI) for factors associated with PPPD (primary outcome) by logistic regression models for the total sample and stratified by gender. RESULTS: Pregabalin was present on 240 (16 %) toxicology reports of 1489 poisoning deaths; significantly rising from 15 (4.5 %) in 2013 to 94 (26 %) in 2016. Women (AOR 2.69, 95 % CI: 1.95-3.70), opioid misuse (AOR 1.74, 95 % CI: 1.17-2.59), in receipt of treatment for problem drug use (AOR 1.95, 95 % CI: 1.33-2.86) and year of death (2016 vs 2013) (AOR 7.95, 95 % CI: 4.58-13.79) were associated with increased odds of PPPD. Alcohol dependence was associated with reduced odds of PPPD (AOR 0.59, 95 % CI: 0.41-0.85). For men, opioid misuse, in receipt of treatment for problem drug use, and year of death were associated with increased odds of PPPD, while alcohol dependence was associated with reduced odds of PPPD. For women, in receipt of treatment for problem drug use and year of death were associated with increased odds of PPPD. CONCLUSIONS: Enhanced training to prescribers and treatment providers on the potential risks associated with pregabalin, particularly among people who use drugs, is required.

Pregabalin misuse-related ambulance attendances in Victoria, 2012-2017: characteristics of patients and attendances.

OBJECTIVE: To compare changes in pregabalin prescribing and misuse-related ambulance attendances; to characterise the patients attended by paramedics for pregabalin misuse-related harms; to assess the association of pregabalin misuse with use of other sedatives and with suicidal ideation and self-harm; to compare the characteristics of pregabalin misuse-related harms in people who misuse pregabalin according to whether or not they also used other sedatives. DESIGN, SETTING, PARTICIPANTS: Retrospective analysis of data on ambulance attendances in Victoria, January 2012 - December 2017, for which pregabalin misuse-related harms were a contributing factor. MAIN OUTCOME MEASURES: Rates of pregabalin misuse-related ambulance attendances, pregabalin prescription rates (each 6-monthly); patient characteristics, including age, sex, history of drug misuse or psychiatric problems, concurrent use of other sedatives, and current suicidal ideation and self-harm. RESULTS: There were 1201 pregabalin misuse-related attendances during the study period; the rate increased from 0.28 cases per 100 000 population in the first half of 2012 to 3.32 cases per 100 000 in the second half of 2017. The attendance rate was strongly correlated with prescription rates in Australia (r = 0.90; P = 0.001). 593 attendances (49%) were for people with a history that may have contraindicated prescribing pregabalin. Pregabalin was frequently misused with other sedatives (812 attendances, 68%), particularly benzodiazepines (440, 37%); 472 attendances (39%) were associated with suicide attempts. People who misused pregabalin with other sedatives more frequently presented with moderate to severe impairments of consciousness, but the frequency of suicide attempts was similar whether other sedatives were concurrently used or not. CONCLUSIONS: Rates of pregabalin misuse-related ambulance attendances in Victoria have increased markedly over the past 6 years. Caution is required when prescribing pregabalin for people taking other sedatives. Limiting the dispensing of this drug may reduce the risks associated with its misuse.

Rising pregabalin use and misuse in Australia: trends in utilization and intentional poisonings.

BACKGROUND AND AIMS: Pregabalin is a gamma-aminobutyric acid (GABA) analogue, used to treat neuropathic pain and epilepsy. Pregabalin was registered in Australia in 2005, and subsidized publically in 2013. We aimed to describe Australian patterns of pregabalin use and intentional poisoning, and identify people potentially at high risk of misuse. DESIGN AND SETTING: Population-based retrospective cohort study of dispensings in the 10% sample of Australian Pharmaceutical Benefits Scheme (July 2012-February 2017); intentional poisoning calls to New South Wales Poisons Information Centre (NSWPIC) (2004-2016); intentional poisonings in two Australian toxicology service databases; and poisoning fatalities in NSW coronial records (2005-2016). PARTICIPANTS: A total of 122 572 people dispensed pregabalin, people with intentional pregabalin overdoses managed by NSWPIC and the toxicology services and pregabalin-associated deaths referred to the NSW coroner. MEASUREMENTS: Trends in dispensing, poisoning, death; demographics and patient characteristics, proportion of users at high risk of misuse (latent class analysis, LCA) and characteristics of high-risk users. FINDINGS: Pregabalin dispensing increased by 73 424 per year [95% confidence interval (CI) = 61726-85 121 P < 0.001] between 2013 and 2016. NSWPIC received 1158 reports of intentional pregabalin poisonings, with a 53.8% increase per year, 2005-2016 (95% CI = 44.0-64.2%, P < 0.001). We identified 88 pregabalin-associated deaths, 57.8% yearly increase (95% CI = 30.0-91.6%, P < 0.001). Patients overdosing on pregabalin commonly co-ingested opioids, benzodiazepines and illicit drugs, and had high rates of psychiatric and substance use comorbidities; 14.7% of pregabalin users were classed by the LCA as at high risk of misuse, and were more likely to be younger, male, co-prescribed benzodiazepines or opioids, have more individual prescribers and higher pregabalin strengths dispensed. CONCLUSIONS: There has been a dramatic increase in pregabalin use, poisonings and deaths in Australia since it became subsidized publicly in 2013. One in seven Australians dispensed pregabalin appears to be at high risk of misuse.

Intentional Drug Overdose Involving Pregabalin and Gabapentin: Findings from the National Self-Harm Registry Ireland, 2007-2015.

INTRODUCTION: Intentional drug overdose (IDO) is a significant public health problem. Concerns about the misuse of gabapentinoids, i.e. pregabalin and gabapentin, including their consumption in IDO have grown in recent years. This paper examines the trends in the prevalence of gabapentinoids taken in IDO, the profile of individuals taking them, and associated overdose characteristics. METHODS: Presentations to emergency departments involving IDO, recorded by the National Self-Harm Registry Ireland between 1 January 2007 and 31 December 2015 were examined. Data items included patient demographics, drug names, total tablet quantity consumed and alcohol involvement. RESULTS: Gabapentinoids were involved in 2115 (2.9%) of the 72,391 IDOs recorded. Presentations involving a gabapentinoid increased proportionally from 0.5% in 2007 to 5.5% in 2015. The majority of IDOs involving a gabapentinoid were made by females (59.9%), with over one-third (37.2%) involving alcohol. Compared with IDOs involving other drugs, presentations with a gabapentinoid were made by persons who were older (median 37 vs. 32 years) and involved a significantly greater median quantity of tablets (30 vs. 21, p ≤ 0.001), with over one-quarter (27.4%) of these involving the ingestion of 50 tablets or more. Admission to hospital was significantly more common following IDOs with a gabapentinoid compared with those without (49.4% vs. 41.4%, p ≤ 0.001). CONCLUSIONS: This study identified the increasing use of gabapentinoids in IDO, describing the profile and overdose characteristics of presentations. It is important for clinicians to exercise vigilance while prescribing gabapentinoids, including being aware of other medications that their patients may have access to. Our findings support the need for routine monitoring for signs of misuse among those prescribed gabapentinoids.

Pregabalin Toxicity Manifesting as Reversible Encephalopathy With Continuous Triphasic Waves in Electroencephalogram.

A 74-year-old man with peripheral neuropathy due to diabetes presented with deliberate ingestion of 450 mg of pregabalin (PBG) over a period of 8 hours followed by altered mental status. A bedside electroencephalogram was performed to rule out nonconvulsive status epilepticus, which showed continuous triphasic waves (TWs) with slow background activity. He recovered after 48 hours of stopping PBG, and his repeat electroencephalogram after 72 hours did not show any TWs. We present a rare case of PBG-induced TWs thereby highlighting the extent of the etiologic spectrum of TWs and discussing the literature related to this association.