Pregabalin use and misuse in Australia Dr. Rose Crossin Senior Research and Policy Officer

Misuse potential Euphoric or euphoric mood is a potential adverse effect of taking pregabalin and dependence has been reported (Pfizer, product information sheet) Has been associated with an increased risk of suicidal ideation and behaviours, and depression CNS depressant effects Potential for additive effects on respiration when ingested with other sedatives As such consumer medication information suggests that: Doctors need to be advised of a history of depression or substance abuse Be alert to potential for dependence and / or psychiatric side effects Concurrent other medication / substance use needs to be considered

International evidence of misuse and harms First approved for medical use in 2004 and on the market in 2005 Academic papers on misuse begin from ~2011 Online reports of recreational pregabalin misuse in Europe (Schifano 2011) Poly-drug use with opioids highly prevalent in pregabalin-related deaths in Finland (Hakkinen 2014) Increased prevalence of pregabalin in intentional drug overdoses in Ireland (Daly 2017) High prevalence of misuse in those who use opioids or have psychiatric co-morbidities (Evoy 2017) All occurring against a background of rapidly increasing prescribing and use

The Australian Context Rapidly increasing number of prescriptions from 2013 By 2015, pregabalin was one of the costliest drugs on the PBS (Mabbott 2015) But, as at the start of 2018 there were no studies on misuse or harms related to pregabalin in Australia …. Question: Is Australia seeing similar patterns of misuse and harms related to pregabalin as had been seen internationally?

Cairns, Schaffer et al. 2018

Methods Study set in NSW Data sources: PBS 10% sample: Jul 2012 to Feb 2017, dispensing data Poisons Information Centre database: Jan 2004 to Dec 2016, calls relating to intentional exposure Toxicology unit databases: Jan 2012 to Dec 2015, intentional pregabalin exposure in poisoned patients at hospitals (deliberate self-poisoning, recreational use, and misuse) Coronial database: 2005 to 2016, deaths where pregabalin was related (from free-text information, not toxicologically confirmed) Aims: to identify dispensing trends, identify people at high risk of misuse, understand demographics of intentional overdoses, and estimate trends in pregabalin-related deaths

Trends in dispensing and intentional poisonings Cairns, R., Schaffer, A. L., Ryan, N., Pearson, S. A., & Buckley, N. A. (2018). Rising pregabalin use and misuse in Australia: trends in utilization and intentional poisonings. Addiction.

Identifying high-risk groups for misuse 14.7% of people prescribed pregabalin were considered high-risk for misuse Defined as: prescribed more and higher strengths, had more prescribers, more likely to be co-prescribed opioids and benzodiazepines More likely to be younger and male More likely to have concessional status High-risk users received 50.8% of pregabalin by volume

Characteristics of pregabalin overdoses and deaths Compared to other gabapentin and carbamazepine, those who overdosed with pregabalin were: More likely to co-ingest opioids, benzodiazepines, other illicit drugs, and alcohol 78% were prescribed pregabalin 64% had a documented substance misuse history Compared to overdoses, pregabalin-related deaths were: More likely to be male More likely to involve co-ingestion (80% involved pharmaceutical opioids, 67% involved benzodiazepines) The majority (81%) were not in paid employment The majority (66%) of deaths were coded as unintentional, 19% intentional, remainder undetermined

Crossin, Scott et al. 2018

Methods Study set in Victoria Data from the Ambo Project: Jan 2012 to Dec 2017 Pregabalin misuse defined as: A person prescribed pregabalin consumes more than prescribed quantity / frequency A person consumes pregabalin prescribed to someone else Prescribed pregabalin is taken with a combination of other substances Aims: compare trends in ambulance attendances relative to prescribing, characterise populations experiencing harm, assess co-occurring other sedative use and harms to self, compare characteristics of attendances between those who misuse pregabalin with and without other sedatives

Ambulance attendances are increasing with prescriptions Crossin, R., Scott, D., Arunogiri, S., Smith, K., Dietze, P. M., & Lubman, D. I. (2019). Pregabalin misuse‐related ambulance attendances in Victoria, 2012–2017: characteristics of patients and attendances. Medical journal of Australia, 210(2), 75-79.

Characteristics of attendances 1,201 pregabalin-related ambulance attendances in 6 years: 50% were male, 50% were female 27% were aged 30-39 24% were aged 40-49 49% had a high-risk history (of depression, or self-harm, or suicidal ideation, or suicide attempt, or AOD misuse) Most commonly history of depression and history of suicide attempt

Co-occurring issues with pregabalin misuse Graphs adapted from data in: Crossin, R., Scott, D., Arunogiri, S., Smith, K., Dietze, P. M., & Lubman, D. I. (2019). Pregabalin misuse‐related ambulance attendances in Victoria, 2012–2017: characteristics of patients and attendances. Medical journal of Australia, 210(2), 75-79.

Pregabalin misuse with and without other sedatives Men more likely than women to misuse pregabalin with other sedatives When pregabalin was misused with other sedatives, more likely to have GCS<13 No significant differences in co-occurring self-injurious behaviours, based on presence / absence of other sedatives Increased medical risk when pregabalin misused with other sedatives, but no difference in psychiatric risk

Overall conclusions Significant increase in pregabalin prescribing, misuse, and harms Many high-risk users in Australia (~86,000 in 2016) Growing harms in vulnerable groups Low SES Strong overlap with SUD history Strong overlap with a high-risk psychiatric history Extensive poly-substance use (particularly benzodiazepines, alcohol, and opioid analgesics) which increases overdose risk Associated with both intentional and unintentional overdoses

Limitations Only limited data available on whether pregabalin was prescribed to the individual (78% from NSW hospital toxicology, no data for Vic) Neither study included private prescriptions (off-label indications), and the condition for which pregabalin was prescribed is unknown NSW coronial data did not have toxicological testing for pregabalin Vic ambulance data not toxicologically confirmed Large population studies, not specific to high-risk groups Neither study can discuss causality, just associated outcomes

Recommendations For regulators For doctors For users Consideration of scheduling changes (recently re-scheduled in US and UK) Consider inclusion in SafeScript in Victoria For doctors Precautions when co-prescribing other sedatives Communication of interaction risks with other sedatives Undertake risk assessment for misuse Avoid off-label prescribing for indications without a strong evidence base Review indications, including psychiatric history For users Awareness of potential adverse effects, incl. risks when taken with other substances Disclosure of relevant history to prescribing doctors

Outstanding questions No good estimates of dependence in Australia, just misuse and harms What are the primary motivations for misuse? Are there long-term outcomes from pregabalin misuse? Do trends and harms differ in high-risk populations? Is information about potential harms and risks getting through? How can we get information to those misusing diverted pregabalin?