How does polydrug use contribute to heroin overdose deaths? Risk to heroin users of concurrent use of pregabalin and gabapentin

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1 How does polydrug use contribute to heroin overdose deaths? Risk to heroin users of concurrent use of pregabalin and gabapentin Graeme Henderson Suzanne Audrey Matt Hickman Abi Lyndon Rob Hill Claudia Wells Erica Burnell Suzanne Ingle University of Bristol Bristol, UK & Office of National Statistics

2 How does polydrug use contribute to heroin overdose deaths? Why are heroin users in Bristol also taking pregabalin and gabapentin?

3 Pharmacology of gabapentinoids Gabapentin Pregabalin Oral absorption <50% >90% (saturable) (non saturable) Time to maximum 2-3 hours 1 hour plasma concentration Excretion renal renal (not metabolised) (not metabolised) Half life in body ~6 hours ~6 hours

4 Pregabalin and gabapentin community prescriptions (England) Gabapentoid prescriptions (m illions) Year Epilepsy Pain Anxiety (pregabalin) insomnia, migraine, mania, and bipolar disorder as well as alcohol withdrawal (gabapentin)

5 Pregabalin and gabapentin community prescriptions (England) Gabapentoid prescriptions (m illions) Year Abuse relaxation enhanced sociability euphoria insomnia, migraine, mania, dissociation and bipolar disorder as sedation well as alcohol withdrawal (gabapentin) Epilepsy Pain Anxiety (pregabalin)

6 Acute deaths involving gabapentin and pregabalin (England & Wales) Deaths mentioning a gabapentoid Year

7 Correlation between number of prescriptions and number of deaths in a year B 5 Log number of deaths Gabapentoid prescriptions (per 100,000) 5% increase in overdose deaths per increase in prescriptions

8 Comparison of acute deaths involving gabapentin and pregabalin in Scotland with those in England & Wales 2016 Scotland England & Wales Gabapentin Pregabalin Total

9 Deaths also involving opioids (England & Wales) Deaths mentioning a gabapentoid Opioids were involved in >80% of gabapentoid deaths (90% in 2016) Year

10 Deaths also involving opioids (England & Wales) Deaths mentioning a gabapentoid Year Is the presence of both just because heroin addicts like gabapenintoids or is there an interaction?

11 Qualitative Research (October 2014 February 2015) Interviews with active heroin users in Bristol - attending Bristol Drugs Project Needle Exchange - screened for known opioid users - 10 fee on completion of interview Areas discussed Perceived protection - from on top heroin use on methadone or Subutex OST Benefits and hazards of also using non-opioid drugs - alcohol - cocaine - benzodiazepines - gabapentin and pregabalin

12 Interviewed 30 users - 19 males and 11 females - different lengths of opioid use 20 long term (>10 years) 4 medium term (5 10 years) 6 short term (<5 years) - different styles of use (smoking and injecting) - different opioid substitution treatments

13 Use of gabapentinoids - 21 of 30 had used gabapentinoids - most (19 of 21) used pregabalin - 3 were daily users - 3 used it weekly - 5 used it intermittently - for 10 it was just a one-off occasion Street purchase mainly - 2 obtained it from friends who were prescribed it - 3 were prescribed pregabalin for chronic pain Taken orally some time prior to heroin injection (unlike cocaine which is mixed with heroin and injected) Doses varied 250mg tablet to 1500mg taken orally as tablets

14 Perceived effects of gabapentinoids - give a buzz on their own (feeling of being drunk) - gouching -enhance the effect of the heroin - caused blackouts and loss of control (zombies) - increased the risk of overdose - helps to cope with withdrawal between heroin doses - reduced craving for heroin

15 Gabapentin Study Glasgow and Lanarkshire by Naloxone Peer Educators 41 individuals completed a brief questionnaire 50% had taken illicit gabapentin Swallowing > snorting >> injecting Taken along with other drugs - heroin 46%, methadone 39%, valium 44% Effects - sleepy, gouchy, chilled, laid back, relaxed Duration - effects lasted for 8 to 24 hours Risks - 50% believed it increased risk of overdose with other drugs

16 Preclinical studies of pregabalin - Does pregabalin depress respiration? - If so is it additive with opioids? - Does pregabalin alter opioid tolerance?

17 Monitoring mouse respiration

18 Pregabalin and morphine additively depress respiration Morphine 10 mg/kg Pregabalin 200 mg/kg 100 Pregabalin Minute volume(% predrug level) Time (min) Minute volume(% predrug level) Morphine/Saline Time (min)

19 Pregabalin opioid interaction Acute - pregabalin (high dose) additive with all opioids tested morphine methadone fentanyl oxycodone

20 Low dose pregabalin reverses morphine tolerance Pregabalin 20 mg/kg Morphine 10 mg/kg 6 day morphine treatment respiration A pregabalin 20 mg/kg drugs 100 naive 100 Minute volume (% predrug level) morphine pretreated Minute volume (% predrug level) morphine pretreated + morphine challenge morphine pretreated + pregabalin + morphine challenge Time post drug (min) Time post drug (min)

21 Pregabalin opioid tolerance Tolerance - pregabalin reversal of tolerance increases danger of heroin overdose - pregabalin (low dose) reverses morphine (heroin) tolerance oxycodone tolerance - pregabalin s long half life (6 h) will allow reversal of morphine tolerance hours after pregabalin is taken - no reversal of methadone tolerance

22 Drug specific mechanisms of opioid tolerance Methadone Morphine GRK2/3 p p arrestin PKCα,γ Methadone Fentanyl Morphine Heroin 6-MAM Oxycodone

23 Agonist specific mechanisms of opioid tolerance Methadone Morphine GRK2/3 p p arrestin PKCα,γ Alcohol Tamoxifen Pregabalin Methadone Fentanyl Morphine Heroin 6-MAM Oxycodone

24 Diversion of gabapentoid prescription - Need for greater awareness amongst GPs - Need for alternative treatments for chronic pain

25 HM Prison Service (South West of England) Dr Catherine Glover, Medical Director