Pharmacological treatment for Substance-Based Addictions

Transcription

1 Pharmacological treatment for Substance-Based Addictions Robert L Tanguay MD, BSc (Hons) Neurosciences PGY5, Psychiatry Addictions Fellow University of Calgary

2 Disclosures Speaking award from Lundbeck, otherwise none All images referenced Images not referenced are clipart Photographs are owned by presenter

3 A prickly subject?

4 and theory??? Evidence!

5 Alcohol and Nicotine: Will be, or has been covered already! Focus: Illicit or Prescription drug addiction

6 Opioid Dependence Opioid Maintenance Relapse Prevention and Abstinence

7 Opioid Maintenance Methadone Maintenance Treatment (MMT) mu receptor agonist Initially for Harm Reduction to reduce spread of disease Main outcomes of recent studies are retention in treatment and reduction of use of illicit substances Ultimate goal is abstinence

8 MMT Evidence? More effective than no opioid replacement for retainment and reduction of heroin use not significant in reducing criminal behaviour (RCT s) not significant in reduction of mortality (RCT s) In large cohorts, significant reduction of BOTH Mattick, R.P., Breen, C., Kimber, J., & Davoli, M. (2009) Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database of Systematic Reviews, Issue 3, Art.No.: CD DOI: / CD pub2.

9 Buprenorphine Maintenance Treatment (BMT) mu receptor partial agonist Goal of reduction of illicit drug use and associated harms and risks More effective than no opioid replacement for retainment and but moderate to high doses required for suppression of heroin use Mattick, R.P., Breen, C., Kimber, J., & Davoli, M. (2014) Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence (Review). Cochrane Database of Systematic Reviews, Issue 2. Art.No.: CD DOI: / CD pub4.

10 BMT may be safer (reduced mortality) MMT vs BMT Cochrane: no difference between high dose MMT and BMT, but MMT better retention in flexible dosing No difference in heroin use, cocaine use, BZD use, or criminal activity Mattick, R.P., Breen, C., Kimber, J., & Davoli, M. (2014) Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence (Review). Cochrane Database of Systematic Reviews, Issue 2. Art.No.: CD DOI: / CD pub4.

11 Others Slow release oral morphine Injectable opioid maintenance Naltrexone- oral and depot formulations Ferri, M., Davoli, M., & Perucci, C. A. (2012) Heroin maintenance for chronic heroin-dependent individuals. Cochrane Database of Systematic Reviews, Issue 5. Art. No.: CD DOI: / CD pub4. Ferri, M., Minozzi, S., Bo, A., & Amato, L. (2013) Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database of Systematic Reviews, Issue 6. Art. No.: CD DOI: / CD pub2. harmful use, addiction and comorbidity: recommendations from BAP. Journal of Psychopharmacology, 26(7): Minozzi, S., Amato, L., Vecchi, S., Davoli, M., Kirchmayer, U., & Verster, A. (2011) Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database of Systematic Reviews, Issue 4. Art.No.: CD DOI: / CD pub4.

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13 Benzodiazepine Dependence Management in therapeutic dose users Management in high dose or illicit users

14 Management of Therapeutic Gradual dose reduction: Dosages Preferable to abrupt discontinuation Switch from short acting to long acting not much support by evidence - but may have less w/d Addition of psychotherapeutic treatment increased cessation rates - generally some CBT particularly beneficial for panic or insomnia Addition of other pharmacotherapies did not show benefit, although recommendations for antidepressants, melatonin, valproate, and flumazenil should be considered on an individual basis

15 Management of high dose and illicit users Maintenance prescribing not recommended due to lack of evidence, although may reduce illicit benzodiazepine use Carbamazepine (Tegretol) withdrawal symptoms Reduction of high dose to therapeutic dose may be useful in some patients Once sufficient psychosocial stability is achieved, further reductions of detoxification should occur

16 Benzodiazepine Detox Pregabalin (Lyrica): Trials titrated to doses of mg QD, while tapers took up to 6 weeks off the benzo Gabapentin (Neurontin): Case reports showing effectiveness with doses at 600mg Carbamazepine: Small trials showing effectiveness at doses of mg QD, with 5 week benzo tapers Antipsychotics not recommended Flumazinil infusion in trials with Clonazepam QHS Sabioni, P., Bertram, J., & Le Foll, B. (2015) Off-label use of medications for treatment of benzodiazepine use disorder. Current Pharmaceutical Design, 21: Crockford, D., White, W.D., & Campbell, B. (2001) Gabapentin use in benzodiazepine dependence and detoxification. Canadian Journal of Psychiatry, 46(3):287

17 Cocaine and Methamphetamine

18 Withdrawal MA- no benefit from mirtazepine (Remeron). Was benefit to mirtazepine in one trial for reduction of hyperarousal and anxiety, but negative on other trials Cocaine- Propranolol (Inderal) associated with better treatment retention and abstinence in highly motivated individuals Minozzi, S., Amato, L., Pani, P.P., Solimini, R., Vecchi, S., De Crescenzo, F., Zuccaro, P., & Davoli, M. (2015) Dopamine agonists for the treatment of cocaine dependence. Cochrane Database of Systematic Reviews, Issue 5 Art. No.: CD DOI: / CD pub4.

19 Cocaine Psychostimulants: Cochrane did not show improvement in treatment retention or reduction of cocaine use, trend towards improved sustained abstinence Topiramate (Topamax) may be beneficial in patients that have obtained some level of abstinence No benefit from antidepressants, antipsychotics, or baclofen Minozzi, S., Amato, L., Pani, P.P., Solimini, R., Vecchi, S., De Crescenzo, F., Zuccaro, P., & Davoli, M. (2014) Dopamine agonists for the treatment of cocaine dependence (review). Cochrane Database of Systematic Reviews, Issue 5. Art. No.: CD DOI: / CD pub4.

20 Cocaine Disulfiram (Antabuse): Independent effect for cocaine alone In combination with CBT most effective reduces reward effect of cocaine and cocaine seeking behaviour: prevents cocaine-induced NA release both in the mpf cortex and in the nucleus accumbens Dose dependent, 4mg/kg shows most benefit, while 2mg/kg has increased cocaine use Haile, C.N., DeLaGarza, R., Mahoney III, J.J., Nielson, D.A., & Kosten, T.R. (2012) The impact of disulfuram treatment on the reinforcing effects of cocaine: a randomized clinical trial. PLoS ONE 7(11): e doi: /journal.pone

21 Methamphetamine Some benefit seen in small trials for dextroamphetamine (Dexadrine), methyphenidate (Ritalin), modafinil (Provigil) Cochrane: Psychostimulants as either maintenance or relapse prevention have not shown significance over placebo Pérez-Mañá, C., Castells, X., Torrens, M., Capellà, D,, & Farre M. (2013) Efficacy of psychostimulant drugs for amphetamine abuse or dependence. Cochrane Database of Systematic Reviews, Issue 9. Art.No.: CD DOI: / CD pub2.

22 Methamphetamine GABA receptor agonists Baclofen (Lioresal) had reduced positive urine in high protocol adherent patients vs gabapentin and placebo Topiramate (Topamax) may enhance euphoric effects of MA and does not worsen cognitive function Although it does not promote abstinence, it may reduce amounts taken and reduce relapse rates Elkashef, A. et al. (2011) Topiramate for the treatment of methamphetamine addiction: a multicenter placebo-controlled trial. Addiction, 107: Ciketic, S., Hayatbakhsh, M.R., Doran, C.M., Najman, L.M., & McKetin, R. (2012) A review of psychological and pharmacological treatment options for methamphetamine dependence. Journal of Substance Use, 17(4):

23 Methamphetamine Haloperidol (Haldol) and risperidone (Risperdol) negative trials, Aripiprazole (Abilify) may increase MA use Disulfuram (Antabuse) enhanced the subjective effects Naltrexone (ReVia) reduced positive urine screens Antidepressants no benefit Ciketic, S., Hayatbakhsh, M.R., Doran, C.M., Najman, L.M., & McKetin, R. (2012) A review of psychological and pharmacological treatment options for methamphetamine dependence. Journal of Substance Use, 17(4):

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25 Club Drugs Ecstacy/MDMA Ecstacy dependence rare, no trials on w/d symptoms GHB Similar w/d as alcohol high dose benzodiazepines recommended for withdrawals May require inpatient detoxification

26 Cannabis Mainstay of research is on treatment of w/d symptoms Dronabinol (Marinol), a pure isomer of THC, provided relief from w/d symptoms, improved treatment retention, and was well tolerated, but did not significantly improve abstinence

27 Cannabis Lithium: Potential benefit of alleviating cannabis based on small trials Anticonvulsants: Mixed, but some evidence of increased irritability, anxiety, and tiredness vs no benefit at all Antidepressants: Bupropion (Wellbutrin) worsened W/D symptoms Mirtazepine (Remeron) improved sleep and appetite, but no difference in other symptoms or abstinence Overall may exacerbate anxiety and insomnia in early stages of W/D

28 Cannabis Baclofen (Lioresal): decreased craving but did not decrease relapse, and worsened cognitive performance Buspirone (Buspar): Single trial showed significant reduction in positive urine drug screens Zolpidem (Ambien): attenuated W/D symptoms on sleep architecture, improving sleep efficacy but not sleep latency

29 N-Acetylcysteine (NAC) Cannabis Cochrane reported a single study by Gray et al. showing reduced positive urine screens, although no difference in self report of cannabis use, and no information on W/D or completion Initial study was open-label by Gray s group, reduced self report but not serum levels, and reduction in cravings as measured by MCQ Another RCT showed no difference in MCQ but significant reductions in positive urine screens in adolescents Gray, K.M., Carpenter, M.J., Baker, N.L., DeSantis, S.M., KrywayE., Hartwell, K.J., McRae-Clark, A.L., & Brady, K.T. (2012) A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry, 169: Gray, K.M., Watson, N.L., Carpenter, M.J., & LaRowe, S.D. (2010) N-Acetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Addict. 19(2): Marshall, K., Gowing, L., Ali, R., & Le Foll, B. (2014) Pharmacotherapies for Cannabis Dependence. Cochrane Database of Systematic Reviews, Issue 12. Art. No.: CD DOI: / CD pub2. Roten, A. T., Baker, N.L., & Gray, K.M. (2013) Marijuana craving trajectories in an adolescent cessation pharmacotherapy trial. Addictive behaviors. 38:

30 Poly Drug Use

31 Opioids and Cocaine One study showed superiority of methadone to buprenorphine, (avg 80mg vs 15mg respectively) BUT two studies over 26 weeks showed no difference Negative studies combining bupropion (Wellbutrin) and methadone, desipramine (Norpramin) and methadone or buprenorphine, and gabapentin (Neurontin) and methadone Disulfuram (Antabuse) with methadone or buprenorphine has shown significant reduction in cocaine use Disulfuram (Antabuse) is dose dependent, must be 4 mg/kg, at lower dose increases cocaine use Cocaine vaccine had positive results in those with high enough IgG levels

32 Opioids and Alcohol Buprenorphine in large RCT more beneficial than methadone in reducing alcohol consumption and in alcohol craving Disulfuram (Antabuse) reduces alcohol with methadone in motivated patients

33 Opioids and Benzo s Opioid patients using benzodiazepines experienced more severe W/D symptoms than opioids alone during inpatient detoxification, including opioid specific symptoms Low-dose maintenance more successful than detoxification in preventing illicit benzodiazepine use

34 Alcohol and Cocaine Cocaethylene produced in this combination, increases euphoric effect and duration of cocaine Naltrexone (ReVia): Ineffective at 50mg QD May be beneficial at mg QD, specifically in men Those with higher cocaine severity vs alcohol there is little benefit

35 Alcohol and Cocaine Disulfiram (Antabuse): At daily doses of mg appears to improve treatment retention and duration of abstinence from both, and sustained response at 12months for cocaine, but not alcohol Naltrexone (ReVia)/Dislufiram (Antabuse) Low adherence in trials Comparing to either individually, the combination more likely to achieve abstinence for 3 consecutive weeks from either alcohol or cocaine

36 Cochrane Review Coming soon: Pharmacological interventions for drug-using offenders. Opioid agonist treatment for pharmaceutical opioid dependent people. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users.

37 Thanks to: Dr Laura Evans and Dr Tashi Kinjo Department of Psychiatry, University of Calgary Dr William White Dr Nady el-guebaly

38 Questions?

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