The biology of addic/on and its medical treatment: an overview

Transcription

1 The biology of addic/on and its medical treatment: an overview Joshua Sonkiss, MD Chief Medical Officer Anchorage Community Mental Health Services October 16, 2017

2 Disclosure statement I have no relevant financial interests to disclose. I will discuss off-label use of some medica/ons. Joshua Sonkiss MD Anchorage Community Mental Health Services 2

3 Learning Objec/ves AQer par/cipa/ng in this ac/vity, prac//oners should be able to: Explain two biomedical models for addic/on. Name three substance use disorders for which there are evidence-based pharmacologic interven/ons. Be familiar with medica/ons most oqen used to treat substance use disorders. Know when to refer pa/ents for pharmacologic treatment of addic/on. Joshua Sonkiss MD Anchorage Community Mental Health Services 3

4 Outline Ingredients of addic/on Neuroanatomy of the reward circuit Models of cogni/ve impairment Research on execu/ve func/oning in addic/on Pharmacologic treatment for addic/on When to refer Joshua Sonkiss MD Anchorage Community Mental Health Services 4

5 Why biology? Joshua Sonkiss MD Anchorage Community Mental Health Services 5

6 The ingredients of addic/on Tolerance Withdrawal Dependence And a li_le something more Joshua Sonkiss MD Anchorage Community Mental Health Services 6

7 Tolerance Tolerance is the need to take more of a drug to get the same effect. Joshua Sonkiss MD Anchorage Community Mental Health Services 7

8 What Causes Tolerance? The brain makes adjustments so it func/ons normally when the drug is present, and abnormally when it s not. Think of tolerance like driving with the brakes on you have to push harder on the gas to get up to highway speed. Joshua Sonkiss MD Anchorage Community Mental Health Services 8

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10 Imaging studies Changes in dopamine receptor density in ventral striatum and effect on rela/ve response natural versus drug reinforcers in cocaine addic/on. Volkow et al. The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology. 2004;47 Suppl 1:3-13. Joshua Sonkiss MD Anchorage Community Mental Health Services 10

11 Withdrawal is what happens when the gas pedal is all the way to the floor and you suddenly take your other foot off the brake. Joshua Sonkiss MD Anchorage Community Mental Health Services 11

12 Dependence Tolerance + Withdrawal Dependence Kosten TR. The neurobiology of opioid dependence: implica/ons for treatment. Sci Pract Perspect Jul;1(1):13-20 Joshua Sonkiss MD Anchorage Community Mental Health Services 12

13 Is dependence the same as addic/on? Joshua Sonkiss MD Anchorage Community Mental Health Services 13

14 Is dependence the same as addic/on? No. Joshua Sonkiss MD Anchorage Community Mental Health Services 14

15 You need something more. Addic&on: a chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences. Na&onal Ins&tute on Drug Abuse: Joshua Sonkiss MD Anchorage Community Mental Health Services 15

16 How does addic/on get started? DiChiara et al. Neuroscience Mar;89(3): Difiorino and Phillips. J Neurosci Jun 15;17(12): Dopamine increases in response to natural rewards such as food. Joshua Sonkiss MD Anchorage Community Mental Health Services 16

17 DiChiara et al. Neuroscience Mar;89(3): Difiorino and Phillips. J Neurosci Jun 15;17(12): Dichiara and Imperato. Proc Natl Acad Sci U S A Jul;85(14): Intoxica/ng drugs cause an exaggerated dopaminergic response. Joshua Sonkiss MD Anchorage Community Mental Health Services 17

18 What sustains addic/on? Condi/oning based on memories of intense pleasure Joshua Sonkiss MD Anchorage Community Mental Health Services 18

19 What sustains addic/on? Salience of drugs eclipses other s/muli, including natural consequences Kosten TR. The neurobiology of opioid dependence: implica/ons for treatment. Sci Pract Perspect Jul;1(1):13-20 Joshua Sonkiss MD Anchorage Community Mental Health Services 19

20 Photo copyright Suresh Eswaren. No changes made. h_ps://crea/vecommons.org/licenses/by-nc-nd/4.0/legalcode Joshua Sonkiss MD Anchorage Community Mental Health Services 20

21 Salience in the healthy brain >>> Joshua Sonkiss MD Anchorage Community Mental Health Services 21

22 Salience in the addicted brain <<< Joshua Sonkiss MD Anchorage Community Mental Health Services 22

23 Benowitz NL. Med Clin North Am Mar;76(2): The nico/ne cycle: running away from withdrawal Joshua Sonkiss MD Anchorage Community Mental Health Services 23

24 The reward circuit Prefrontal cortex: the seat of will Glutamate: inhibi/on (though excitatory NT) Nucleus accumbens: the seat of pleasure Dopamine: desire Serotonin: sa/ety and inhibi/on Ventral tegmental area: the seat of reward Dopamine: pleasure Locus coeruleus: the seat of arousal Norepinephrine: sympathe/c response Joshua Sonkiss MD Anchorage Community Mental Health Services 24

25 The reward circuit Kosten TR. The neurobiology of opioid dependence: implica/ons for treatment. Sci Pract Perspect Jul;1(1):13-20 Joshua Sonkiss MD Anchorage Community Mental Health Services 25

26 Biomedical models of addic/on Changed set point Opioid use causes permanent structural and chemical changes that create a new biological and behavioral baseline for the addict. Kosten TR. The neurobiology of opioid dependence: implica/ons for treatment. Sci Pract Perspect Jul;1(1):13-20 Joshua Sonkiss MD Anchorage Community Mental Health Services 26

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28 Biomedical models of addic/on Cogni.ve deficits Opioid use degrades prefrontal cor/cal inhibi/on of the drive to use, undermining the addicted person s will at a neurological level. Kosten TR. The neurobiology of opioid dependence: implica/ons for treatment. Sci Pract Perspect Jul;1(1):13-20 Joshua Sonkiss MD Anchorage Community Mental Health Services 28

29 Cogni/ve deficit model x Kosten TR. The neurobiology of opioid dependence: implica/ons for treatment. Sci Pract Perspect Jul;1(1):13-20 Joshua Sonkiss MD Anchorage Community Mental Health Services 29

30 Domains of cogni/ve impairment Impulsiveness I m not going to think too much deciding to get high. Reward hypersensi/vity I want to get high more than anything else. Harm hyposensi/vity I forgot how bad it felt the last &me I went to jail. Increased risk-taking My proba&on officer probably won t find out. Outcome myopia (i.e. temporal discoun/ng) My kids might get taken away, but not right now. Joshua Sonkiss MD Anchorage Community Mental Health Services 30

31 IGT and abs/nence in methamphetamine users Decision-making ability on the Iowa Gambling Task (IGT) in METH abusers at different abs/nence /mes and healthy controls over 100 card choices. Wang et al. Effects of length of abs/nence on decision-making and craving in methamphetamine abusers. PLoS One Jul 24;8(7):e Joshua Sonkiss MD Anchorage Community Mental Health Services 31

32 Decision-making in opioid users Biernacki et al. Decision-making ability in current and past users of opiates: A meta-analysis. Neurosci Biobehav Rev Sep 17;71: Joshua Sonkiss MD Anchorage Community Mental Health Services 32

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34 A word about detoxifica/on Not a treatment medically-assisted withdrawal Useful as a bridge to psychosocial or pharmacologic treatment Very high relapse rates when used alone With opioids, elevated risk of overdose death within one month of any detox protocol Nosyk B et al. A call for evidence-based medical treatment of opioid dependence. Health Aff (Millwood) Aug;32(8): Joshua Sonkiss MD Anchorage Community Mental Health Services 34

35 Tobacco Joshua Sonkiss MD Anchorage Community Mental Health Services 35

36 A road map for quiung * * One way to do this is to recommend calling the Quit Line. Joshua Sonkiss MD Anchorage Community Mental Health Services 36

37 The Quit Line Joshua Sonkiss MD Anchorage Community Mental Health Services 37

38 Medica/ons for TUD Nico/ne Replacement Therapy (NRT) Increases quit rates by 50-70% regardless of se?ng FDA-approved, safe Patch, gum, lozenge, spray Quit Line Joshua Sonkiss MD Anchorage Community Mental Health Services 38

39 Medica/ons for TUD Bupropion (Zyban) Increases dopamine, norepinephrine and serotonin Doubles 6-month quit rate compared to placebo An/depressant FDA-approved Varenicline (Chan/x) Partly blocks nico/ne receptor More than doubles quit rate compared to placebo FDA-approved Suicide? Psychosis? Gonazles it al. Clin Pharmacol Ther. 2001;69: Jorenby et al. JAMA Jul 5;296(1):56-63 Joshua Sonkiss MD Anchorage Community Mental Health Services 39

40 Medica/ons for TUD Nortriptyline (Pamelor) Tricyclic (old school) an/depressant Not FDA-approved Clonidine (Minipress) Blood pressure medicine Not FDA-approved Joshua Sonkiss MD Anchorage Community Mental Health Services 40

41 Medica/ons for AUD Disulfiram (Antabuse) The one that makes you sick when you drink Blocks aldehyde dehydrogenase Ethical concerns May be effec/ve when observed Rarely used FDA-approved Joshua Sonkiss MD Anchorage Community Mental Health Services 41

42 Medica/ons for AUD Acamprosate (Campral) Restores balance between GABA and NMDA neurotransmission Reduces relapse by half compared with placebo 666 mg three /mes daily Reduces cravings FDA-approved Joshua Sonkiss MD Anchorage Community Mental Health Services 42

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44 Medica/ons for AUD Naltrexone (Revia) Blocks opioid receptors 30-40% reduc/on in relapse to heavy drinking Reduces the pleasure associated with drinking Reduces cravings Four-week injec/on available (Vivitrol) FDA-approved Srisurapanont M, Jarusuraisin N. Cochrane Database Syst Rev 2005;(1):CD Joshua Sonkiss MD Anchorage Community Mental Health Services 44

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46 Emerging AUD treatments (not FDAapproved) Gabapen/n (Neuron/n) Effec/ve for anxiety Abusable May be FDA-approved soon Topiramate (Topamax) Stupamax, Dopamax Weight loss Baclofen (Gablofen, Lioresal) Joshua Sonkiss MD Anchorage Community Mental Health Services 46

47 Benzodiazepines and AUD Benzos include clonazepam (Klonepin), lorazepam (A/van), alprazolam (Xanax) and many others Important for detox Cross-tolerant Can cause relapse Can cause respiratory depression/arrest Joshua Sonkiss MD Anchorage Community Mental Health Services 47

48 Opioids ORT ORT Not ORT Joshua Sonkiss MD Anchorage Community Mental Health Services 48

49 Full Agonist Treatment (ORT) Methadone Spectacular results since 1965 Full agonist but long half-life Administered only in specially licensed methadone clinics when used for addic/on treatment Can be used for pain treatment FDA-approved Joshua Sonkiss MD Anchorage Community Mental Health Services 49

50 Par/al Agonist Treatment (ORT) Buprenorphine (Suboxone, Subutex, etc.) Par/al agonist harder to overdose Prescribers need special training and DEA cer/ficate, but in theory can be administered in any prescriber s office. Can be used for pain treatment, no special training required FDA-approved Joshua Sonkiss MD Anchorage Community Mental Health Services 50

51 Advantages of ORT Consistent evidence to support efficacy Be_er treatment reten/on Fewer overdose deaths Less hospitaliza/on Cost effec/veness Dugosh K. A Systema/c Review on the Use of Psychosocial Interven/ons in Conjunc/on With Medica/ons for the Treatment of Opioid Addic/on. J Addict Med Mar-Apr;10(2): Mauck R. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev Apr 16;(2). Nosyk B et al. A call for evidence-based medical treatment of opioid dependence. Health Aff (Millwood) Aug;32(8): Joshua Sonkiss MD Anchorage Community Mental Health Services 51

52 Disadvantages of ORT Poten/al for abuse and diversion of medica/on Lifelong treatment for many up to 95 percent relapse when taper a_empted Some people see ORT as subs/tu/ng one addic/on for another. Nosyk B et al. A call for evidence-based medical treatment of opioid dependence. Health Aff (Millwood) Aug;32(8): Joshua Sonkiss MD Anchorage Community Mental Health Services 52

53 Why use ORT? Mauck et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev Jul 8;(3):CD Joshua Sonkiss MD Anchorage Community Mental Health Services 53

54 Antagonist Treatment (not ORT) Oral or long-ac/ng injectable naltrexone (Vivitrol) Advantages: Blocks high from opioids Avoids s/gma of ORT (doesn t replace one addic/on with another ) Appeals to policymakers who favor abs/nence Can t be abused or diverted Joshua Sonkiss MD Anchorage Community Mental Health Services 54

55 Antagonist Treatment (not ORT) Disadvantages: Oral naltrexone no be_er than placebo Minozzi S et al, Cochrane Database Syst Rev 2011 Long-ac/ng injectable naltrexone (Vivitrol) promising, but limited evidence Lee J et al. Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Jus/ce Offenders. N Engl J Med Mar 31;374(13): Krupitsky E et al.injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effec/veness. Addic/on Sep;108(9): High treatment dropout rates May interfere with pain treatment Joshua Sonkiss MD Anchorage Community Mental Health Services 55

56 Pregnancy and OUD Opioid use and opioid withdrawal have adverse effects on fetus. Withdrawal is usually more serious (premature delivery, s/llbirth). Therefore, abs/nence-based treatment is not recommended during pregnancy for anyone who is ac/vely using opioids. Kampman and Jarvis. American Society of Addic/on Medicine (ASAM) Na/onal Prac/ce Guideline for the Use of Medica/ons in the Treatment of Addic/on Involving Opioid Use. J Addict Med 2015; Joshua Sonkiss MD Anchorage Community Mental Health Services 56

57 Pregnancy and OUD Opioid replacement therapy is the standard of care in pregnancy. Medically-assisted withdrawal is not recommended. Neonatal abs/nence syndrome is treatable and usually resolves in several weeks. Joshua Sonkiss MD Anchorage Community Mental Health Services 57

58 Behavioral addic/ons Sexual addic/ons SSRI an/depressants (e.g. fluoxe/ne have shown benefit Cau/on with s/mulants, benzodiazepines, bupropion Gambling addic/on Naltrexone (Revia, Vivitrol) has shown benefit SSRIs have shown benefit Cau/on with s/mulants, some an/psycho/cs Joshua Sonkiss MD Anchorage Community Mental Health Services 58

59 Substances with li_le or no evidence to support pharmacologic treatment Seda/ve-hypno/cs Medically managed withdrawal S/mulants Con/ngency management Cannabis and synthe/c cannabinoids Counseling, 12-step Hallucinogens Not addic/ve Joshua Sonkiss MD Anchorage Community Mental Health Services 59

60 When should you refer to an addic/on medicine specialist? When pharmacologic treatments exist for the substance your pa/ent is using When psychosocial interven/ons alone have not been successful When a pa/ent asks for a referral Whenever a pa/ent has opioid use disorder If your pa/ent is pregnant Joshua Sonkiss MD Anchorage Community Mental Health Services 60

61 Learning assessment 1. Which of the following is true about psychosocial interven/ons in addic/on? a. According to recent studies, they offer li_le benefit for opioid use disorder. b. Research has shown some psychosocial interven/ons are worse than doing nothing. c. They are the cornerstone of treatment for cannabis use disorder. d. a and b only e. all of the above Joshua Sonkiss MD Anchorage Community Mental Health Services 61

62 Learning assessment 2. Which of the following neurotransmi_ers plays a central role in all addic/ons? a. GABA b. Norepinephrine c. Serotonin d. Dopamine e. Dynorphins Joshua Sonkiss MD Anchorage Community Mental Health Services 62

63 Learning assessment 3. Which of the following are true about abs/nence-based treatment for OUD? a. It increases the risk of overdose death. b. It should always be tried before ORT. c. It works for a small minority of pa/ents. d. a and c only e. all of the above Joshua Sonkiss MD Anchorage Community Mental Health Services 63

64 Learning assessment 4. What is the safest treatment for pregnant women with opioid use disorder? a. Opioid replacement therapy b. Rapid detoxifica/on c. Slow detoxifica/on d. a and c only e. all of the above Joshua Sonkiss MD Anchorage Community Mental Health Services 64

65 Learning assessment 5. Which of the following is true about smoking cessa/on drugs? a. The Quit Line offers coaching only. b. E-cigare_es are effec/ve for smoking cessa/on. c. Varenicline (Chan/x) causes suicide. d. NRT should never be combined with varenicline (Chan/x) or bupriopion (Zyban). e. NRT increases quit rates by 50-70% regardless of psychosocial treatment. Joshua Sonkiss MD Anchorage Community Mental Health Services 65

66 Ques/ons? Photo by Sylvain Pedneault Joshua Sonkiss MD Anchorage Community Mental Health Services 66