PHARMACOTHERAPY OF ADDICTIVE DISORDERS

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1 Sidarth Wakhlu,M.D. Addiction Team Leader North Texas VA HCS Addiction Psychiatry Fellowship Director Associate Professor Of Psychiatry University Of Texas Southwestern Medical School PHARMACOTHERAPY OF ADDICTIVE DISORDERS

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3 OUTLINE OF MY PRESENTATION Veteran s Story Addiction definition Addiction as a chronic medical disease Barriers to the use of medications Alcohol Use Disorders Alcohol Pharmacotherapy

4 OUTLINE OF MY PRESENTATION Prevalence of Nicotine addiction Nicotine Pharmacotherapy Current Trends of Opioid Addiction in the US Opioid Maintenance Therapy (OMT)

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6 5CS OF ADDICTION: Chronic brain disease Control (loss of) Continued use Compulsive use Cravings

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8 Factors Contributing to Vulnerability to Develop a Specific Addiction Use of the drug of abuse essential 100% Genetic (25=50%) DNA SNPs Other polymorphisms Environmental (very high) prenatal postnatal Contemporary Cues Comorbidity Stress-responsivity mrna levels peptides proteomics Drug-Induced Effects (very high) neurochemistry Synaptogenesis behaviors Kreek et al., 2000; 2004

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11 BARRIERS TO ADDICTION PHARMACOTHERAPY Don t treat addiction like a medical disorder Blame the patient Lack of will power Just say no Can stop if.. He s flunked several rehabs. There s no hope. If she really cared about her kids, she d stop using

12 BARRIERS TO ADDICTION PHARMACOTHERAPY Lack of knowledge/unfamiliarity Pharmacotherapy is ineffective doesn t work With the aid of pharmacotherapy patients don t think they have true sobriety Methadone is government sponsored dope Smoking is one of the few joys left in their life

13 Henny Youngman WHEN I READ ABOUT THE EVILS OF DRINKING, I GAVE UP READING

14 ALCOHOL USE DISORDERS (US) 19 million people (7.7%) meet criteria for alcohol abuse and dependence 7.5 million children less than 18years live with a parent with an alcohol use disorder 85,000 deaths per year $185 billion is health care costs plus lost productivity

15 COLLEGE DRINKING: 40% college students have binged in the previous two weeks In one large study 31% college surveyed meet criteria for alcohol abuse and 6% for alcohol dependence 1700 deaths and 1.3 million yearly alcohol related injuries and assaults

16 COLLEGE DRINKING: Over 400,000 students had unprotected sex and 100,000 reported being too intoxicated to know whether or not they consented to sex

17 ALCOHOL USE DISORDERS (WORLD WIDE) 76.3 million people meet criteria for alcohol abuse and dependence 2.5 million deaths per year According to the WHO, 4% of global burden of disease related to alcohol The fastest growing per capita alcohol consumption has been in developing countries in the Asian subcontinent, increased by > 50% between 1980 and 2000

18 TYPE 1/A TYPE 2/B Less severe Late onset Fewer childhood risk factors Fewer alcohol related problems Good premorbid functioning More severe Early onset Childhood risk factors Familial alcoholism More chronic treatment history Axis II pathology ALCOHOLIC SUBTYPES (CLONINGER/BABOR)

19 Alcohol: Pharmacokinetics Metabolism of Ethanol Ethanol(grain alcohol) Alcohol Dehydrogenase Acetaldehyde Acetaldehyde dehydrogenase Acetic Acid CO 2 + H 2 O 19

20 EFFECTS OF ACUTE ALCOHOL ON REWARD CIRCUITS Dopamine and Opioid Systems Indirectly increase dopamine levels in the mesocorticolimbic system Associated with positively reinforcing/ rewarding levels of alcohol Indirect interaction with opioid receptors results in activation of opioid system Associated with reinforcing effects via -receptors Sources: Koob, GF, et.al., Neuron, 1998, 21: Messing RO In, Harrison s Principals of Internal Medicine 15 th Ed. 2001:

21 ALCOHOL STIMULATES OPIATE RECEPTORS Continued Alcohol use Or Withdrawal Starts Alcohol raises Beta endorphin, Stimulating mu Opiate receptors Stop alcohol, Beta endorphin Drops & Craving Starts

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24 ALCOHOL PHARMACOTHERAPY FDA approved Disulfiram Oral Naltrexone Intramuscular Naltrexone (Vivitrol) Acamprosate Non-FDA approved Baclofen Topiramate

25 DISULFIRAM Alcohol-sensitizing agent Serendipitous discovery FDA approved in 1949 Inhibits acetaldehyde dehydrogenase resulting in disulfiram-ethanol reaction (DER) Symptoms and signs of DER include nausea, vomiting, flushing, tachycardia, palpitations and hypotension Most DERs are self limited, lasting 30mins

26 DISULFIRAM Side effects are dizziness, metallic taste, acne, urticaria, acneform eruptions, headaches. Rarely can cause optic neuritis, peripheral neuropathy and hepatotoxicity (initial Danish studies done with 1-3grams per day) Maintenance dose 250mg daily

27 DISULFIRAM Warn patients about hidden alcohol Works well for highly motivated patients who intake is supervised Another mechanism that may be playing is inhibition of dopamine beta-hydroxylase presumably in the dopaminergic areas related to alcohol reinforcement

28 NALTREXONE: Full mu antagonist In 1984 approved to treat opioid addiction (Trexan) 10 years later approved for alcohol dependence (Revia) Decreases cravings Increases time to first drink Increases time to heavy drinking

29 Dose range mg daily, may titrate up to mg if needed Liver function tests (LFTs) at baseline and then every 3-6 months Cannot start Naltrexone if baseline LFTs greater than 3Xs the upper limit of normal Safe effect profile is benign,common side effects are nausea and headaches

30 DEPOT NALTREXONE Medisorb drug delivery technology Naltrexone is embedded within biodegradable polymer microspheres released over at least 30 days Recommended dose 380mg every month intramuscular in the gluteal region Can improve adherence

31 NALTREXONE RESPONDERS Type 2/B alcoholics Family history of alcoholism Strong alcohol cravings Patients with alcoholism who carry the Asp40 allele of the mu-opioid receptor gene (OPRM1) Patients who experience an exaggerated response in their opioid system when they consume alcohol ( feel-good drinkers )

32 NALTREXONE IN THE TREATMENT OF ALCOHOL DEPENDENCE 32 Volpicelli et al., 1992

33 MEAN CRAVING SCORES (SHOWS LESS CRAVING WITH NALTREXONE) 33 Volpicelli et al., 1992

34 DRINKING DAYS WHILE ON MEDICATION (SHOWS LESS DRINKING DAYS WHILE ON NALTREXONE) 34 Volpicelli 1992, 1994

35 SUBJECTIVE HIGH (BLOCKED OPIATE RECEPTOR EFFECT) 35 Volpicelli 1992, 1994

36 ACAMPROSATE Calcium salt of N-acetyl homotaurine Approved in 2005 Partial NMDA receptor antagonist Blocks increased glutamate release in nucleus accumbens during withdrawal Normalizes alcohol-induced decrease in basal GABA concentration

37 ACAMPROSATE Decreased arousal, cravings and dysphoria Recommended dose 666mg TID, compliance can be an issue No hepatic metabolism Renally excreted in unmetabolized form No dose adjustment in mild renal disease

38 Dose adjustment is necessary in moderate renal disease (i.e. creatinine clearance, ml/min) Contraindicated in severe renal disease (i.e., creatinine clearance, 30 ml/min)

39 Acamprosate Balances Glutamate Physiology a a a acamprosate a a a 39

40 TOPIRAMATE Originally synthesized as an anti-diabetic agent Approved for partial onset and primary generalized tonic-clonic seizures Half life hours No hepatic metabolism, 50-80% excreted unchanged in urine Increases GABA A facilitated neuronal activity Antagonizes AMPA and kainate glutamate receptors

41 TOPIRAMATE Shown in two large-scale randomized, placebocontrolled trials to reduce of heavy drinking and promote abstinence and decrease medical consequences of alcoholism Dosage initiated at 25mg/day, slowly titrated to 300mg /day over 8 weeks Common adverse effects paresthesias, taste perversion, anorexia and decreased cognition

42 BACLOFEN GABA B receptor agonist Renewed interest since publication of Dr Olivier Amiesen s book The End of My Addiction Recent double-blind placebo controlled study done in Italy found baclofen to be safe and effective in alcoholdependent patients with liver cirrhosis In 2012 approved for use in France on a case by case basis

43 Tobacco taking is a vile and stinking custome that is hurtful to the health of the whole body King James I The Counterblaste to Tobacco 1604

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46 NICOTINE ADDICTION (US) 42 million smokers Current prevalence 19.3% Prevalence rates continue to be high in patients with mental illness, low educational & socioeconomic status, veterans and Native Americans & Alaskans 440,000 smokers and 40,000 non-smokers die annually

47 NICOTINE ADDICTION (US) Mid-West has the highest prevalence followed closely by the South States with the highest prevalence - Kentucky and West Virginia Over 80% of all mentholated cigarettes purchased by Africans-Americans 3800 children smoke their first cigarette every day and rates of tobacco initiation are no longer declining

48 NICOTINE ADDICTION (US) Every day 1200 Americans die from smoking and each of those people is replaced by 2 young smokers Large persistent increases in risks of smoking related deaths among female smokers over the past half century Smoking costs $100 billion in health care costs and $97 billion in lost productivity annually Geisinger Healthcare System will not hire smokers

49 NICOTINE ADDICTION (WORLD WIDE) 1 billion smokers in the world 350 million smokers in China 5 million deaths annually from smoking WHO estimates by million will die in the world annually 600,000 non-smokers die from second hand smoke High prevalence rates persist in many parts of the world

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51 THE EFFECTS OF NICOTINE IN THE BRAIN Dopamine Norepinephrine Acetylcholine Glutamate Serotonin GABA Beta-endorphin Pleasure, appetite suppression Arousal, appetite suppression Arousal, Cognitive enhancement Learning, memory enhancement Mood modulation, appetite suppression Decreased anxiety, tension Decreased anxiety, tension

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53 FIRST LINE AGENTS Nicotine patch Nicotine gum Nicotine lozenges Nicotrol inhaler Nasal spray Nicotine sublingual tablet Bupropion Varenicline SECOND LINE AGENTS Nortriptyline Clonidine PHARMACOTHERAPY

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55 NRT: NICOTINE PATCH 24 hr (21, 14, 7mg) Nicoderm/generic Available OTC A new patch is applied each morning Rotating placement site can reduce irritation Treat for 6-9 months or longer Side effects: Insomnia, local rash, nightmares

56 PATCHES NEED TO BE INDIVIDUALIZED ½ pack daily= 14mg/day patch Upto a pack daily = 21 mg/day Over a pack daily but less two packs= 28mg/day Two packs= 35mg/day

57 57 FOR SMOKELESS TOBACCO Cans/Pouches/Week Mg NRT/day <

58 NRT: NICOTINE GUM 2 mg, 4 mg Add on treatment for breakthrough cravings Park and Chew Absorbed in a basic environment, avoid acidic beverages 15 minutes pre and during dose (coffee, soda, juice) Side effects: dyspepsia, mouth soreness

59 NRT: NICOTINE INHALER Available by prescription Continuous puffing over 20 minutes per dose (80 puffs per dose delivers 4 mg) 6-16 cartridges per day for 6-9 months Eating or drinking before and during administration should be avoided

60 NRT: NICOTINE NASAL SPRAY Available by prescription Patient should not sniff, swallow, or inhale the medication A dose is 2 squirts, one to each nostril Initial dosing should be 1 to 2 doses per hour, increasing as needed Dosing should not exceed 40 doses per day

61 BUPROPION SR Mechanism of action: presumably blocks neural reuptake of dopamine and/or norepinephrine Dosing: start 2 weeks before quit date 150 mg orally once daily x 3 day 150 mg orally twice daily Maintenance - efficacious as maintenance medication for 6 months post-cessation

62 BUPROPION SR (ZYBAN ) Contraindications Seizure disorder Eating Disorders MAO inhibitor in past 14 days Side effects: Dry mouth Insomnia (avoid bedtime dose)

63 VARENICLINE NAR partial agonist Dosing: Day 1-3: 0.5mg every day Day 4-7: 0.5mg twice a day Day 8 onwards: 1mg twice a day Quit smoking on Day 8 Black box warning Side effects are nausea, nightmares

64 PLASMA NICOTINE CONCENTRATIONS FOR NICOTINE- CONTAINING PRODUCTS 64 Cigarette Moist snuff Time (minutes)

65 COMBINATION THERAPIES SUPERIOR RCT of 5 smoking cessation pharmacotherapies n=1504 (58% female, 85% white) Participants were randomized to 1 of 6 treatment conditions Nicotine lozenge Nicotine Patch Bupropion SR Patch plus lozenge Bupropion + lozenge Placebo

66 Comparitive Effectiveness of 5 Smoking Cessation Pharmacotherapies in Primary Clinics

67 MY APPROACH Nicotine Patch 21mg/day Nicotine Gum or Lozenges 4mg 5-6 pieces daily for breakthrough cravings Consider addition of Bupropion SR for patients with weight issues or history of significant weight gain with quit attempts

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69 QUITTING INCREASES LIFE EXPECTANCY Doll et al., BMJ,

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72 EPIDEMIOLOGY OF HEROIN ADDICTION 12 million heroin users world wide 1 million here in the US Only about 225,000 are enrolled in treatment One third women, 60% Caucasian 25% are HIV positive and over 75% Hepatitis C positive

73 EPIDEMIOLOGY OF PRESCRIPTION OPIOID ADDICTION (NSDUH 2009) 5.3 million persons 12 or older used opioid medications nonmedically in the past month In 2009, 1.9 million persons met criteria for prescription opioid addiction Of the 3.1 million persons aged 12 or older who used illicit drugs for the 1 st time, 17.1% initiated with narcotic pain medications

74 INITIATION OF ILLICIT DRUG USE

75 SOURCES OF NARCOTIC PAIN MEDICATIONS Initiation of nonmedical opioid use 55.3% obtained drug from friend or relative 17.6% obtained drug from one doctor 4.8% bought drug from a stranger 0.4% reported purchasing through the internet

76 OPIOID ADDICTION: MEDICAL COMPLICATIONS Infections: HIV, Hepatitis B & C, endocarditis, meningitis, septicemia, TB, abscesses, cellulitis, phlebitis, necrotizing fasciitis & wound botulism (skin popping black tar heroin) Nephropathy, rhabdomyolysis, PE, lymphedema, menstrual irregularity Impaired immune function Hepatic and renal toxicity from acetaminophen and NSAID use

77 MORTALITY Death rate several times greater than the general population Drug overdose most common cause Other causes include suicide, homicide, MVAs, Liver disease, cancers and cardiovascular disease

78 PHARMACOLOGICAL TREATMENT OF OPIOID ADDICTION Short term Detoxification using nonopioids Detoxification using opioids Long term Opioid maintenance therapy (OMT) Opioid antagonist

79 OPIOID DETOXIFICATION EFFICACY Extremely high relapse rates > 90% High risk for HIV, OD upon relapse Must be followed up with structured treatment, 12 step recovery Abstinence based approach is not the best treatment for opioid addiction

80 ROLE OF ANTAGONISTS Naltrexone (PO and depot intramuscular injection) Useful only in highly selected, highly leveraged patient populations i.e. physicians & nurses High non-compliance rates

81 OPIOID MAINTENANCE TREATMENT (OMT): Medication assisted treatment for patients with a history of opioid addiction Dispensing and/or prescribing of a full or a partial mu agonist

82 GOALS OF OMT Eliminate or reduce illicit opioid use Eliminate drug cravings and withdrawal symptoms Decrease in HIV/Hepatitis seroconversion Decrease in criminal behavior Improve social and occupational functioning

83 FDA APPROVED MEDICATIONS USED FOR OMT: Methadone Buprenorphine/Naloxone (Suboxone) Buprenorphine (Subutex)

84 METHADONE Full mu agonist NMDA antagonist and is an SNRI Approved for opioid addiction (liquid/wafer) and analgesia (tablets) Approved for pregnant opioid addicted women Schedule II BUPRENORPHINE Partial mu agonist Weak kappa antagonist Tablets/Film approved for opioid addiction Transdermal patch approved for pain Studied in pregnant opioid addicted women Schedule III

85 METHADONE Dispensed through opioid maintenance clinics for opioid addiction, can be prescribed for pain May prolong QTc Limited to people in large metropolitan areas BUPRENORPHINE Can be prescribed to treat opioid addiction No cardiotoxicity Has increased access to care

86 Full Agonist (Heroin, methadone) % Efficacy Log Dose of Opioid Partial Agonist (Buprenorphine) Antagonist (Naloxone)

87 METHADONE 18 month follow up of HIV negative subjects showed conversion rates of 3.5% versus 22% Metzger et al (1993)

88 Remaining in treatment (nr) KAKKO, LANCET Detoxification Maintenance Treatment duration (days)

89 MATERNAL OPIOID TREATMENT HUMAN EXPERIMENTAL RESEARCH (MOTHER STUDY) Double blind double dummy flexible dosing RCT 175 women enrolled between May 2005 to October 2008 at eight sites Primary outcomes were the number of neonates requiring treatment for neonatal abstinence syndrome (NAS), the peak NAS score, amount of morphine needed, length of hospital stay and neonatal head circumference

90 MATERNAL OPIOID TREATMENT HUMAN EXPERIMENTAL RESEARCH (MOTHER STUDY) Discontinuation rates higher in the buprenorphine group (33% vs 18%) Neonates exposed to buprenorphine requires significantly less morphine (1.1mg vs 10.4mg),shorter hospital stay (10.0 days vs 17.5days) and shorter duration of treatment (4.1days vs 9.9days)

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