Medical Interventions for Addiction in Primary Care Settings R. Douglas Bruce, MD, MA, MSc Assistant Professor Yale University School of Medicine March 23, 2010
NIH Consensus on Drug Treatment Drug Addiction is a disorder of the brain and therefore a medical disorder d Broader access to drug treatment Reduce federal and state barriers impeding access to treatment Stressed the importance of providing substance abuse counseling, psychosocial therapies, and other supportive services March 23, 2010 2
Summary Slide Just as medication can help with depression, medication can help in the treatment of alcohol dependence, opioid dependence, cocaine dependence, nicotine dependence, etc. March 23, 2010 3
Outline Neurobiology of addiction Mdi Medication i assisted treatment Opioids - methadone, buprenorphine, naltrexone Cocaine disulfiram Methamphetamine - buproprion Alcohol naltrexone, topiramate Nicotine NRT, buproprion, varenicline March 23, 2010 4
Neurotoxicity NEUROTOXICITY AIDS, Cancer AIDS Mental illness CANCER MENTAL ILLNESS Homelessness Crime Violence March 23, 2010 5 Health care Productivity Accidents
If the societal cost is so high, why do people do drugs? March 23, 2010 6
Common Myths About Drug Abuse Drug abuse equates to drug addiction Alcohol is not a drug Addiction is a moral weakness You have to hit rock bottom to recover You have to want treatment for it to be successful Drug abuse is more common among minorities March 23, 2010 7
Addiction A state in which an organism engages in compulsive li behavior bh The behavior is reinforcing (that is, pleasurable or rewarding) There is a loss of control in limiting the intake of the substance March 23, 2010 8
Why Do People Take Drugs in The First Place? To feel good To have novel: feelings sensations experiences AND to share them To feel better To lessen: anxiety worries fears depression hopelessness March 23, 2010 9
Vulnerability Why do some people become addicted d while others do not? March 23, 2010 10
Biology/genes Biology/ Environment Interactions Environment March 23, 2010 11
High DA receptor Low DA receptor DA Receptors and the Response to Methylphenidate (MP) high low Dopa amine rece eptor level As a group, subjects with low receptor levels found MP pleasant while those with high levels found MP unpleasant March 23, 2010 12 Adapted from Volkow et al., Am. J. Psychiatry, 1999.
used to be March 23, 2010 13
Circuits Involved In Drug Abuse and Addiction All of these must be considered in developing strategies to March effectively 23, 2010 14 treat addiction
Natural Rewards Elevate Dopamine Levels % of Basal DA Output 200 150 100 50 0 FOOD Empty Box Feeding NAc shell 0 60 120 180 Time March (min) 23, 2010 DA Concentratio on (% Baselin ne) 200 150 100 Sample Number SEX Female Present 1 2 3 4 5 6 7 8 15 10 5 0 Copulation Frequency Mounts Intromissions Ejaculations Di Chiara et al., Neuroscience, 1999. Fiorino and Phillips, J. Neuroscience, 1997.
Effects of Drugs on Dopamine Release Release % of Basal 1100 1000 900 800 700 600 500 400 300 200 100 0 Accumbens AMPHETAMINE DA DOPAC HVA 0 1 2 3 4 5 hr Time After Amphetamine % of Basal Release 400 300 200 100 0 Accumbens COCAINE DA DOPAC HVA 0 1 2 3 4 5 hr Time After Cocaine % of Basa al Release 250 200 150 100 NICOTINE Accumbens Caudate % of Basal 200 Release250 150 100 Accumbens MORPHINE Dose (mg/kg) 0.5 1.0 25 2.5 10 0 0 1 2 3 hr Time After Nicotine 0 0 1 2 3 4 5hr Time After Morphine March 23, 2010 16 Di Chiara and Imperato, PNAS, 1988
Dopamine D2 Receptors are Lower in Addiction Control Addicted Cocaine DADA DA DA DA DA DA DA DA DA DA DA Meth Reward Circuits Non-Drug Abuser Alcohol DADA DA DA DA DA Heroin March 23, 2010 17 Reward Circuits Drug Abuser
Drugs Are Usurping Brain Circuits and Motivational Priorities March 23, 2010 18
Addiction Changes Brain Circuits Non-Addicted Brain Addicted Brain Control Control NOT Saliency Drive GO Saliency Drive GO Memory Memory Source: Adapted from Volkow et al., Neuropharmacology, 2004. March 23, 2010 19
This is why addicts can t just quit This is why treatment is essential March 23, 2010 20
Treatment for Addiction Includes: 1. Pharmacological (medications) 2. Behavioral Therapies 3. Medical treatment for the complications of addiction (e.g., HIV, HCV therapy) 4. Social Services March 23, 2010 21
Pharmacology in Primary Care: Opioids = buprenorphine March 23, 2010
Heroin Heroin is a short-acting, semisynthetic opioid produced from opium that can be smoked, sniffed, or injected Heroin euphoria begins shortly after injection and lasts ~ 1 hour, followed by 1-4 hours of sedation; withdrawal symptoms or craving begin several eral hours later. Most heroin dependent individuals inject 2-4 times per day. Many mediate sedating effects by injecting a small amount of cocaine, if available (not in Russia or Asia), known as a "speedball." Sometimes crack is smoked as a substitute. []. Unsterile use, unpredictable concentrations in street samples, adulterants in injection mixture, lifestyle necessary to procure drugs are responsible for most heroin-associated medical complications. March 23, 2010 23
Effects of Buprenorphine Dose on µ-opioid Receptor Availability in a Representative Subject Binding Potential (Bmax/Kd) MRI 4 - Bup 00 mg Bup 02 mg 0 - Bup 16 mg Bup 32 mg March 23, 2010 24 Slide Courtesy of Laura McNicholas, MD, PhD
Medication Assisted Treatment - Opioids Rationale Cross-tolerance prevent withdrawal relieve craving for opioids Narcotic blockade block or attenuate euphoric effect of exogenous opioids Pharmacotherapy Buprenorphine Methadone LAAM Naltrexone March 23, 2010 25
Intrinsic Activity 100 Intrinsic Activity 90 80 70 60 50 40 30 20 10 0 Full Agonist (Methadone) Partial Agonist (Buprenorphine) Antagonist (Naltrexone) -10-9 -8-7 -6-5 -4 Log Dose of Opioid March 23, 2010 26
100 Buprenorphine, Methadone, LAAM: Treatment tr Retention ti ned Percen nt Retai 80 73% Hi Meth 60 58% Bup 40 53% LAAM 20 20% Lo Meth 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 March 23, 2010 27 Study Week
Buprenorphine, Methadone, LAAM: Opioid Urine Results % Nega ative Mean 100 80 60 40 20 All Subjects 49% 40% 39% 19% LAAM Bup Hi Meth Lo Meth 0 1 3 5 7 9 11 13 15 17 March 23, 2010 28 Study Week
Buprenorphine Every physician treating HIV-infected drug users should have an X waiver and be ready to prescribe. The 1, 2, 3 of BUP: 1. It is easier than HIV/HCV treatment. 2. It is safer than prescribing oxycodone for pain or alprazolam for anxiety. 3. It is desperately needed to expand access to treatment. 3/23/2010 29
Pharmacology in Primary Care : Cocaine = Disulfiram March 23, 2010
Cocaine Cocaine C i hydrochloride hl is a water-soluble salt which his injected or taken by nasal inhalation, snorted. Although cocaine hydrochloride is destroyed by heat, it may be chemically converted to a free-base ("crack") cocaine, which can be smoked. Pulmonary absorption of crack is as rapid as IV injection. Cocaine s half-life is short, resulting in the need for frequent administration; active cocaine users may inject or inhale cocaine as many as 20 times a day. Cocaine induces feelings of elation, omnipotence and invincibility i ibili and with volatile behavior and rapid development of dependence. Cocaine use is associated with high risk sexual behavior. March 23, 2010 31
Site of Cocaine Binding March 23, 2010 32
Disulfiram Increases dopamine in the brain by inhibiting dopamine beta hydroxylase. 6 RCTs have demonstrated efficacy in treating cocaine dependence. Dosage: 250 mg/day No studies in HIV/HCV populations so need to watch AST/ALT Problem remains adherence. Works well with the motivated patient or the patient who is administered it with methadone. 3/23/2010 33
Pharmacology in Primary Care : Methamphetamine = Buproprion March 23, 2010
Methamphetamine (MA) MA is a psychostimulant similar in chemical structure to amphetamine with more profound effects on the CNS and can be smoked, snorted, injected, or administered rectally. Produces stimulation and feelings of euphoria and dh has a long duration of action (6t to 8h hours after a single dose) Tolerance develops rapidly and escalation of dose and df frequency is required. As with cocaine, MA use is associated with high risk sexual behavior (especially in MSM) Neurocognitive effects of MA use worse in HIV positive patients.. March 23, 2010 35
Dopamine Transporters in Methamphetamine Abusers Dopamine Transporte er Bmax/K Kd 2.0 1.8 1.6 1.4 1.2 1.0 7 8 9 10 11 12 13 Time Gait (seconds) 2.0 1.8 1.6 1.4 1.2 1.0 16 14 12 10 8 6 Delayed Recall (words remembered) Motor Task Loss of dopamine transporters in the meth abusers may result in slowing of motor reactions. Memory task Loss of dopamine transporters in the meth abusers may result in memory impairment. 4 Normal Control March 23, 2010 36 Methamphetamine Abuser Volkow et al., Am. J. Psychiatry, 2001..
Treatments Bupropion 150 mg twice daily has shown some reduction in use among mild methamphetamine users (Shoptaw DAD 2008) Counseling remains the mainstay 3/23/2010 37
Pharmacology in Primary Care: Alcohol = Naltrexone March 23, 2010
Alcohol Main Points Disinhibition that leads to increased risk taking behaviors and poor adherence to all treatments Withdrawal seizures The drug that really is frightening because it is neurotoxic and accelerates HCVdi disease progression CAGE Questions March 23, 2010 39
ETOH Treatment Naltrexone FDA approved and standard of care Watch for hepatotoxicity (black box warning) Dosages: 100 mg per day (based on COMBINE study) Acamprosate FDA approved, but inferior to naltrexone Disulfiram FDA approved, but inferior to naltrexone 3/23/2010 40
Topiramate Not FDA approved for ETOH dependence 8 papers showing efficacy of topiramate for ETOH dependence Doses varied by trial, but typically patients were started low (25 mg daily) and titrated up to a max of 300 mg over 6 weeks. Important choice because: 1. Can give to patients on opioids 2. Moderates symptoms of withdrawal 3/23/2010 41
Pharmacology in Primary Care: Nicotine = Nicotine 3/23/2010 42
The 5 A s Ask about tobacco use Advise smokers to quit Assess willingness to quit Assist with quitting Arrange follow-up Brief advice to quit does make a difference! 3/23/2010 43
Pharmacotherapy Nicotine replacement helps Buproprion doubles quit rates (but is metabolized by CYP 2B6 so possible interactions with NFV, RTV, and EFV). Doses 150 mg to 300 mg effective. Varenicline better than buproprion and nicotine in comparison trials watch for suicidality and exacerbation of neuropsychiatric symptoms. Slow upward titration to minimize side effects. 3/23/2010 44
Continuum of Interventions Knowing the Pieces March 23, 2010
Range of Treatments Risk (Harm) Reduction Decrease frequency of adverse events related to a behavior Change in use behavior e.g., Changing from injection use to sniffing Risk (Harm) Removal Cessation of substance abuse Abstinence based 12 Steps Agonist based buprenorphine, methadone March 23, 2010 46
Harm reduction is critical because drug addiction is a chronic illness with relapse rates similar il to those of fh hypertension, diabetes, and asthma McLellan et al., JAMA, 2000. March 23, 2010 47
Relapse Rates Are Similar for Drug Addiction & Other Chronic Illnesses 100 90 80 70 Relapse 60 50 40 30 20 ent of Patients Who 40 to 60% 30 to 50% to 70% to 70% 10 Perc 50 50 0 g Addiction Drug Type I Type I Diabetes Hypertension Asthma McLellan et al., JAMA, 2000. March 23, 2010 48
DAT Recovery with prolonged abstinence bti from methamphetamine [C-11]d-threo-methylphenidate Normal Control high There is hope!! Methamphetamine Abuser (1 month detoxification) low Methamphetamine Abuser (14 month abstinent) March 23, 2010 49 Volkow et al., J. Neuroscience, 2001.
Questions? Robert.bruce@yale.edu 3/23/2010 50