* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project
Download 0 - THD Internal Medicine Training Program
Drug design wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Prescription costs wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Neuropharmacology wikipedia , lookup
Ms. Alvarez is a 45 year old Latin-American female with a history of multiple episodes of alcoholic pancreatitis. She presents to the ER complaining of epigastric abdominal pain and nausea for 2 days. The ER physician picks up her chart, rolls his eyes after recognizing her name, and mumbles to himself in disgust, “Why in the hell is she here again? What do you want me to do…why doesn’t she just stop drinking?” He barges into her room, says a few words, smashes on her abdomen until she screams, and rushes out of the room. He orders a CBC, chem-14 and lipase, and starts IVF. The lipase is only mildly elevated, but she is admitted with a diagnosis of pancreatitis. She tells the hospitalist that she quit drinking 9 months ago, but he does not believe her. She is made NPO, and given IVF and morphine prn. Overnight, her abdominal pain worsens, and she continues to ask for more pain medicine. Her nurse reluctantly gives her more morphine. At the nursing station, she is referred to as “the alcoholic lady in 742,” and the nurses talk about how many times they have taken care of her. When her admitting physician makes rounds the next morning, her nurse is annoyed and comments, “This one kept me up all night.” He examines the patient, and notes that her abdomen is much more tender, and she now has rebound tenderness. Her temperature is 101º and her WBC is 22K. He obtains a CT of the abdomen and a surgical consult. The CT shows an inflamed gallbladder with a surrounding fluid collection. She develops obvious peritoneal signs, and she is taken to the operating room. The surgeon finds a perforated gallbladder. Points to Ponder…. All of us have admitted patients with poorly controlled diabetes mellitus. We pardon their morbid obesity, poor dietary habits, and noncompliance, and we continue to treat them with respect. So, why do we excuse noncompliant diabetics BUT we stigmatize noncompliant or relapsing patients with substance abuse disorders? How often do we treat the medical complications but never address the underlying substance abuse disorder? If it were that simple, writing “stop drinking” on the discharge sheets would actually work. Update on Substance Abuse Disorders Nilam J. Soni, MD Overview 1. 2. 3. 4. 5. 6. Epidemiology Neurobiology of Addiction Definitions Screening for Substance Abuse Brief Interventions and Motivational Interviewing Alcohol a. b. 7. Opioids a. b. 8. Inpatient Management Outpatient Management Inpatient Management Outpatient Management Resources Epidemiology Epidemiology In 2002, approximately 19.5 million Americans, or 8.3% of the population ages 12 or older, were current illicit drug users [ 2002 National Survey on Drug Use and Health (NSDUH), SAMHSA] 53% of students have tried an illicit drug by the time they finish high school In 2003, 4.5% of 12th graders used Oxycontin in the past year and 10.5% used Vicodinmaking Vicodin the second-ranked drug after marijuana (University of Michigan, 2003 Monitoring the Future Study) Any Illicit Drug Including Inhalants: Trends in Lifetime Use (8th, 10th, and 12th Graders) Percent Who Ever Used 70 65 60 55 50 45 40 35 30 25 20 '91 '92 '93 '94 Twelfth Grade '95 '96 '97 '98 Tenth Grade '99 '00 '01 '02 '03 Eighth Grade Source: Monitoring the Future Study, 2003, NIDA Mr. and Mrs. Smith come to see you in the clinic. Mrs. Smith is very angry about her husband’s drinking, but he doesn’t feel like he has a problem. His father was an alcoholic, but Mr. Smith adamantly says, “There is no way that I am.” Mrs. Smith says, “I think that he is just weak, mentally that is, and he just needs to strengthen his will power. After all, isn’t alcoholism just a matter of will power.” How would you respond to her? Neurobiology of Addiction (National Institute on Drug Abuse) Advances in science have revolutionized our fundamental views of drug abuse and addiction This is your brain on drugs….. YELLOW shows areas of brain stimulated by cocaine (striatum) 1-2 Min 3-4 5-6 6-7 7-8 8-9 9-10 10-20 20-30 Disease Model for Drug Addiction Genes CYP 2A6 levels and tobacco dependence Mu-receptor and heroin addiction Environment Early physical/sexual abuse Witnessing violence Stress Drug availability Dopamine and Serotonin Pathways Dopamine Receptor Levels and Response to Methamphetamine Subjects with low dopamine receptor levels found methamphetamine pleasant while those with high dopamine receptor levels found methamphetamine unpleasant Thus, drugs have variable effects on the brain which determine a pleasant from an unpleasant response. 2.5 unpleasant response 0 pleasant response Dopamine Pathways Serotonin Pathways striatum frontal cortex hippocampus substantia nigra/VTA Functions •reward (motivation) •pleasure, euphoria •motor function •compulsion •perseveration nucleus accumbens raphe Functions •mood •memory processing •sleep •cognition Accumbens 1100 1000 900 800 700 600 500 400 300 200 100 0 AMPHETAMINE Accumbens % of Basal Release 400 DA DOPAC HVA 250 1 2 3 4 Time After Amphetamine NICOTINE 200 Accumbens Caudate 150 100 0 0 1 2 3 hr Time After Nicotine COCAINE DA DOPAC HVA 300 200 100 0 5 hr % of Basal Release 0 % of Basal Release % of Basal Release Effects of Drugs on Dopamine Release 250 0 1 Accumbens 2 3 4 Time After Cocaine 5 hr MORPHINE Dose (mg/kg) 0.5 1.0 2.5 10 200 150 100 0 Source: Di Chiara and Imperato 0 1 2 3 4 Time After Morphine 5hr Development of Addiction Genetic Predisposition ↓ Environmental Stress ↓ Drug Abuse (Initiation of drug use, pleasurable experiences, hazardous use) ↓ Drug Addiction (Neurochemical brain changes, uncontrollable drug use) Amygdala Nature Video Cocaine Video Anterior Cingulate Prolonged drug use→ development of pathways that cause craving Cocaine Craving Population (cocaine addicts vs. controls) x Films (cocaine, erotic) Signal Intensity (AU) Cingulate Ant Cing Cocaine Film Erotic Film Controls IFC Cocaine Addicts Garavan et al A .J. Psych 2000 Effects of Abstinence Abstinence from methamphetamine for 24 months demonstrated some recovery, but not complete normalization. Therefore, addicts are always at risk for relapse. [C-11]d-threo-methylphenidate Normal Control Methamphetamine Abuser (1 month detoxification) Methamphetamine Abuser (24 month abstinent) Volkow, N.D. et al., Journal of Neuroscience, 21(23), pp. 9414-9418, December 1, 2001. Summary Normal (at risk) Drug Use Addiction Treatment Definitions Spectrum of Substance Use Substance Use Disorders Dependent Abuse Hazardous Low Risk Abstinence Drug Abuse DSM IV Criteria 1 or more adverse effects over 12 months: 1. Recurrent use resulting in failure to fulfill major role obligations 2. Recurrent use in hazardous situations 3. Recurrent substance-related legal problems 4. Continued use despite interpersonal or social problems related to use Drug Dependence DSM IV Criteria 3 or more in 12 months Tolerance Withdrawal Much time obtaining, using, recovering Activities given up or reduced More or longer than intended Unable to cut down or control Use despite knowledge of health consequences (Preoccupation and compulsion addressed in 3-7) 1. 2. 3. 4. 5. 6. 7. What is Addiction? Compulsive substance use without medical purpose in the face of negative consequences A different neurobiological state; the addicted brain is different from the non-addicted brain A condition involving activation of the brain’s mesolimbic dopamine system; a common denominator in the acute effects of drugs of abuse Leshner AI. Science-based views of drug addiction and its treatment. JAMA. 1999;282:1314-1316. Alcohol Use in Primary Care Setting Adults > 18 Low-risk Drinkers 38% Hazardous Drinkers 9% Alcohol Abuse 8% Alcohol Dependent 5% Abstainers 40% Manwell, et al, 1997 Case A 36 year old white male presents to your clinic for the first time. He reveals that he smoked marijuana occasionally in high school. Currently, he drinks “socially” and does not use any drugs. You investigate his drinking further. He reports drinking a 6-pack with friends on Friday night and 6-pack while watching sports on Saturday or Sunday. His drinking has never interfered with his daily activities. Are his drinking habits consistent with hazardous drinking, alcohol abuse, or alcohol dependence, OR is his drinking of no concern? Screening for Substance Abuse Screening for Alcohol Abuse Alcohol Use None Light Moderate Heavy Hazardous Low Risk Abuse Dependent Severe Moderate Small None Alcohol Problems NIAAA Guidelines Low risk drinking Men: < 14 drinks/wk; < 4 drinks/occ Women:< 7 drinks/wk; < 3 drinks/occ No use in risky situations Hazardous (at risk) drinking Men: >14 drinks/wk; >4 drinks/occ Women & over 65: >7 drinks/wk; >3 drinks/occ National Institute on Alcohol Abuse and Alcoholism. Physicians’ Guide to Helping People with Alcohol Problems, 1995,2003 What is a Standard Drink? 1 can of ordinary beer or ale 12 oz. single shot of spirits, gin, whiskey, vodka, etc.. 1.5 oz. glass of wine 5 oz. small glass of sherry 4 oz. small glass of liqueur or aperitif 4 oz. Screening Instruments Common in Practice Quantity & frequency CAGE AUDIT-C Other Screens MAST (25 items) S-MAST AUDIT (10 items) TWEAK (pregnancy) T-ACE (pregnancy) Piccinelli ‘97, Bradley ‘98, ‘03, Reid ‘99, Knight ‘01, Isaacson ‘94, Brown ‘95 CRAFFT (adolescent) POSIT (adolescent) CAGE-AID (drugs) CAGE Questions Cut down on your drinking? Annoyed at others’ criticism of your drinking? Guilty about something that happened when you were drinking? Eye-opener (drink 1st thing in the morning) Cut- off point: > 2 positive Mayfield, et al; Am J Psychiatry 131:1121-1123, 1974 CAGE > 2 Positive Responses Sensitivity 77 - 94% Limitations: Specificity 76 - 96% Lifetime use Positive predictive More reliable for alcohol value: 55-75%, assuming 20% prevalence abuse and dependence Not as sensitive for: women elderly African-Americans Summary of Screening ASK about alcohol use CAGE consumption (per week, per occasion) if >14 drinks/week or >4/occasion (men) >7/week or >3/occasion (women) or CAGE 1 or more ASSESS for alcohol-related problems medical, behavioral, social alcohol dependence alcohol-related problems at risk for developing problems Summary of Screening alcohol dependence alcohol-related problems at risk for developing problems advise to abstain refer to a specialist advise to cut down set a drinking goal Monitor patient progress Detection Time in Urine 1-3 days marijuana, heroin, cocaine, codeine, morphine 2-4 days Amphetamine, methamphetamine, shortacting barbiturates, methadone Up to 30 days chronic marijuana or PCP use long-acting benzodiazepines Case A 36 year old white male present to your clinic for the first time. He reveals that he smoked marijuana occasionally in high school. Currently, he drinks “socially” and does not use any drugs. You investigate his drinking further. He reports drinking a 6-pack with friends on Friday night and a 6-pack while watching sports on Saturday or Sunday. His drinking has never interfered with his daily activities. Are his drinking habits consistent with hazardous drinking, alcohol abuse, or alcohol dependence, OR is his drinking of no concern? Brief Interventions and Motivational Interviewing Readiness to Change Model Precontemplation Contemplation Relapse Determination Maintenance Action Motivational Interviewing Motivational interviewing is a directive, client-centered counseling style for eliciting behavior change by helping clients explore and resolve ambivalence. Stephen Rollnick, William R. Miller, 1995 Rollnick, S., & Miller, W. R. What is motivational interviewing? Behavioral and Cognitive Psychotherapy. 1995;23:325-334. Motivational Interviewing Techniques Develop discrepancy Avoid argumentation Role with Resistance Express Empathy Support Self-efficacy Miller WR, Rollnick S, Conforti K. Motivational Interviewing, Second Edition: Preparing People for Change. New York: Guilford Press; 2002. Brief Intervention 5-15 minute counseling session Four components State your concerns about patient’s use of alcohol/drugs Make explicit recommendation for change in behavior Discuss patient’s reaction Review treatment options; negotiate plan Case A 42 year old Navajo male is brought by EMS to the ER with altered mental status. He ended a 7-day alcohol binge 1 day ago. His blood alcohol level is negligible, and he is admitted for alcohol withdrawal. He is given 4mg of lorazepam IV in the ER followed by 2mg upon arrival to the floor. He receives scheduled lorazepam, 2mg IV every 6 hours. Over the next 12-16 hours, he becomes progressively more agitated. His nurse calls you, and you give him a booster of lorazepam 4mg IV. Case She calls you back in 1 hr and tells you that he is still very agitated with a pulse of 140 bpm and BP of 185/100. You give him an additional 4mg of lorazepam. The nurse calls you after 30min and says that he is “out-ofcontrol.” He is pulling fiercely at his restraints, screaming, and complaining of insects on the wall, and his BP and pulse are still elevated. You give him 4mg more of lorazepam, but he does not improve. What should you do next? Management of Alcohol Abuse Inpatient and Outpatient Management Alcohol Withdrawal Onset 5-10 hrs, peak 2-3 days, resolve 4-5 days Signs and symptoms ( ≥ 2 by DSM IV criteria) Autonomic hyperactivity (sweating, tachycardia, ↑ BP) Tremor Nausea/vomiting Anxiety Psychomotor agitation Anxiety Grand mal seizures Hallucinations (tactile, visual, auditory) Management of Alcohol Withdrawal ASAM Guidelines Symptom-triggered (q1h when severe) Chlordiazepoxide 50-100 mg Diazepam 10-20 mg Lorazepam 2-4 mg Fixed Schedule (q6h for 4/8 doses + prn) Chlordiazepoxide 50mg/25mg Diazepam 10mg/5mg Lorazepam 2mg/1mg Mayo-Smith and ASAM working group JAMA 1997;278:144-51 Saitz and O’Malley Med Clin N A 1997;81:881-907 Management of Alcohol Abuse or Addiction (Inpatient or Outpatient) 1. Detoxification (inpatient vs. outpatient) 2. Social Services (psychological, medical, 3. 4. 5. 6. employment, and legal problems) Removal from drinking environment Mutual/self-help groups (AA, NA, cocaine anonymous, etc.) Counseling (cognitive-behavioral, family, psychotherapy,etc.) Pharmacotherapy Disulfiram Relevant mechanism Inhibits ALDH allowing acetaldehyde to accumulate Desired effects (take qd or before risky situation) Flushing, tachycardia, nausea, vomiting, hypotension, blurred vision, confusion, dizziness (30 minutes) Side effects Lethargy, neuropathy, liver toxicity, psychosis, HTN Disulfiram (DS) Multicenter RCT, 12 month follow-up, N=605 DS 250 mg, 1 mg, or none More abstinence in those adherent to DS (43% vs. 8%, p<0.001) Fewer drinking days in the 162 who were assigned to DS, adhered, and completed follow-up, compared with the other 2 groups (p=0.05) ***Need supervised administration and involvement of counselor*** Fuller RK et al. JAMA 256:1449, 1986 Supervised Disulfiram: randomized studies Author, Year Followup Disulfiram Abstinence Gerrein, ‘73 85% 39% Supervised Unsupervised 40 % 7% Azrin,1976 90% Supervised Unsupervised 90-98 % 55 % Azrin,1982 100% Supervised Unsupervised 73% * 47% * Liebson,’78 78% Supervised Unsupervised 98% 79% Length of follow-up was as follows: Gerrein 1973: 8 weeks; Azrin 1976: 2 years, Azrin 1982: 6 months; Liebson 1978: 6 months. * Thirty-day abstinence at 6-months Naltrexone Relevant mechanism Blocks endogenous opioids release due to dopamine release in reward center Desired Effects Less pleasurable effect of alcohol, reinforcement Side Effects Nausea, dizziness, hepatotoxicity, difficult pain management Contraindications Opiate dependence, pregnancy, active liver disease Naltrexone for Alcohol Dependence Combined analysis from Volpicelli (1992) and O’Malley’s (1992) studies, N=186. Taken from O'Brien CP, McLellan AT. Lancet 1996;347:237-240. Naltrexone: Initial and Maintenance Treatment STUDY 1: Initial Naltrexone Treatment Randomized (n = 197) 10 weeks Received CBT + NTX (n = 97) STUDY 2. CBT Naltrexone Maintenance Responders randomized (n = 60) 24 weeks Received CBT + NTX (n = 30) Received PCM + NTX (n = 93) STUDY 3. PCM Naltrexone Maintenance Responders randomized (n = 53) 24 weeks Received CBT + PLA Received PCM + NX Received PCM + PLA (n = 30) (n = 26) (n = 27) O'Malley SS et al. Arch Intern Med 2003;163:1695 - 1704. Naltrexone: Initial and Maintenance Treatment CBT (n=97) PCM (n=93) Primary Outcomes Responder (n, %) Percentage of days abstinent 77 (79.4%) 79.9 + 31.4 74 (79.6%) 77.9 + 30.9 3.3 + 5.6 60 (61.9%) 43 (44.3%) 3.3 + 4.7 52 (55.9%) 31 (33.3%) -43.1 + 75.3 -37.9 + 65.7 8.0 + 5.4 8.2 + 5.8 Secondary Outcomes Drinks per drinking day No relapse to heavy drinking Continuous Abstinence (n, %) GGT end point change from baseline (mean + SD) OCDS total score Therapy (mean + SD) Acamprosate Relevant mechanism: unclear; GABA analogue Desired effects: unclear Side effects: diarrhea Increased abstinence, decreased drinking days Not available (yet) in the US Management of Opioid Abuse and Addiction Inpatient and Outpatient Management Opioids Natural (opiates), Semisynthetic, and synthetic Opioid Intoxication Altered level of consciousness Respiratory rate <12 breaths per minute Direct effect on brainstem respiratory center Reduction of responsiveness to CO2 Miotic pupils Response to naloxone Opioid Overdose Treatment Adequate ventilation Observation until normal level of consciousness Inadequate ventilation Ventilate with 100% O2 Naloxone 0.2-0.4 mg IV, SQ, or IM, repeat with 1-2 mg if no improvement in 5-7 minutes Observe for 2-3 hours for complications or re-sedation 3-7% complicated by pneumonia, pulm edema No prospective clinical trials comparing IV vs IM vs. SQ or different doses Opioid Overdose Treatment Higher doses may be required for semi-synthetic oral opioids Small rate (6 of 453 patients) of complications with naloxone treatment* Seizure, arrhythmias, pulmonary edema and severe agitation with violent behavior All complications occurred within 10 minutes Complication rate similar to flumazenil treatment for benzodiazepine overdose Osterwalder JJ. J Toxicol Clin Tox 1996 Naloxone Opioid antagonist at mu, kappa and delta receptors No agonist activity Absorbed IV, IM, SQ and endotracheal Rapid onset IV but offset by time to place IV Orally inactivated by hepatic metabolism Highly lipid soluble Onset of action: 1-2 minutes Peak Action: 15 minutes Duration of action: 45-90 minutes Opioid Withdrawal Hours Grade after use 4-6 6 8-12 12-72 Symptoms / Signs 0 Anxiety, Drug Craving 1 Yawning, Sweating, Runny nose, Tearing eyes, Restlessness Insomnia 2 Dilated pupils, Gooseflesh, Muscle twitching & shaking, Muscle & Joint aches, Loss of appetite 3 Nausea, extreme restlessness, elevated blood pressure, Heart rate > 100, Fever 4 Vomiting / dehydration, Diarrhea, Abdominal cramps, Curled-up body position Short-term Treatment Methadone or buprenorphine (more expensive) Other Clonidine (hyperadrenergic state) + NSAIDS (muscle cramps and pain) + Benzodiazepines (insomnia) + Dicyclomine (abdominal cramps) + Bismuth subsalicylate (Diarrhea) Heroin versus Methadone Methadone Hydrochloride Full opioid agonist available in tablets, oral solution, parenteral PO onset of action 30-60 minutes Duration of action 24-36 hours to prevent opioid withdrawal 6-8 hours analgesia* Proper dosing Acute withdrawal 20-40 mg Chronic withdrawal >80 mg Inpatient Methadone Dosing Guidelines Start with 20 mg of methadone Reassess q 2-3 hours, give additional 5-10 mg until withdrawal signs abate Do not exceed 40 mg in 24 hours Monitor for CNS and respiratory depression Inpatient Methadone Dosing Guidelines On following day, give total dose QD 20 - 40mg QD 10 - 20 mg q12 Goal is to alleviate acute withdrawal Patient will continue to crave heroin **Referral for long-term substance abuse treatment** Allows 24-36 hour withdrawal-free period after discharge Long-term Goals Detoxification Program (<15% success) Medically supervised withdrawal, a tapering of an approved drug to a medication-free state. Maintenance Program Sustained administration of an approved opioid medication at stable doses Residential Program Outpatient counseling Narcotics Anonymous (NA) Maintenance Programs 1. Methadone Maintenance Program 2. Buprenorphine and Buprenorphine/Naloxone Treatment Program 3. Naltrexone Methadone Maintenance Treatment Daily methadone dosing Daily nursing assessment Weekly individual and/or group counseling Random supervised toxicology screens Psychiatric services Medical services Acupuncture Methadone Effect Methadone 20-40 mg Treats acute withdrawal Methadone >80 mg Treats chronic withdrawal (craving, insomnia) Blocks effects of other opioids (e.g. heroin) Methadone Dose Response Acute w/d Chronic w/d MMT: Decrease Drug Use Over Time MMT: Relapse After Leaving Treatment Methadone Maintenance Treatment The “Gold” Standard In a Comprehensive Rehabilitation Program… Improves overall survival Increases retention in treatment Decreases illicit opioid use Decreases seroconversion of hepatitis and HIV Decreases criminal activity Increases employment Improves birth outcomes Buprenorphine Treatment Program Partial agonist Ceiling effect on respiratory and CNS depression Antagonizes effect to full agonists Buprenorphine Treatment Program Retention rates comparable to methadone Efficacy comparable to methadone (80mg) Milder withdrawal syndrome Very low risk for overdose Decreased risk of abuse and diversion (Buprenorphine/Naloxone) Available in Primary Care Settings Buprenorphine Precipitated Withdrawal Displaces a full agonist off the mu receptors Buprenorphine only partially activates receptors Net decrease in activation occurs and withdrawal develops (must be in withdrawal to start) 100 90 80 70 Full Agonist (e.g. heroin) A Net Decrease in Receptor Activity if a Partial Agonist displaces Full Agonist 60 % 50 Mu Receptor Intrinsic 40 Activity 30 20 10 0 Partial Agonist (e.g. buprenorphine) no drug low dose DRUG DOSE high dose Naltrexone Opioid antagonist Low interest among “street addicts” No better than placebo except in highly motivated patients Impaired physicians > 80% abstinence at 18 months Resources Resources Resources National Institute on Drug Abuse www.nida.nih.gov www.drugabuse.gov Presbyterian Hospital MHMR Inpatient and outpatient treatment programs Pat Tally (214) 345-7196 Greater Dallas Council on Drug and Alcohol Abuse (214) 522-8600