Substance Abuse & Dependence: According to DSM IV… Substance Abuse

Substance Related Disorders Section 4

CME Financial Disclosure Statement

I, or an immediate family member including spouse/partner, have at present and/or have Substance Related Disorders had within the last 12 months, or anticipate NO financial interest/arrangement or Ximena Sanchez Samper, M.D. affiliation with one or more organizations Board Certified Addictions that could be perceived as a real or apparent conflict of interest in context to the design, Psychiatrist implementation, presentation, evaluation, etc Harvard Medical School of CME activities –Ximena SanchezSamper Children’s Hospital (Boston) American Physician Institute For Advanced Professional Studies, LLC 1 2

Lecture Outline Vignette: Office Presentation

1. Definitions & Diagnostic John is an 18yearold male with past h/o non Criteria verbal LD and ADHD, inattentive type. With hard work and academic support, he graduated 2. Etiologic/pathogenic factors (Biopsychosocial theories) high school in the middle of his class. He lives with his parents and 2 younger 3. Components of Comprehensive Assessment and Treatment siblings. He will be the first member of his family to attend college. 4. Intoxication and Withdrawal of Psychoactive Substances He reports occasional drinking with friends at parties, but denies ever using illicit drugs. Current medication is Ritalin SR 20 mg QAM. 3 4

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Vignette: Management Vignette: Epilogue

You refer John to his PCP for a Three days later, John attends an endof meningococcal vaccine. summer party with some high school friends. You discuss prescribing of his stimulant While driving home, John’s car crosses over medication while away at college. the median and strikes another vehicle head You discuss student support services available on. at the college. John is pronounced dead at the scene. His You congratulate him on admission to college, blood alcohol concentration at autopsy is and encourage him to continue to work hard 0.24. and stay away from drugs. 5 6

In memory of… JOHN PAUL S. (May 9, 1983 - Oct 16, 2004) SubstanceRelated Disorders: Definitions & Diagnostic Criteria

7 American Physician Institute For Advanced Professional Studies, LLC 8

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DSM IV Substance Related Disorders Substance Induced Disorders

Substance Use Disorders Intoxication Mood Disorder A- Abuse (social) Withdrawal Anxiety Disorder Delirium B- Dependence (physiological/medical & LOC) Sexual Disorder Persisting Sleep Disorder Dementia (Hallucinogen) Substance Induced Disorders Persisting Amnestic Disorder Persisting Perception Disorder Psychotic Disorder

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Substance Abuse & Dependence: According to DSM IV… Substance Abuse

“ A maladaptative pattern of substance Any 1 OF 4: use leading to clinically significant Major role failure impairment or distress, as manifested by Arrests/recurrent legal problems or more of the following, occurring Physically hazardous use within a 12 month period …” Social/interpersonal problems

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Substance Dependence

3 or > in 12 months, maladaptive w/distress/impairment The 3 C’s of Addiction 1. Tolerance* absolute (or relative) 2. Withdrawal* characteristic symptoms Craving (or avoided through substance use) Compulsion 3. Larger amounts or periods of use than intended Loss of Control 4. Persistent desire or unsuccessful cutting down 5. Excessive time obtaining, using or recovering 6. Activities given up 7. Continued use despite knowledge of problem

13 * Specify if: with or without physiological dependence 14

"First a man takes a drink, then Dependence: Course Specifiers the drink takes a drink, then the Early Partial Remission: 1m < 12m ; some criteria drink … for abuse or dependence met Early Full Remission: 1m < 12 m ; no criteria ... takes the man." Sustained Partial Remission: >12m ; some criteria for abuse or dependence met Sustained Full Remission: > 12m ; no criteria

-Native American saying On Agonist Therapy In a Controlled Environment 15 16

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Substance Intoxication Substance Withdrawal

Reversible substancespecific syndrome due to Reversible substance specific syndrome recent ingestion/exposure State of hyperexcitability due to decline in Significant maladaptive behavior or blood level of substance psychological changes due to the effects of the Significant distress or impairment substance on the central nervous system (CNS) Not due to general medical condition or Not due to a general medical condition or another mental disorder another mental disorder

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Withdrawal: Signs & Symptoms Polysubstance Dependence Using at least 3 groups of substances (not Opposite to direct pharmacological effects of a drug including caffeine & nicotine) in 12 month Same symptoms with substances in a given period but no predominating substance pharmacologic class (reversal with crosstolerant drug) Dependence criteria met for substances as a Variable in onset, duration, and intensity group but not for any specific substance Dependent on: agent used Same pharmacological class effects are duration of use additive degree of neuroadaptation Different pharmacologic class half life & active metabolites: Alprazolam (Xanax) vs. detoxification strategy must accommodate Chlordiazepoxide (Librium) 19 20 each drug class

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Polysubstance Dependence

Opiate and sedativehypnotic dependence: most complex; both require medication treatment Etiologic/ Pathogenic Factors: Stimulants and opiates: managed as opiate Biopsychosocial Theories withdrawal; no specific medication regimen for stimulants Traditionally, not advisable to withdraw both drugs at the same time (opiates and sedative hypnotic symptoms overlap. Thus confusion 21 about which drug is causing the symptoms). American Physician Institute For Advanced Professional Studies, LLC 22

Models of Addictive Behavior Psychological Models

1. Addictive Personality not substantiated

A. Psychological & Behavioral 2. Psychopathologic Model increased Models comorbidity w/ Conduct Disorder, ASPD, Bipolar I, Schizophrenia B. Social Models 3. SelfMedication Hypothesis C. Biological Models 4. ? Role of “dysfunctional family” of origin

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Behavioral Model Social Model: Availability & Social Norms Addictive Behavioral Component construct Treatment Focus 1. Subcultures evolve specific drug use patterns Pleasure + reinforcement Motivation “Hippies” & marijuana Truckers & amphetamines Self medication - reinforcement Detox, Motivation, mutual-help, Rx Performers & cocaine Habit Conditioned + Cognitive/bhvioral * Crystal Meth mainly in West and Midwest reinforcement relapse prevention Habit Conditioned - CBT, relapse 2. Vietnam Vets, 3 yrs later… reinforcement prevention 50% used opioids in Vietnam; 20% dependent

95% remitted in U.S. 25 26

Biological Models

1. Pharmacologic basis of dependence: Globus Pallidus a. Pharmacokinetics (faster is worse) Ventral Tegmental Area b. Pharmacodynamics (tolerance at the receptor, i.e. BZs)

2. Genetic vulnerability confers > =50% of risk Nucleus Accumbens

3. Neuropharmacology: all addictive drugs (except LSD) affect mesocorticolimbic dopaminergic

27 reward thresholds 28

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Your Brain After Drugs Psychoactive Substances & Neurotransmitters

Dopamine Serotonin Normal Noradrenaline GABA Glutamate Endogenous Opioids Cocaine Abuser (10 days)

Interfere in Normal Simulate Function Reuptake Cocaine Abuser (100 days) actions Altering/Blocking: Blockade of NT’s * Storage 29 Less yellow means less normal activity occurring in the brain— 30 * Release even after the cocaine abuser has abstained from the drug for 10 days.

Course of Addiction As An “Illness”

Disease w/o a cure but with effective treatments Most severe during the first 3 to 18 months of Comprehensive Substance Abuse sobriety Assessment and Treatment Lifelong tendency of symptoms to return during times of physical or psychosocial stress. Chronic nature and the risk of relapse are reasons why the diagnosis of Substance Dependence should be maintained, even when sobriety is maintained over long periods of

American Physician Institute For Advanced Professional Studies, LLC 31 32 time.

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Principles of Treatment Motivation to Enter / Sustain

Sobriety is the FIRST priority (reevaluate when Treatment sober) Effective treatment need not be voluntary Relapse is an expectation, not a failure Sanctions/enticements (family, employer, If dual diagnosis, the more severe the disorders, criminal justice system) can increase the more important is integrated treatment treatment entry/retention (pharmacologic & behavioral) Treatment outcomes are similar for those Progress, not perfection who enter treatment under legal pressure vs If the system is not ready for you, be ready for voluntary the system 33 Ostacher, 2005 34

Interviewing Style (Not Preferred) Sergeant Friday Don’t Do How much? Be supportive: Provide Use scare tactics: medications to minimize How often? “scared straight” doesn’t work withdrawal symptoms and a Where did you get it? Judge: supportive physical and “If you keep doing this you’re emotional environment Closed ended going to become a druggie.” questions Punish: Be aware of your biases “We’re not going to give you and park them at the door Cold, distant, anything to make this more Use brief interventions (BI): interrogational comfortable for you, that way you won’t do this again.” Small steps, large gains… “one “Just the facts…” day at a time” 35 36

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Interviewing Style (Preferred) Lieutenant Columbo CAGE vs. CRAFFT What happened? Cut down Car Intoxicated How did that make Annoyed Relax /fit in /peer influence you feel? Why? Guilty Alone Open ended questions Mutual discovery and Eye Opener Forget / blackouts/ dep risk problem solving Family / friends worry Empathy Trouble because of use “Can you help me out here…” 37 38

The CRAFFT Questions* A Brief Screening Test for Adolescent Substance Abuse TRAPPED Mnemonic

Have you ever ridden in a CAR driven by someone (including yourself) who was C “high” or had been using alcohol or drugs? Treatment History (inpt/outpt/MM, etc.) R Do you ever use alcohol or drugs to RELAX, feel better about yourself, or fit in? Route of administration (IV, IN, smoked) A Do you ever use alcohol or drugs while you are by yourself, ALONE? Amount (used, types, $pent; grams, bags, pints) Do you ever FORGET things you did while using alcohol or drugs? Pattern (w/ changes over time) F Do your family or FRIENDS ever tell you that you should cut down on your Prior Abstinence (why,? helped, mood, ? relapse) F drinking or drug use? Effects (O.D., withdrawal, consequences) T Have you ever gotten into TROUBLE while you were using alcohol or drugs? *Two or more yes answers suggest a serious problem. Comprehensive assessment is Duration of use (incl. most recent & fam hx) available through the Adolescent Substance Abuse Program (ASAP) at Children’s Hospital Boston. For appointments call: 617355ASAP 39 ©Children’s Hospital Boston, 2001 40 All Rights Reserved

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Matching Patients to Individual Needs

No single treatment is appropriate for all Social individuals Psychological Effective treatment attends to multiple Biological needs of the individual, not just his/her drug use Treatment must address medical, psychological, social, vocational, and legal problems 41 42

Medical Detoxification

Removal of toxins / management of w/d Three immediate goals 1. To provide a safe withdrawal and enable the patient to become free of substances 2. To provide a withdrawal that is humane and that protects the patient's dignity 3. To prepare the patient for ongoing treatment of his or her dependence (CSAT, 1995a): Detox alone, does little to change longterm drug use! 43 44

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CostEffectiveness of Drug Treatment Adherence and Relapse Rates Drug treatment is disease prevention Drug treatment is opportunity for screening, Treatment counseling, and referral reduces drug use by 4060% Reduced interpersonal conflicts, improved workplace Reduces crime productivity, fewer drugrelated accidents by 4060% Reduces HIV infection by 6 fold in IV users Increases Treatment is less expensive than not treating or employment by incarceration ($4,700 = 1 yr methadone vs. $18,400 40% for imprisonment) As successful as treatment of Every $1 invested in treatment yields up to $7 in diabetes, reduced crimerelated costs; 12:1 when health care asthma, and costs included hypertension 45 46 McLellan, 2000

Motivational Enhancement Therapy

Helps people recognize and do something about their present or potential problem Useful in people who are reluctant to change and Psychotherapy for Addictions ambivalent about changing Intended to resolve ambivalence and aid an Motivational Enhancement Therapy individual along a path of change CBT Used as a brief “ boost” for those who have the 12 Step Programs skills and resources to make a lasting change Prelude to treatment creating an openness to change

American Physician Institute For Advanced Professional Studies, LLC 47 48 that is key to further therapeutic work

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Motivational Interviewing Stages of Change A counseling style that creates conditions favorable Precontemplation to behavioral change Core assumptions: Contemplation Determination Motivation is NOT an innate character trait Motivation IS a product of Relapse Action interpersonal interaction Ambivalence to change is normal and acceptable Maintenance

Source: Prochaska and DiClemente 49 50

Stage Specific Strategies CBT Vs. Motivational Interviewing PRE Develop therapeutic relationship; CONTEMPLATION empathy; raise doubt, increase awareness CBT Approach MI Approach of risks and problems Assumes patient is motivated Employs specific strategies for (action stage ) building patient motivation for CONTEMPLATION Acknowledge ambivalence, evoke reasons change No direct strategies used for to change, tip the balance, success stories Explores and reflects building motivation DETERMINATION Help find best course of action (timelines) perceptions without labeling or Seeks to identify and modify correcting them ACTION Assist in moving forward (referrals, maladaptive cognitions Elicits possible change reassurance despite “rollercoaster”) Prescribes and teaches strategies from the patient and specific coping strategies significant others MAINTENANCE Relapse prevention strategies, positive Uses modeling, directed Responsibility for change is left reinforcement with the patient, no training, practice, and feedback RELAPSE Avoid demoralization, enhance movement modeling, or practice Specific problem solving back to action, assist in learning process Natural problem solving strategies are taught processes are elicited 51 52

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Things do not change: we change . – Henry David Thoreau, Walden Pond

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12 Step Programs: AA 12 Step Programs AA

AA founded in 1935 Philosophy to obtain and maintain sobriety 2 million members worldwide Mutual help; positive role modeling Adapted to a variety of other addictions Group affiliation Features – open to all, apolitical, non Identification professional, selfsupporting, non Spirituality – “higher power” defined by the denominational, multiracial. person & represents faith & hope in recovery Addiction is an illness which can only be Pragmatism – belief in doing “whatever works” controlled by lifelong abstinence Cognitive restructuring – “alcoholic thinking” = emotional immaturity, self centeredness, and 55 56 irresponsibility = cognitive distortion

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Drug Testing Types of Drug Tests

Breath: Good reflection of the blood alcohol level at time of test. Available for alcohol only. Not generally useful in primary care.

Saliva: Available for alcohol and other drugs. Reflects blood level of drugs. Not standardized, “cutoff levels” for 57 58 positive tests varies between products.

Types of Drug Tests Types of Drug Tests Hair: Gives up to 90 day “history” of drug use. Blood: Cannot determine when use occurred. Gives accurate assessment of acute Ability to “hold” chemicals dependent on hair type. intoxication. Marijuana test not considered reliable. More useful in emergency situations than in primary care. Urine (Immunoassays): Well studied, standardized, quick, inexpensive. Sweat: Multiple drugs screened at once Patch worn for up to 14 days Drug concentrations relatively high. High rate of false positives from Drugs and metabolites are excreted in the urine for a “environmental contact” period of time after acute intoxication. 59 60 Positive results require confirmation

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Department of Transportation Definitive (Confirmatory) Testing Protocol Gas chromatography/Mass spectrometry (GCMS) Patient is required to: Show picture identification •Gold standard in drug testing Empty pockets/ wash hands •Highly specific, can be used to Facility: confirm positive screen No running water •Can give quantitative levels Toilet water is dyed blue •Can test for substances not Temperature is checked immediately detected by a screen (Many commercial labs offer this service) 61 62

Urine Drug Testing Pitfalls Urine Drug Testing Pitfalls Defeating Drug Tests False Negatives Urine drug testing is easy to evade. Adulterants: A sample of products are available on the Internet: In vivo: Large fluid volume + creatine + vitamin B In vitro: Synthetic urine Gluteraldehyde, potassium nitrate, pyridinium chlorochromate, hydrogen Urine “detoxifier” (invitro adulterant) peroxide Real powdered urine Household products: bleach, salt, Visine, soap 63 64

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The Urinator “The NIDA 5” … a one of a kind, state of the art, electronic Marijuana urine testing device Cocaine that will maintain testing temperature for Opiates a minimum of 4 hours Amphetamines with one set of PCP batteries.

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Urine Drug Testing Detection Windows Substance Detection Cocaine, Opiates = 3 days Window Amphetamines = 12 days THC 333030 days Amphetamines 2233 days Alcohol = loose detection of 1oz/hour Barbiturates 1133 days Cannabis (THC) Benzodiazepines 1177 days Casual user = 3 days Cocaine & metabolite 6 hours ––33 days Heavy user = 2 weeks months Methadone 7799 days PCP 8 days

67 68 Opiates 1133 days

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Alcohol Testing

Alcohol has a short half life in urine Blood alcohol level: determines whether patient is acutely intoxicated or has been drinking recently. The Action of Alcohol Breath and saliva tests: reflective of the blood alcohol level Ethyl glucuronide (ETG): longer half life* and may improve sensitivity up to 5 days Carbohydrate Deficient Transferrin (CDT):helps detect HEAVY alcohol consumption

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Question: Which of the following Question: Which of the following is coverts alcohol into acetaldehyde? inhibited by Disulfiram?

A. Alcohol dehydrogenase A. Alcohol dehydrogenase B. Aldehyde dehydrogenase B. Aldehyde dehydrogenase C. Both A & B C. Both A & B D. Glucose6Phosphatase D. Glucose6Phosphatase E. Acetate dehydrogenase E. Acetate Dehydrogenase

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Question: Which of the following Question: Which of the following is coverts acetaldehyde into acetic acid? decreased in Asian people?

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Question: Which of the following Question: Which of the following three laboratory tests is not useful in making diagnoses are most likely to predate alcohol the diagnosis of alcohol abuse or abuse or dependence and be considered true comorbid conditions? dependence? A. Antisocial personality disorder, schizophrenia, and A. GGT bipolar I disorder B. MCV B. Antisocial PD, panic disorder, and bipolar I disorder C. Triglycerides C. Bipolar I disorder, major depression, and schizophrenia D. Reticulocyte count D. Major depressive disorder, agoraphobia, and E. AST obsessivecompulsive disorder E. None of the above

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Question: Mr. Van Damme is a 79 y/o male admitted to the Orthopedic service for scheduled hip replacement surgery. Four hours after his procedure, you are paged to his bedside by his nurse who just witnessed him having a seizure. His daughter, who was also in the room tells you “the same thing happened the last time he stopped drinking cold turkey” prior to his last surgery. All of the following statements about seizures associated with alcohol withdrawal are true except:

A. They are tonicclonic in character. B. They usually recur 3 to 6 hours after the first seizure. C. They often progress to status epilepticus. D. They do not respond to anticonvulsants. E. They may be associated with hypomagnesemia. 77 78

Defining the “Standard Drink” American Medical Association: Consumption Guidelines A standard drink = 14 g ethanol Standard Drink = 0.6 oz (14 grams) 12 oz of regular beer or cooler (5% alcohol) 5 oz of table wine (12% alcohol) 12 oz beer (5 %) 1.5 oz of hard liquor (40% alcohol, 80 proof) 5 oz wine (12 %) 5 oz 33--44 oz 22--33 oz 1.5 oz 1.5 oz table wine fortified wine cordial, brandy spirits 8-9 oz 1.5 oz spirits (40 %) 12 oz liqueur, malt liquor (such as sherry (a single jigger) (a single jigger beer or or port) or aperitif of 8080--proofproof gin, cooler 8.5 oz shown in a 3.5 oz shown vodka, whiskey, etc.) 12 oz glass that, 2.5 oz shown shown straight and in if full, would hold a highball glass with ice about 1.5 standard to show level before drinks of malt liquor adding mixer Limits: Men: < 14 per week or < 4 max/day Women: < 7 per week or < 3 max/day 12 oz 8.5 oz5 oz3.5 oz2.5 oz1.5 oz1.5 oz

79 Source: National Institute on Alcohol Abuse and Alcoholism. Bethesda, Md: NIAAA; 2004. NIH Publication No. 04-3769. 80 –The average person metabolizes about 1 standard drink per hour

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XSS1 XSS2 Morbidity and Mortality Psychosocial Impact

ER admissions: 931% of chief complaints 15% of heavy ETOH users missed work due to D.A.W.N. (Drug Abuse Warning Network): drugs “illness”/ injury and… alcohol: 34% (204,524) cases in 2000 12% missed work due to drinking …in previous 100,000 annual unexpected deaths 30 days 15% of all MVA’s Suicide 50% de fatalities in MVA’s Domestic violence Liver cirrhosis: 8% of all Abuse and neglect of minors deaths due to medical causes (50% alcohol related) Annual cost US economy1998: $184.6 bill; $26.3 bill health care

81 D.A.W.N. (Drug Abuse Warning Network):2000 data 82 U.S. Health Report

Alcohol Dependence: Natural Prevalence of Alcohol Use History NIAAA – National Epidemiologic Survey on Established dependency: Alcohol and Related Conditions (NESARC) Exacerbations and remissions Mid-20s to early 40s: 1st major alcohol-related life problem emerges Any Alcohol Disorder 17.6 million (8.5%) Early to mid-20s: Long-term abstinence: Difficulties with • Without formal alcohol use treatment or self-help escalate groups: 20% chance long-term abstinence Early: • With treatment: 50% to Drinking behavior 66% maintain similar to peers Alcohol Abuse Alcohol Dependence abstinence ≥≥≥1 year 9.7 million (4.7%) 7.9 million (3.8%) Use Alcohol

Time 83 84 NIAAA= National Institute on Alcohol Abuse and Alcoholism Source: Schuckit MA. In: Harrison’s Principles of Internal Medicine . New York: McGraw-Hill, 2001:2561-2566. Source: Grant BF, et al. Arch Gen Psychiatry . 2004;61:807-816.

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XSS1 - ETOH use d/o's, including intoxication, abuse and dependence, are major causes of physical and behavioral morbidity and mortality and require emergency intervention. - Studies conducted in ER settings find anywhere from 9-31% of all ER visits are ass w/ ETOH use. - ETOH also involved w/other drug use and abuse; DAWN (monitors drug emergencies) reported ETOH in combo w/other drugs mentioned in 34% (204,524) of ER drug episodes in yr 2000 - ETOH use causes considerable impact on health care and on society in general - Estimated to cause 100,000 excess deaths annually - Approx 15% of all MVA's and 50% of fatal car crashes estimated to be ETOH related - Liver cirrhosis accounts for 8% of all deaths and 1/2 of these are directly due to ETOH Ximena Sanchez Samper, 9/24/2004

Slide 82

XSS2 - Psychosocial impact of ETOH is also considerable - Survey data show that 15% of heavy ETOH users missed work bc of illness/injury in previous 30 days and 12% skipped work b/c drinking in previous 30d. - ETOH use is commonly ass w/ suicide, community and domestic violence and child abuse. - Total annual costs to US economy in 1998 estimatd to be $184.6 bill, w/ $26.3 bill incurred b y health care costs Ximena Sanchez Samper, 9/24/2004 Substance Related Disorders Section 4

Features of Alcohol Dependence Substance (Alcohol) Induced Disorders Normal Acute Alcohol Intake Tolerance Alcohol Intoxication Alcohol Alcohol Adaptation Alcohol Withdrawal Alcohol Intoxication Delirium Alcohol Withdrawal Delirium (Delirium Tremens) Alcohol Induced Persisting Dementia Inhibition Excitation (GABA) (Glutamate) Alcohol Persisting Amnestic Disorder (Wernicke’s Acute Withdrawal Post-Acute Withdrawal Encephalopathy & Korsakoff’s Syndrome) Adaptation Adaptation Alcohol Induced Psychotic Disorder (with del. / hall.) Alcohol Induced Mood Disorder Alcohol Induced Anxiety Disorder

Extended symptoms Alcohol Induced Sexual Disorder (eg, sleep/mood disturbances) 85 86 Source: De Witte. Addict Behav . 2004;29(7):1325-1339. Alcohol Induced Sleep Disorder

Alcohol Intoxication Alcohol Intoxication Signs and Symptoms Treatment Recent ingestion of alcohol MildMild--Moderate:Moderate: Maladaptive behavior/psychological changes: Poor coordination, ataxia, Observation and supportive care, (inappropriate sexual/aggressive behavior, poor conjunctival injection, slurred protect airway, position on side to judgment, mood lability) speech, gastrointestinal avoid aspiration bleeding, orthostatic hypotension One or more: Severe: 1. Slurred speech Respiratory depression, coma, Ventilatory support, intensive care 2. Incoordination death 3. Unsteady gait (Chronic ––pancreatitis,pancreatitis, cirrhosis) 4. Nystagmus Pathologic: 5. Impairment in attention or memory Belligerent, excited, combative, Physical restraint, Benzodiazapine psychotic state ((lorazepamlorazepam 1155 mg prnprn)) or 6. 6 stupor or coma haloperidol 87 88

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Alcohol Withdrawal Alcohol Assessment Cessation or reduction in alcohol use Lab tests: complete blood count, TGL, Two or more within hours or days: electrolytes, magnesium, liver enzymes, (GGT, AST >ALT), urine drug screen, 1. Autonomic hyperactivity (sweating; HR>100) pregnancy test, and Breathalyzer or blood 2. Increased hand tremors alcohol level. 3. Insomnia 4. Nausea or vomiting Others: skin test for tuberculosis, chest x 5. Transient visual, auditory, tactile hallucinations ray, electrocardiogram, and tests for viral 6. Psychomotor agitation hepatitis, HIV, or other STD’s. 7. Anxiety * CDT, ETG 8. Grand mal seizures 89 90

Alcohol Withdrawal Substance (Alcohol) Withdrawal Seizures: within 48 hours of cessation Delirium 1. Stereotyped, generalized, tonic clonic 2. Repeat within 36 hours Disturbance of consciousness (focus, sustain, 3. Status epilepticus rare (< 3%) shift attention) 4. Consider head tx, CNS infections, 5. Neoplasms, CV disease Cognition impaired (memory, orientation, 6. Treat w/ Benzo’s (not anticonvulsants) language, perception) Acute & fluctuating course OTL: “Out The Liver”: Consequence of substance withdrawal Oxazepam/Temazepam/Lorazepam 91 92

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Alcohol Withdrawal Delirium Alcohol Withdrawal Delirium (Delirium Tremens) (Delirium Tremens)

4872 hrs after cessation Preceded by early withdrawal symptoms) Sympathetic Hyperactivity Masked or delayed by illnesses or medications Tachycardia, hypertension, fever, diaphoresis, hallucinations, delusions 5% of hospitalized Alcohol Dependent patients Treatment: Prevention! Medical emergency! Benzo’s, hydration, caution with neuroleptics Mortality: up to 20% & restraints, support Increases w/ delayed diagnosis, inadequate treatment & concurrent medical conditions 93 94

Alcohol Induced Persisting Predictors of Delirium Tremens Amnestic Disorder

Prior history of severe withdrawal symptoms Wernicke’s Encephalopathy Korsakoff’s Syndrome Impaired short term memory due to “ “ prolonged/heavy ETOH use “ “ High blood alcohol level w/o signs of Thiamine deficiency (poor nutrition or intoxication malabsorption) Chronic condition Rare < 35 y/o 20% recovery rate Withdrawal signs with high blood alcohol Acute symptoms Anterograde amnesia in level Reversible with treatment alert, responsive pt Triad: Ataxia, Nystagmus, +/ confabulation Concurrent use of sedativehypnotics Ophthalmoplegia Tx: 100mg tid 312 months Tx: Thiamine 100mg IM/IV x 3d; Medical problems (hepatitis, pancreatitis) 100mg PO tid x 2 wks 95 96

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Pharmacotherapy for Alcohol Dependence Disulfiram: 125500 mg PO/daily Mammillary Bodies Acamprosate: 666 mg PO tid

Naltrexone (PO) : 50 mg PO daily

Naltrexone (IM): 380 mg IM monthly

The mammillary bodies are atrophic and discolored brown, which is associated with vitamin B1 (thiamine) deficiency. Microscopically97 there is capillary proliferation, gliosis and, in severe cases, neuronal loss and hemorrhage. It is commonly 98 seen in chronic alcoholics but may also be found in other nutritionally deprived populations.

Undertreatment of Alcohol Use Comprehensive Alcohol Dependence Disorders Treatment

99 100

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Challenges of Current Therapies

High relapse rate w/ psychosocial support alone: 50% at 12 months : 90% at 48 months Poor medication adherence is common and associated w/ higher relapse rates NIAAA guidelines: consider adding medication in active ETOH dependence or if stopped but experiencing cravings/slips

101 102

Disulfiram

Inhibits metabolism (ALDEHYDE DEHYDROGENASE) accumulation of acetaldehyde unpleasant physical symptoms on exposure to alcohol (aversive agent) Serious side effects include hepatotoxicity, depression, and psychosis. Use in motivated & reliable patients only

103 Fuller et al, 1986 104

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Acamprosate Features of Alcohol Dependence Normal Acute Alcohol Intake Tolerance Glutamate receptors & transmission Alcohol Alcohol Adaptation Moderation of prolonged withdrawal Insomnia, fatigue, mood lability, anxiety Inhibition Excitation Possible effect on attenuating cravings (GABA) (Glutamate) European data > 3000 subjects, superior to Acute Withdrawal Post-Acute Withdrawal placebo in maintaining abstinence Adaptation Adaptation Optimal treatment combination with naltrexone, psychosocial therapy, 12 step Extended symptoms (eg, sleep/mood disturbances) 105 Fox et al, 2003 Ait-Daoud et al, 2003 106 Source: De Witte. Addict Behav . 2004;29(7):1325-1339.

Relapse and Conditioning Pathophysiology of Potential

Bed nucleus of the Prefrontal Cortex •Repeated alcohol use Relapse stria terminalis has caused “conditioning” to occur in related circuits Hippocampus

•Now “cues” associated with alcohol use can activate the reward and withdrawal circuit Ca 2+

Nucleus •This can evoke accumbens anticipation of alcohol NMDA Receptor or feelings similar to withdrawal that can Glutamate Amygdala Ventral tegmental area precipitate relapse in (VTA) an abstinent patient mGluR5 107 108 Source: Messing RO. In: Harrison’s Principles of Internal Medicine. 2001:2557-2561.

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Neuroadaptation: Potential for Balancing Pathophysiology Relapse Acamprosate Normal Acute Alcohol Intake Tolerance Alcohol Alcohol Adaptation

Inhibition Excitation C (GABA) (Glutamate) Reduction in Reduction in post- glutamate release synaptic effects Acute Withdrawal Post-Acute Withdrawal and Cue-Induced Responses Adaptation C C NMDA C Receptor

Glutamate C Acamprosate may balance glutamate C Acamprosate mGluR5 109 110 overactivity thus reducing the potential for relapse

Acamprosate: Dosage and Acamprosate: Indications and Usage Administration

Maintenance of abstinence from alcohol Initiate as soon as possible after alcohol in patients with alcohol dependence who withdrawal when patient achieves are abstinent at treatment initiation abstinence Maintain treatment if patient relapses Recommended dose: two 333mg tablets tid Should be part of a comprehensive management program that includes Patients with moderate renal impairment psychosocial support Starting dose of 1 x 333 mg tid Can be taken with or without meals *Precaution: Acamprosate does not eliminate or diminish acute withdrawal symptoms. 111 112 *creatinine clearance of 30-50 mL/min.

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Acamprosate: Safety Acamprosate: Pharmacokinetics Acamprosate is Safe to Use With Medications Bioavailability 11% Commonly Used in This Population Tmax 3-8 hours C 180 ng/mL max Acute Co-occurring Alcohol C (steady state) 350 ng/mL (5 days) max Detoxification Psychiatric Dependence* Food Effect Minimal (can be taken with food) Disorders Plasma Protein Binding Negligible and Detoxification Metabolism None (eliminated via kidneys) Hypnotics/Sedatives Antidepressants Ethanol Anxiolytics t1/2 (steady state) 20-33 hours (including Disulfiram benzodiazepines) Nonopioid Naltrexone Volume Distribution 72-109 L (approx. 1 L/kg) Analgesics (following IV administration)

113 114

Naltrexone Naltrexone Synthetic opioid antagonist: FDA (1994) Can be used safely without prior detox approved as adjunct to psychotherapy in alcohol dependence Effective even if only taken when drinking is expected World Health Organization (1996): “safe and effective treatment for alcohol dependence” 50mg/day effective, if compliant, w/ Reduces drinking frequency psychosocial therapy Reduces likelihood of relapse to heavy drinking Monthly intramuscular preparation (Vivitrol) Reduces reinforcing response to ETOH Improved compliance, enhanced steady state Safety & efficacy: > 8 doubleblind RCT plasma levels, fewer GI side effects Adverse events: nausea, anorexia Sinclair 2001 *Srisurapanont et al. 2003 115 Contraindicated: severe liver damage 116

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Naltrexone: Oral vs. IM Naltrexone: Oral vs. IM

Oncemonthly injection (Vivitrol) Medical alert card carried at all times Elimination of daily decisions to take oral Emergency pain management (IM/Vivitrol): medications= ttmt adherence regional analgesia, conscious sedation w/ a Consistent and measurable plasma levels of benzo and nonopioid analgesic, general the active drug naltrexone anesthesia I.M.= reduction first pass hepatic metabolism * Comprehensive management w/ psychosocial support

117 118

Naltrexone IM: Potential Side Effects Alcohol Dependence: Subtypes

Nausea/Vomiting Type I/A = less Type II/B = more Headache severe dependence, severe dependence, later onset > 25, early onset < 25, Fatigue/Dizziness fewer childhood childhood risk factors, Injection Site Reaction problems, fewer family history, alcohol related Contraindicated in acute hepatitis, liver failure polydrug use, problems, less psychopathology, life & opioid dependent pt’s (min. 710 days opioid psychopathology stress free) Sertraline…? Eosinophilic Pneumonia (rare; dyspnea; Ondansetron…? hypoxemia) Pettinati et al, 2000 Johnson et al, 2000 119 No significant change in LFT’s 120

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Question: Which of the following Question: Which of the following coverts alcohol into acetaldehyde? is inhibited by Disulfiram?

121 122

Question: Which of the following Question: Which of the following is coverts acetaldehyde into acetic acid? decreased in Asian people?

123 124

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Question: Which of the following three Question: Which of the following diagnoses are most likely to predate laboratory tests is not useful in making alcohol abuse or dependence and be the diagnosis of alcohol abuse or considered true comorbid conditions? dependence? A. Antisocial personality disorder, schizophrenia, and A. GGT bipolar I disorder B. MCV B. Antisocial PD, panic disorder, and bipolar I disorder C. Triglycerides C. Bipolar I disorder, major depression, and schizophrenia D. Reticulocyte count D. Major depressive disorder, agoraphobia, and E. AST obsessivecompulsive disorder E. None of the above

125 126

Question: Mr. Van Damme is a 79 y/o male admitted to the Orthopedic service for scheduled hip replacement surgery. Four hours after his procedure, you are paged to his bedside by his nurse who just witnessed him having a seizure. His daughter, who was also in the room tells you “the same thing happened the last time he stopped drinking cold The Action of Sedatives/ turkey” prior to his last surgery. All of the following statements about seizures associated with alcohol Hypnotics / Anxiolytics withdrawal are true except:

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Question: Lolita is a 39 y/o nurse with GAD whom Sedative, Hypnotic, Anxiolytic you suspect has been “taking more than the prescribed amount” of Klonopin. She arrives to your Intoxication office 5 days early and says she has “run out of Recent ingestion medications early this month due to increased stress Maladaptive behavior/psychological changes at work”. The symptoms of benzodiazepine (inappropriate sexual/aggressive behavior, poor withdrawal that you would expect to see include all judgment, mood lability) of the following except? One or more: A. Dysphoria 1. Slurred speech B. Intolerance for bright lights 2. Incoordination 3. Unsteady gait C. Nausea 4. Nystagmus D. Muscle twitching 5. Impairment in attention or memory

129 E. Pinpoint Pupils 130 6. Stupor or coma

Sedative, Hypnotic, Anxiolytic Sedative, Hypnotic, Anxiolytic Intoxication Withdrawal Signs and Symptoms Treatment A. Cessation or reduction in use MildMild--Moderate:Moderate: Observation and supportive care, CNS sedation, pupillary protect airway, position on side to B. Two or more within hours or days: avoid aspiration constriction, disorientation, 1. Autonomic hyperactivity (sweating; HR>100) slurred speech, staggering gait 2. Increased hand tremors Severe: Acute overdose ––gastricgastric lavage; 3. Insomnia Respiratory depression, Supportive ––ventilator,ventilator, warming 4. Nausea or vomiting hypothermia, coma, death blanket, ICU Care; Flumazenil 5. Transient visual, auditory, tactile hallucinations Symptoms pass in a matter of Pathologic: 6. Psychomotor agitation Paradoxical disinhibition, hours; physical restraint, lo 7. Anxiety hyperexcitability 131 132 8. Grand mal seizures

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Sedative, Hypnotic, Anxiolytic Withdrawal

Longacting sedativehypnotic (diazepam, The Action of Marijuana/ chlordiazepoxide, clonazepam, or phenobarabital) Cannabis/ Hashish (THC) Drug of dependence may be gradually tapered by 10% daily May need anticonvulsant for smooth & gradual withdrawal

133 American Physician Institute For Advanced Professional Studies, LLC 134

Cannabis Intoxication Cannabis Intoxication Signs and Symptoms Treatment Recent cannabis use Acute: Euphoria, sensory stimulation, pupillary Maladaptive behavior or psychological changes constriction, conjunctivalInjection, Reassurance and observation (impaired motor coordination, euphoria, anxiety, photophobia, diplopia,diplopia , increased appetite, sensation of slowed time, impaired judgment, social autonomic dysfunction, temporary withdrawal) bronchodilation Two or more within 2 hours of use: Chronic: 1. Conjunctival injection Gynecomastia, reactive airway disease, Discontinuation of use, decreased sperm count, weight gain, lethargy symptomatic treatment/care 2. Increased appetite (bronchodilators for wheezing) 3. Dry mouth Intoxication: 4. Tachycardia Panic, delirium, psychosis Psychosis: neuroleptic medication

135 136

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Cannabis Withdrawal Question: Lolita is a 39 y/o nurse with GAD whom you suspect has been “taking more than the prescribed amount” of Klonopin. She arrives to your Signs & Symptoms Treatment office 5 days early and says she has “run out of Chronic Users: medications early this month due to increased stress Physical: mild increases in heart Reassurance; symptoms at work”. The symptoms of benzodiazepine rate, blood pressure, and body disappear in 3344 days withdrawal that you would expect to see include all temperature (sometimes longer) of the following except?

Psychological: anxiety, A. Dysphoria depression, irritability, agitation, B. Intolerance for bright lights insomnia, tremors, and chills. C. Nausea D. Muscle twitching

137 NIDA developing oral THC tablet for withdrawal management 138 E. Pinpoint Pupils

Question: An 18yearold high school senior was brought to the ER by police after being picked up wandering through traffic. He was agitated and aggressive, and talked of people who were deliberately The Action of Stimulants trying to confuse him with misleading directions. His story was rambling and disjointed, but he admitted that (Cocaine, Crack, Amphetamines, he had used speed. In the ER he had difficulty focusing Crystal Meth…) his attention and had to ask that questions be repeated. He was disoriented to time and place and was unable to repeat the names of 3 objects after 5 minutes. His family gave a history of patient’s regular use of pep pills over the last 2 years, during which time he was frequently high and did poorly in school.

American Physician Institute For Advanced Professional Studies, LLC 139 140

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Question: Which of the following would not Question: The abrupt discontinuation be a clinical effect of amphetamine of amphetamine in this patient would intoxication in this patient? produce all of the following except?

A. Increased libido A. Fatigue B. Formication B. Dysphoria C. Delirium C. Nightmares D. Catatonia E. Pupillary dilation D. Agitation E. Appetite decrease

141 142

Question: Amphetamines and cocaine Question: Which of the following are similar in which of the following is true about Cocaine? ways?

A. Competitively blocks dopamine reuptake by A. Their mechanisms of action at the cellular the dopamine transporter level B. Does not lead to physiological dependence B. Their duration of action C. Induced psychotic disorders are most common in those who snort cocaine C. Their metabolic pathways D. Has been used by 40 percent of the United States D. The induction of paranoia and production population since 1991 of major cardiovascular toxicities E. Is no longer used as a local anesthetic

143 144

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Question: In distinguishing schizophrenia Question: Pharmacologic agents that from amphetamineinduced toxic psychosis, have been confirmed to reduce the presence of which of the following is most helpful? cocaine use include:

A. Paranoid delusions A. Dopaminergic agonists B. Auditory hallucinations B. Bupropion C. Clear consciousness C. SSRIs D. Tactile or visual hallucinations D. Desipramine E. Intact orientation E. None of the above

145 146

(Free Base)

(Hydrochloride salt)

147 148

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Cocaine/Amphetamine Intoxication Your Brain on Cocaine A. Recent cocaine/amphetamine use B. Maladaptive behavioral or psychological changes (euphoria or Minutes affective blunting; sociability changes; hypervigilance; 1-2 Min 3-4 5-6 interpersonal sensitivity; anxiety, tension or anger; sterotyped 1-2 3-4 5-6 behaviors; impaired judgment) 6-7 7-8 8-9 C. Two or more of the following: 9-10 10-20 20-30 1. Tachycardia or bradycardia 2. Pupillary dilation 3. Elevated or lowered blood pressure 6-7 7-8 8-9 4. Perspiration or chills 5. Nausea or vomiting 6. Evidence of weight loss 7. Psychomotor agitation or retardation 8. Muscular weakness, respiratory depression, chest pain or cardiac arrhythmias 9. Confusion, seizures, dyskinesias, dystonia or coma 149 9-10 10-20 20-30 150

Cocaine/Amphetamine Withdrawal Cocaine/Amphetamine Withdrawal Cessation or reduction in use Dysphoric mood & 2 or more of the following: Signs & Symptoms Treatment 1. Fatigue Chronic users: 2. Vivid, unpleasant dreams Severe depression with Close observation, 3. Insomnia or hypersomnia suicidal/ homicidal ideation, reassurance; symptoms exhaustion, prolonged sleep, disappear in 3344 days 4. Increased appetite voracious appetite 5. Psychomotor retardation or agitation

151 152

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Methamphetamines Methamphetamines Chemically related to amphetamines Referred to as: "speed,” "meth,“ "chalk “, More potent, longlasting and “ice,” "crystal," "glass," and "tina." harmful to CNS (damages DA and serotonin nerve terminals) Taken orally, intranasally, IV, or by smoking White, odorless, bittertasting (rapidly addictive); varies by geographical crystalline powder (easily region and use varies through time dissolves in water or alcohol) Approx. 10 million people in the United Schedule II stimulant( high States > age 12 (4.3%) have tried at least abuse potential; available only once (2005 NSDUH) through a prescription (ADHD, Narcolepsy) 153 154

Primary Methamphetamine/Amphetamine Admission Rates per 100,000 Population Aged 12 and Over Methamphetamine vs. Cocaine

January 2006 : methamphetamine continues to be a problem in the West, with indicators persisting at high levels 155 in Honolulu, San Diego, Seattle, San Francisco, and Los Angeles; and that it continues to spread to other areas of 156 the country, including both rural and urban sections of the South and Midwest. In fact, methamphetamine was reported to be the fastest growing problem in metropolitan Atlanta.

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Methamphetamine Short-term effects: Long-term effects: Smoking/ I.V.: intensely Increased attention and Addiction decreased fatigue Paranoia/hallucinations pleasurable rush or Increased activity and Repetitive motor activity "flash" wakefulness Changes in brain Snorting: ”high” 35 m. Decreased appetite structure and function Euphoria and rush Memory Loss Oral ingestion: 15 to 20 Increased respiration Aggressive or violent m. Rapid/irregular heartbeat behavior Increased BP Mood disturbances “Binge and crash" Severe dental problems Increased risk for stroke pattern: maintain high by Weight loss Hyperthermia Increased transmission of taking more drug ↑↑↑ libido & disinhibition HIV and Hepatitis “Run”: foregoing food and Unsafe, risky behaviors

157 sleep for several days. 158 Seizures and death

Recovery of Brain Dopamine Transporters in HOW TO GET HELP

Chronic Methamphetamine (METH) Abusers The Matrix Model: combines behavioral therapy, family education, individual counseling, 12Step support, drug testing, and encouragement for nondrugrelated activities

Contingency management interventions: tangible incentives in exchange for engaging in treatment and maintaining abstinence

No specific medications to counteract effects or prolong abstinence (Bupropion: reduced the methamphetamine induced "high" as well as drug cravings) 159 160

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Stimulants: Management Stimulants: Management “Dopamine deficiency” hypothesis: not consistently supported βBlockers/Nitroprusside (hypertensive crisis) Dopamine agonists: bromocriptine and amantadine Risk of relapse is high during early withdrawal inconsistent results Drug craving is easily triggered by encounters Shortacting benzodiazepines: for agitation or sleep with or thinking of drugassociated stimuli. Typical Neuroleptics: contraindicated (dysphoric side effects may increase drug craving) Psychosocial treatment behavioral therapy, Atypical neuroleptics – no data but clinically may be desensitization & cue extinction of benefit.

161 (Gawin and Ellinwood, 1988). 162

Question: An 18yearold high school senior was Question: Which of the following would not brought to the ER by police after being picked up be a clinical effect of amphetamine wandering through traffic. He was agitated and intoxication in this patient? aggressive, and talked of people who were deliberately trying to confuse him with misleading directions. His story was rambling and disjointed, but he admitted that A. Increased libido he had used speed. In the ER he had difficulty focusing B. Formication his attention and had to ask that questions be repeated. C. Delirium He was disoriented to time and place and was unable D. Catatonia to repeat the names of 3 objects after 5 minutes. His E. Pupillary dilation family gave a history of patient’s regular use of pep pills over the last 2 years, during which time he was frequently high and did poorly in school.

163 164

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Question: The abrupt discontinuation Question: Which of the following of amphetamine in this patient would is true about Cocaine? produce all of the following except?

A. Fatigue A. Competitively blocks dopamine reuptake by the dopamine transporter B. Dysphoria B. Does not lead to physiological dependence C. Nightmares C. Induced psychotic disorders are most common D. Agitation in those who snort cocaine E. Decreased appetite D. Has been used by 40 percent of the United States population since 1991 E. Is no longer used as a local anesthetic

165 166

Question: Amphetamines and cocaine Question: In distinguishing schizophrenia are similar in which of the following from amphetamineinduced toxic psychosis, ways? the presence of which of the following is most helpful? A. Their mechanisms of action at the cellular level A. Paranoid delusions B. Auditory hallucinations B. Their duration of action C. Clear consciousness C. Their metabolic pathways D. Tactile or visual hallucinations D. The induction of paranoia and production E. Intact orientation of major cardiovascular toxicities

167 168

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Question: Pharmacologic agents that have been confirmed to reduce cocaine use include: The Action of Opioids A. Dopaminergic agonists (Heroin, Opium, Morphine, B. Bupropion Prescription Narcotics, ect.) C. SSRIs D. Desipramine E. None of the above

169 American Physician Institute For Advanced Professional Studies, LLC 170

Question: Which of the following Question: Opioid intoxication is drugs is not an opioid antagonist? generally characterized by:

A. Naloxone B. Naltrexone A. Pupillary dilation C. Nalorphine B. Piloerection D. Apomorphine C. Increased blood pressure E. Oxycodone D. Depressed respiration E. Increased body temperature

171 172

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Fact… History Use of prescription pain Opioids have been used for 6000 killers (OC’s, Percocet, years (pain) Vicodin) and heroin has increased in 10 years Hippocrates: treatment of headaches, coughing, asthma, melancholy, etc. 2000: 810,0001 million Americans addicted Unfortunately, increased potency (stronger) 2003: 1.5 million has increased physical and psychological Americans dependence 2006: 2.4 million (4X the population of Boston) 173 174

Concerns… Fact… Heroin today is almost 7 times stronger than in the 70’s…more addictive FASTER!!! Almost half (44%) of new recreational use of Loss of control and inability to stop prescription painkillers in 2001 was by people despite problems or consequences under younger than age 18. Through time, tolerance and The number of 18 to 25yearolds admitted to dependence develop, and physical/or treatment for prescription painkillers more than psychological symptoms can occur if doubled between 1993 and 2002. the opioid use is reduced or stopped abruptly.

175 176

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Medical & Social Problems Barriers to treatment HIV/AIDS Hepatitis B and C Number seeking treatment is greater than Tuberculosis resources available Fetal effects Stigma limits people from seeking help Crime Violence Only 1 in 5 receive treatment Family problems Opioid dependence is a Workplace MEDICAL problem, not a School moral issue! Economy ( $100 billion in unemployment, missed work, criminal activities, medical care and social welfare) 177 178

Addiction vs. Dependence

• Snorted Nucleus Cerebral Cortex • Smoked Accumbens and VTA • Injected Thalamus

VS. NA & VTA Enz conversion to Morphine

Brain Stem Thalamus and Brain Stem (Withdrawal sx’s)

Spinal Cord * Analgesia

179 180

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Opioid Intoxication Opioid Intoxication Signs & Symptoms Treatment A. Recent opioid use Acute: B. Maladaptive behavior (euphoria followed by Euphoria, pupillaryconstriction, Airway protection, judicious depression of respirations use of naloxone apathy, dysphoria, psychomotor and gag reflex, bradycardia,bradycardia , agitation/retardation, impaired judgement) hypotension, constipation C. Pupillary constriction & one or more: Chronic: Complication of IV use include Discontinuation of use, targeted 1. Drowsiness hepatitis B, HIV/AIDS, medical care for infectious 2. Slurred speech endocarditis, brain abscesses complications 3. Impairment in attention or memory Intoxication/overdose: Acute overdose may cause Intubation and ventilation,

181 182 respiratory arrest and death naloxone

Opioid Withdrawal A. Either of the following: 1. Cessation or reduction in opioid use 2. Administration of opioid antagonist after period of opioid use B. Three or more of the following: 1. Dysphoric mood 2. Nausea or vomiting 3. Muscle aches 4. Lacrimation or rhinorrhea 5. Pupillary dilation, piloerection or sweating 6. Diarrhea 7. Yawning 8. Fever 183 9. Insomnia 184

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“Quitting Cold Turkey” and… Relief of Opioid Withdrawal Symptoms Headache, muscle pain, joint or bone pain: Ibuprofen 600800 mg q68h or acetaminophen 650 mg q4h. Muscle spasm: Quinine Sulfate 325mg q 6h prn Anxiety: Hydroxyzine 2550 mg or lorazepam 12 mg or chlordiazepoxide 25 mg q68h. Insomnia: Lorazepam 2 mg or chlordiazepoxide 25 “Kicking the Habit”… mg or trazodone 50100 mg or doxepin 1020 mg. Abdominal cramps: Dicyclomine 1020 mg q6h. Nausea: Phenergan 25 mg PO/IM q6h or metoclopramide 20 mg q6h. Loose stool: Bismuth subcarbonate (PeptoBismol) 30 cc or Imodium 2 mg after each loose stool, up to 8 185 186 doses total.

Clonidine Methadone

Synthetic opioid agonist Reduces opiate withdrawal signs & symptoms Acute Opioid Withdrawal in Detox Centers decreases sympathetic outflow Most researched treatment for opioid replacement therapy Suppresses autonomic mediated signs & (1970’s) symptoms of withdrawal (less effective for other • *Better treatment retention rates subjective symptoms). • *Reduces morbidity and mortality • *Curbs spread of infectious disease Side effects: Drowsiness & orthostatic • *Work best if program is numerous, hypotension common (monitor BP) accessible, and flexible Oral and transdermal presentations *** Approved in pregnancy *Mattick et al. 2003

187 188 **Single, 2000

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Buprenorphine / Suboxone What Is Suboxone?

Newer medication; approved in US since early 2000’s Suboxone is a Can be given in primary care offices by combination of Naloxone physicians who have completed brief two medicines: training and obtained a waiver buprenorphine Good first choice for adolescents and naloxone Buprenorphine

189 190

Buprenorphine/Suboxone How Does Buprenorphine / Suboxone Work? Long acting, potent, partial (mu) agonist Subutex/Suboxone safe & effective in ttmt retention, use reduction/ craving Mixed ag/antag (kappa): decrease risk of resp. depression, fewer autonomic w/d sx’s, less euphoria

191 192

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Partial vs. Full Opioid Agonist Perfect Fit - Maximum Opioid Effect death

Full Agonist Empty Opiate Receptor Effect (e.g., methadone)

Partial Agonist No Euphoric (e.g. buprenorphine) Withdrawal Opioid Pain Antagonist Effect (e.g. Naloxone) Courtesy of NAABT, Inc. (naabt.org)

Opioid receptor satisfied with a full-agonist opioid . The strong opioid effect of heroin and painkillers stops the withdrawal for a period of time (424 hours). Initially, euphoric effects can be felt. However, after prolonged use, tolerance and physical dependence can develop. Dose of Opiate Now, instead of producing a euphoric effect, the opioids are primarily just preventing withdrawal symptoms. 193 194

Following abrupt With ongoing, discontinuation (or marked reduction in escalated use, use), withdrawal tolerance develops, symptoms begin. upregulation of However, even after receptors occurs and patients stop patients need larger withdrawing, the brain doses in order to get can still interpret this “high”. situation as “something not being quite right”.

195 196

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How does Buprenorphine / Suboxone work?

Buprenorphine Replacement/ Empty Substitution Receptor Opioid Therapy Curbs Opioid withdrawal Opioid symptoms Receptor in the brain Decreases Withdrawal cravings Courtesy of NAABT, Inc. (naabt.org) Pain Opioid receptor unsatisfied -- Withdrawal . As someone becomes “tolerant” to opioids their opioid receptors become less sensitive. More opioids are then required to produce the same effect. Once “physically dependent” the body can no longer manufacture enough natural opioids to keep up with this increased demand. Whenever there is an insufficient amount of opioid receptors activated, the body feels pain. This is withdrawal. 197 198

Imperfect Fit Buprenorphine – Limited Still Blocks Euphoric Opioids as It Courtesy of NAABT, Inc. (naabt.org) Opioid Effect Dissipates Courtesy of NAABT, Inc. (naabt.org)

Opioids replaced and blocked by buprenorphine. Buprenorphine competes with the full agonist opioids for the receptor. Since buprenorphine has a higher affinity (stronger binding ability) it expels existing opioids and blocks others from attaching. As a partial Over time (24-72 hours) buprenorphine dissipates, but still creates a limited opioid effect agonist , the buprenorphine has a limited opioid effect, enough to stop withdrawal but not enough to cause intense euphoria. (enough to prevent withdrawal) and continues to block other opioids from attaching to the opioid receptors. 199 200

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Buprenorphine Buprenorphine Blocks Other Opioids

Buprenorphine Must be started when has a high patients are in affinity for withdrawal (or clean) opioid receptors. Buprenorphine displaces Other opioids other opioids from the receptor; if this occurs, cannot bind to opioid withdrawal the receptor if symptoms will soon buprenorphine is there. 201 follow. 202

What Does Naloxone Do? Naloxone Is A Safety Feature Naloxone also binds to the opioid When Suboxone is taken SL receptor, but as an as prescribed, the body ANTAGONIST! absorbs only the If Suboxone is buprenorphine, NOT the injected, rather than Naloxone taken SL, the If Suboxone is injected, patient will rather than taken SL, the immediately begin patient will immediately to withdraw. begin to withdraw.

203 204

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Buprenorphine/Suboxone Buprenorphine/Suboxone

Unique pharmacologic properties In combination w/ naloxone 4:1 (2 mg & 8 mg) No effect unless administered parenterally Ceiling effect, safer in overdose, less S.L. only addictive than full agonists, easier in w/d vs. = decrease IV abuse/diversion/O.D methadone (agonist effect at low doses) = less tightly controlled M.D. waiver needed (8 hrs ASAM training); no High mu rct affinity blocks rct activation by longer 30 patient limit other full agonists or displaces them

205 206

Buprenorphine/Suboxone Question: Which of the following drugs is not an opioid antagonist? Unique pharmacologic properties

A. Naloxone Quick onset of action (100 vs 150 min), slow dissociation rate, less frequent dosing B. Naltrexone (option of alternative day dosing) C. Nalorphine D. Apomorphine SE’s: HA/ nausea/constipation/monitor E. Oxycodone LFT’s/CYP 450 3A4 metab (decrease dose if on azoles or protease inhibitors)

207 208

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Question: Opioid intoxication is generally characterized by:

The Action of Anabolic Steroids A. Pupillary dilation B. Piloerection C. Increased blood pressure D. Depressed respiration E. Increased body temperature

209 American Physician Institute For Advanced Professional Studies, LLC 210

Anabolic Steroid Intoxication

Signs and Symptoms Evidence suggests that steroid use has effects on mood and emotional functioning including anxiety, exhilaration, agitation, and depression, psychotic reactions can occur

211 212

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Anabolic Steroid Withdrawal

Signs and Symptoms The Action of Hallucinogens and Mood swings, depression with suicidal behavior, and aggression with violent and Dissociative Drugs assaultive behavior, sometimessometimesdramaticdramatic reductions in size and strength (PCP, LSD, Ketamine, DXM)

213 American Physician Institute For Advanced Professional Studies, LLC 214

Question: An 18 y/o male is brought to the ER with extreme agitation. He needs to be held down by 4 Question: The patient in the previous security officers. He has prominent drool which is question should not be treated with which of getting on everyone. When he is subdued you note the presence of vertical nystagmus and tachycardia. Which the following? substance is this patient most likely intoxicated with? A. Diazepam (Valium) A. Alcohol B. Reduction of environmental stimulation B. Cocaine C. Phentolamine (Regitine) C. Inhalant D. Phenothiazines (Chlorpromazine) D. LSD E. Supportive measures (cardiopulmonary E. Phencyclidine resucitation) 215 216

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Question: Current recommendations state that the patient in the previous question Hallucinogen Intoxication should not have his urine acidified. Why 1. Recent hallucinogen use 2. Maladaptive behavior/psychological changes (anxiety or depression, ideas of reference, fear of losing one’s mind, not? paranoid ideation, impaired judgement) 3. Perceptual changes in a state of full wakefullness & alertness A. Diazepam will be inactivated (depersonalization, derealization, illusions, hallucinations, synesthesias) B. Pt intoxicated with PCP is more likely to 4. Two or more of the following: display violent behavior 1. Pupillary dilation C. Pt intoxicated with PCP is at high risk of 2. Tachycardia aspirating the cranberry juice 3. Sweating 4. Palpitations D. Pts intoxicated with PCP are at risk for 5. Blurring of vision acidosis and rhabdomyolisis 6. Tremors 217 218 7. Incoordination

LSD/Acid Ketamine One of the strongest moodaltering drugs "K," "Special K," "cat Valium“: dissociative anesthetic ; replaced PCP (1963) Sold: tablets, capsules, liquid, absorbent paper Currently used in human anesthesia and veterinary Psychological Effects medicine unpredictable Diverted from veterinarians' offices (evaporated to form a powder; snorted or compressed into pills) delusions and visual hallucinations with high doses Chemical structure, mechanism of action & effects Physical Effects similar to PCP but less potent & of shorter duration. hyperthermia, tachycardia, HTN, insomnia and loss Range of sensations range:pleasantly floating to of appetite sensory detachment: “Khole.” 2005 MTF study: 1.8% of 12th graders used Odorless and tasteless = amnesia = daterape drug

219 Source: NIDA Infofacts: High School and Youth Trends. 220 Source: NIDA Infofacts: High School and Youth Trends.

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Dextromethorphan PCP/ Phencyclidine "DXM" or "robo“; coughsuppressing Illegally manufactured in labs ingredient in a variety of overthe counter cold / cough medications. Variable routes of administration (snorted, NMDA receptor antagonist smoked, P.O.) At doses recommended for coughs, it Developed in the 1950s as an IV anesthetic is safe and effective. Street Names: angel dust, ozone, wack, rocket Effects similar to PCP and ketamine fuel (vary with dose) Effects: overdose; unpleasant psychological Distorted visual perceptions to effects; increased violence/suicidality complete dissociation (for 6 hours) Often contain antihistamine and NIDA's 2005 MTF study: 2.4% of high school 221 decongestant ingredients 222 seniors/lifetime

PCP/ Phencyclidine Intoxication Hallucinogen/PCP Treatment Signs and Symptoms Treatment A. Recent use Acute: Reassurance and observation (some Perceptual distortion and symptoms may be more severe B. Maladaptive behavior (belligerence, assaultiveness, hallucinations, mild nausea, tremors, depending upon type of hallucinogen) impulsiveness, agitation, impaired judgement) tachycardia, hypertension, *PCP: Diazepam for seizures or hyperreflexia agitation; NO Ammonium Chloride, C. Two or more within an hour: Ascorbic Acid, Cranberry juice to 1. Vertical or horizontal nystagmus acidify urine as leads to metabolic 2. Hypertension or tachycardia acidosis, rhabdomyolysis, etc); Phentolamine for HTN 3. Numbness or diminished response to pain Chronic: Discontinuation of use 4. Ataxia Flashbacks 5. Dysarthria Intoxication/ovedose: Psychosis: close observation in quiet 6. Muscle rigidity Panic, paranoia, psychosis room, benzodiazepines: NO 7. Seizures or coma Phenothiazines (anticholinergics worsen effects/seizure risk) 223 8. Hyperacusis 224

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Hallucinogen Persisting Perception Hallucinogen/PCP Withdrawal Disorder (Flashbacks) The reexperiencing, following cessation of hallucinogen use, of perceptual sx’s Signs and Treatment experienced while intoxicated previously Symptoms (geometric hallucinations, false perceptions of movement in peripheral visual fields, flashes Acute users: of color, trails of images of moving objects, Psychological Reassurance halos, macropsia, micropsia) Cause distress or impairment in social/ occupational functioning 225 226 Not due to general medical condition

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Question: Current recommendations state that the patient in the previous question should not have his urine acidified. Why not? The Action of Inhalants A. Diazepam will be inactivated B. Pt intoxicated with PCP is more likely to display violent behavior C. Pt intoxicated with PCP is at high risk of aspirating the cranberry juice D. Pts intoxicated with PCP are at risk for acidosis and rhabdomyolisis 229 American Physician Institute For Advanced Professional Studies, LLC 230

Question: The lifetime use of Question: Adverse effects on the inhalants is highest in which of brain that have been associated with the following age groups? longterm inhalant use include all the following except: A. Young adults aged 18 to 25 years

B. Adults aged 26 to 34 years A. Rhabdomyolysis C. Youth aged 8 to 17 years B. Brain atrophy D. Adults 40 to 65 years old C. Decreased intelligence quotient (IQ) D. Electroencephalographic (EEG) changes E. Adults over the age of 65 E. Decreased cerebral blood flow

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Inhalants How can inhalant abuse be recognized? Often common household products that Early identification and intervention are the best ways to stop inhalant abuse before it causes serious health consequences. contain volatile solvents or aerosols Parents, educators, family physicians, and other health care Rapid high resembling alcohol intoxication practitioners should be alert to the following signs of a serious (anesthesia, a loss of sensation & inhalant abuse problem: unconsciousness at higher doses) Chemical odors on breath or Drunk or disoriented Among the first drugs that young kids use clothing appearance NIDA's 2005 MTF study: Paint on or other stains on Slurred speech 17.1% of 8th graders, 13.1% of 10th graders, and face, hands, or clothes Nausea or loss of appetite 11.4% of 12th graders said they had abused Hidden empty spray paint or inhalants at least once Inattentiveness, lack of solvent containers and coordination, irritability, and chemicalsoaked rags or depression clothing 233 Source: NIDA Infofacts: High School and Youth Trends . 234

Inhalants of Abuse Inhalants of Abuse cont.

Arnyl Nitrite, Butyl Nitrite Benzene Butane, Propane Freon (“poppers” or “video head (Found in gasoline) (found in lighter fluid, hair (used as a refrigerant cleaner”) Bone marrow injury, and paint sprays) and aerosol propellant) Sudden sniffing death impaired immunologic Sudden sniffing death Sudden sniffing death syndrome, suppressed function, increased risk syndrome via cardiac syndrome, respiratory immunologic function, injury of leukemia, effects, serious burn obstruction and death to red blood cells (interfering reproductive system injuries (because of (from sudden cooling/ with oxygen supply to vital toxicity. flammability) cold injury to airways), tissues) liver damage.

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Inhalants of Abuse cont. Inhalants of Abuse cont.

Nitrous Oxide Methylene Chloride Toluene Trichloroethylene Hexane (found in paint thinner (found in gasoline, paint “Laughing gas” (found in spot and removers, thinners and removers, Death from lack of removers, degreasers) degreasers) correction fluid) oxygen to the brain, Sudden sniffing death Reduction of oxygen Brain damage (loss of altered perception and syndrome, airhosts of carrying capacity of brain tissue mass, motor coordination, the liver, reproductive blood, changes to the impaired cognition, gall loss of sensation, limb complications, hearing heart muscle and disturbance, loss of spasms, blackouts and vision damage. heartbeat. coordination, loss of caused by blood equilibrium, limb spasms, pressure changes, hearing and vision loss), depression of heart liver and kidney damage 237 muscle functioning. 238

Brain atrophy in Demyelination in a toluene abuser an inhalant abuser Inhalant Intoxication A. Recent use of inhalants B. Maladaptive behavior/psychological changes (belligerence, assaultiveness, apathy, impaired judgment) C. Two or more of the following: 1. Dizziness 8. Psychomotor retardation 2. Nystagmus 9. Tremor 3. Incoordination 10. Generalized muscle weakness 4. Slurred speech 11.Blurred vision or diplopia 5. Unsteady gait 12.Stupor or coma 13.Euphoria 6. Lethargy

240 7. Depressed reflexes

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Inhalant Intoxication Signs and Symptoms Treatment Inhalant Withdrawal Acute: Euphoria, disorientation, Symptomatic medical sedation, acute toxicity to treatments Signs and Treatment CNS, liver, kidneys, sudden hypoxemia, hypotension Symptoms Chronic: Discontinuation of use, Acute users: Reassurance, support Perpetual nerve, CNS, liver, supportive therapies (plumbism and kidney damage, plumbism ––chelationchelation therapy) Psychological (if leaded gasoline) Intoxication: Resuscitation, hospitalization Cardiac arrhythmia and arrest

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Question: Which of the following is true about MDMA (“Ecstasy”):

A. Produces selective, long lasting damage to serotonergic nerve terminals in animals The Action of Ecstasy (MDMA) B. Produces sympathomimetic effects of tachycardia, palpitations, increased blood pressure, sweating, and bruxism C. Can cause psychotic reactions D. Produces feelings of increased selfconfidence, sensory sensitivity, peacefulness, and decreased appetite E. All of the above

American Physician Institute For Advanced Professional Studies, LLC 245 246

* regulation of several processes within the brain, including mood, emotions, aggression, sleep, appetite, anxiety, memory, and perceptions.

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Reported Undesirable Effects (up to 1 week postMDMA, or longer)

Anxiety Lack of appetite Restlessness Thirst Irritability Reduced interest in Sadness and pleasure from sex Impulsiveness Significant reduction Aggression in mental abilities Sleep disturbances

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Potential Adverse Health Effects Symptoms of MDMA Overdose

High blood pressure Nausea Marked rise in body Chills temperature Faintness Sweating (hyperthermia) Panic attacks Involuntary jaw Dehydration Loss of consciousness clenching and teeth High blood pressure grinding Heart failure Seizures Muscle cramping Kidney failure Blurred vision Arrhythmia

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Question: Which of the following is true about MDMA (“Ecstasy”):

A. Produces selective, long lasting damage to Acknowledgements serotonergic nerve terminals in animals B. Produces sympathomimetic effects of tachycardia, palpitations, increased blood pressure, sweating, and John Knight, M.D. bruxism Sharon Levy, M.D. C. Can cause psychotic reactions ASAP (Adolescent Substance D. Produces feelings of increased selfconfidence, Abuse Program; Boston Children’s sensory sensitivity, peacefulness, and decreased Hospital) appetite ASAP (Adolescent Substance Abuse Program) E. All of the above CEASAR (Center for Adolescent Substance Abuse Research) Children’s Hospital (Boston) 261 262 Harvard Medical School

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