1. Presented by : Adenike Atanda, Pharm.D. COMBATING SUBSTANCE ABUSE: A review of therapeutic management

2. OBJECTIVES Utilize the Virginia prescription monitoring program (PMP) to recognize prescription medication misuse Explain the physiological effects of commonly abused substances Differentiate between CNS depressing and CNS stimulating substances Identify signs and symptoms of overdose and withdrawal syndromes of commonly abused substances and symptoms of neonatal abstinence syndrome Given a patient case, select an appropriate treatment plan for the management of a substance abuse disorder and neonatal abstinence syndrome

3. Epidemiology of substance abuse The use of illicit drugs has increased from 8.3% in 2002 to 9.4% in 2013 (24.6 million people) In 2009, there were approximately 4.6 million emergency department visits related to drug abuse. 21.2% of those visits involving illicit drugs use and 14.3% involving alcohol abuse with other medications Substance Abuse and Mental Health Services Administration. Substance Use and Mental Health Estimates from the 2013 National Survey on Drug Use and Health-Overview of Findings. The NSDUH Report. Sept 2014. National Institute on Drug Abuse. Drug-Related Hospital Emergency Room Visits. Drug Facts. May 2011.

4. Epidemiology of substance abuse in Virginia A survey conducted by the CDC in Virginia in 2013 showed that, for at least one day in the 30 day survey period;  11% of high school students had smoked a cigarette  27% of high school students had at least one drink of alcohol  32% of high school students had used marijuana  6% of high school students had used some form cocaine Increase in the number of methamphetamine lab seizures in Virginia by 958% from 2008 to 2011 (19 vs 201 incidents) U.S. Department of Health and Human Services: Office of Adolescent Health. Virginia Adolescent Substance Abuse Facts. Nov 2014. The Office of National Drug Control Policy-The White House. Virginia Drug Control Update. Jan 2013.

5. Epidemiology of substance abuse in Virginia 2012 Annual Report of the Office of the Chief Medical Examiner

6. Substance abuse in Virginia The state has implemented the following strategies to help combat the problem of substance abuse:  A prescription monitoring program started in 2003  Drug take back programs  The Virginia Board of Pharmacy now requires all pharmacists to obtain at least 1 hour of continuing education (CE) on opioid use or abuse, in the year 2015 The Office of National Drug Control Policy-The White House. Virginia Drug Control Update. Jan 2013.

7. VIRGINIA PRESCRIPTION MONITORING PROGRAM Website http://www.pmp.dhp.virginia.gov/pmpwebcenter

8. Virginia prescription monitoring program Controlled substances in schedule II to IV Data transmitted to the department within 7 days of dispensing All data is confidential and may only be released:  To the patient (over the age of 18) if requested  To a prescriber or dispenser who has a direct patient care relationship  If the information is relevant to an investigation by a health regulatory board, investigational grand jury or federal law enforcement agency authorized to conduct drug diversion investigation Department of Health Professions- Virginia Board of Pharmacy. The pharmacy act and the drug control act with related statues. 2013

9. Virginia prescription monitoring program Required data: Patient’s name, address and date of birth Medication name, quantity dispensed, total number of refills and date of the prescription Prescriber and dispenser’s DEA number Method of payment Reporting exemptions: Samples Administering covered substances Dispensing of covered substances in a licensed narcotic maintenance treatment program Dispensing of covered substances in a hospital, nursing facility or hospice Dispensing by a veterinarian to animals Department of Health Professions- Virginia Board of Pharmacy. The pharmacy act and the drug control act with related statues. 2013

10. POP QUIZ Which of the following is not a strategy implemented in the state of Virginia to combat substance abuse? a) Prescription monitoring program b) Drug take back programs c) Tracking device on prescription bottles d) Opioid abuse CE requirement for pharmacists Which of the following is true regarding the Virginia prescription monitoring program? a) All dispensed CII to CV drugs should be reported b) Required data include patient’s name, address and method of payment c) Data from the program can be released to a patient’s employer d) CII drugs dispensed in a licensed narcotic treatment program must be reported

11. MANAGEMENT OF SUBSTANCE ABUSE DISORDERS Pathophysiology Special considerations Clinical presentation Assessment tools Management

12. Commonly abused substances Alcohol Cocaine Heroin Marijuana Methamphetamines Nicotine

13. Substance abuse disorder DSM-V criteria Presence of at least 2 of the following within a 12 month period: Substance often taken in larger amounts or over a longer period than intended Persistent desire or unsuccessful efforts to control use of the substance Significant time spent in activities to obtain, use or recover from the substance Craving or strong desire or urge to use the substance Recurrent use resulting in failure to fulfill major obligations Continued use despite social and interpersonal problems Continued use despite knowledge of problem that can be worsened by the substance Tolerance: Need for increased amounts to achieve effect or diminished effect with use of the same amount Important activities reduced or abandoned because of use Withdrawal: Symptoms of withdrawal or the substance is taken to avoid symptoms Recurrent use in hazardous situations Diagnostic and statistical manual of mental disorders, 5th ed., text revision. Washington, DC: American Psychiatric Association, 2013.

14. Classification of abused substances CNS depressants Alcohol Heroin and prescription opioids CNS stimulants Methamphetamines Cocaine

15. CNS DEPRESSANTS

16. ALCOHOL USE DISORDER Contributes to 79,000 deaths annually in the US $223.5 billion in societal cost annually in the US 9% of Americans meet criteria for alcohol use disorder Nicknames: Booze, moonshine, liquid courage etc. Friedmann PD. Alcohol Use in Adults. N Engl J Med 2013;368:365-73.

17. Pathophysiology Glutamate - Excitatory Inhibited at low doses Increased effect with chronic intake GABA - Inhibitory Stimulated with acute intoxication Decreased effect with chronic intake Dopamine - Reward Release stimulated Mu (Opiate) - Reward Increased release of endogenous opioids Anton RF. Naltrexone for the management of Alcohol Dependence. N Engl J Med 2008;359:715-21.

18. Clinical presentation Acute intoxication Slurred speech Cognitive impairment Unsteady gait and incoordination Stupor or coma Metabolic acidosis Long term effects Steatosis (fatty liver) Alcoholic hepatitis and cirrhosis Pancreatitis Cardiomyopathy Withdrawal Nausea and vomiting Anxiety and insomnia Sweating Hand tremors Delirium tremens  Autonomic hyperactivity  Altered mentation; hallucinations, disorientation, decreased attention or fluctuating cognition  Psychomotor agitation  Generalized tonic-clonic seizures and severe tremors Schuckit MA. Recognition and Management of Withdrawal Delirium. N Engl J Med 2014;371:2109-13. Diagnostic and statistical manual of mental disorders, 5th ed., text revision. Washington, DC: American Psychiatric Association, 2013.

19. Clinical presentation Labs Abnormal markers of hepatic function, nutrition and elevated blood alcohol levels ↑ AST ↑ ALT↑ Alk Phos ↑ INR↑ PT↑ MCV ↑ GGT↑ CDT↓ Albumin ↓ Mg↓ K↓ Glu Thompson W, Lande GR, kalapatapu RK. Alcoholism workup. Medscape. 2014

20. Assessment tools CAGE Questionnaire 1. Have you ever felt you should cut down on your drinking? 2. Have people annoyed you by criticizing your drinking? 3. Have you ever felt bad or guilty about your drinking? 4. Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover ( eye-opener )? Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised(CIWA-Ar) 0 - 7= Mild 8 – 15 = Moderate >15 = Severe Schuckit MA. Recognition and Management of Withdrawal Delirium. N Engl J Med 2014;371:2109-13.

23. Supportive care Fluids Thiamine, folic acid and multivitamins can be added to fluids, commonly know as “banana bag” Thiamine is needed to prevent Wernicke encephalopathy Electrolyte supplementation Replete K, Mg, PO 4 as necessary Benzodiazepines Control agitation and seizures Chlordiazepoxide, lorazepam or diazepam given IV or PO Lorazepam is short acting and preferred in hepatic dysfunction/ elderly patients Adrenergic agonist and antagonist Used to reduce autonomic hypersensitivity (BP, HR and tremors) Propranolol or clonidine Anticonvulsants Control seizures Carbamazepine or divalproex Antipsychotics Control delirium and hallucinations Haloperidol preferred Can be used as adjunct therapy to BZD Manasca A, Chang S, Larriviere J et.al. Alcohol Withdrawal. Southern Medical Journal. 2012; 105(11): 607-612 American Psychiatric Association. Treatment of Patients with substance use disorders. 2006

24. Maintenance therapy Disulfiram (Antabuse) Interferes with aldehyde dehydrogenase and causes an increase in acetaldehyde levels with alcohol consumption leading to flushing, nausea, palpitations, vertigo and hypotension. Initial dose of 500 mg once daily for 1-2 weeks then 250 mg once daily (MAX: 500 mg daily) Efficacy: Mixed results, but a RCT showed that disulfiram has a higher rate of abstinence when compared to naltrexone (79.3% vs. 51.7%) in adolescent patients. More beneficial in combination with CBT. Adverse effects : Metallic aftertaste, rash and hepatotoxicity Kalra G, Sousa A and Shrivastava A. Disulfiram in the management of alcohol dependence: A comprehensive clinical review. Open Journal of Psychiatry, 2014, 4, 43-52

25. Maintenance therapy Acamprosate (Campral) Increase the activity of GABA and decrease glutamate Reduces alcohol intake and craving Dose: 666 mg PO three times daily Efficacy: A metaanalysis of 24 trials showed that acamprosate reduced the risk of returning to any drinking by 86% and increased the cumulative duration of abstinence by 11% when compared to placebo. Adverse effects: Metallic aftertaste, diarrhea, insomnia rash and hepatotoxicity Witkiewitz K, Saville K and Hamreus K. Acamprosate for treatment of alcohol dependence: mechanisms, efficacy and clinical utility. Ther Clin Risk Manag. 2012; 8: 45–53.

26. Maintenance therapy Naltrexone Oral (Revia) or extended release IM injection (Vivitrol) Opiate receptor (mu) antagonist Prevents the euphoria and reward sensation associated with alcohol consumption (reduction in dopamine levels) Dose: 50 mg PO daily or 380 mg IM once every 4 weeks Efficacy: COMBINE study showed that naltrexone 100 mg PO daily for 16 weeks was more effective than placebo at increasing the percentage of abstinence days (80.6% vs. 75.1%) and reducing the risk of heavy drinking days (66.2% vs. 73.1%) Adverse effects: Opioid withdrawal, nausea, vomiting, dysphoria, fatigue, ALT elevation and hepatotoxicity (especially at higher doses) Anton RF. Naltrexone for the management of Alcohol Dependence. N Engl J Med 2008;359:715-21.

27. Summary of management Supportive care Maintenance therapy Naltrexone Disulfiram Acamprosate Acute intoxicationWithdrawal Hydration Decrease external stimulationBenzodiazepines Adrenergic agonist and antagonist Anticonvulsants Antipsychotics (Haloperidol) Ethanol

28. HEROIN AND PRESCRIPTION OPIOID Increased prevalence of heroin addiction admissions in patients aged 20 - 34 years from 2001 to 2011 (23% vs 45% ) 4 out of 5 heroin users state that they started with prescription opioid misuse 16,651 people died in the US due to prescription opioid use in 2010 Nicknames Heroin: Big H, china white, skag, black tar, smack, dope etc. Opioids: Oxy, blue, kickers, monkey, miss Emma, dollies, wafers, subs etc. Dart RD, Surratt HL, Cicero TJ et.al. Trends in Opioid Analgesic Abuse and Mortality in the United States. N Engl J Med 2015;372:241-8.

29. Pathophysiology Mu receptor Heroin is converted into morphine in vivo Opioids bind to mu receptors and cause the release of dopamine Results in an initial “high” that is followed by CNS and respiratory depression Dopamine - Reward Release stimulated Goldstein, A. Heroin addiction: neurobiology, pharmacology, and policy. J Psychoactive Drugs 23(2):123–133, 1991.

30. Clinical presentation Acute intoxication CNS depression Reduced respiratory rate (<12 bpm) Constricted “pin point” pupils Constipation Hypothermia Coma Withdrawal Restlessness and anxiety Nausea, vomiting and diarrhea Muscle and bone pain Cold sweats Tachycardia Dilated pupils Long term effects Infections Blood borne diseases Respiratory infections National Institute on Drug Abuse. Heroin. National Institute on Drug Abuse. Bethesda, MD: November 2014

31. Assessment tools Clinical Opiate Withdrawal Scale (COWS) 5-12 = Mild 13-24 = Moderate 25-36 = Moderately severe > 36 = Severe withdrawal Wesson DR and Ling W. The Clinical Opiate Withdrawal Scale (COWS). Journal of Psychoactive drugs. 2003; 35(2): 253-259

34. Supportive care Naloxone Short acting opioid antagonist Doses are started at 0.04 mg IV, IM or SQ and titrated up. Usual doses range from 0.4mg to 2mg repeated q2 to 3 mins Reversal can cause withdrawal Clonidine Alpha 2 agonist 0.1 to 0.3 mg every hour until symptom resolution Reduces noradrenergic hyperactivity Boyer EW. Management of Opioid Analgesic overdose. N Engl J Med 2012;367:146-55.

35. Methadone Long acting opioid agonist Onset 30 mins to 1 hour Dose Induction: 20 to 30 mg PO daily Maintenance: Titrate up by 5 to10 mg as needed until patient’s symptoms are controlled (range 80 to 120 mg/day) Withdrawal: Titrate down by 10 to 20% every 10 to 14 days Adverse effects: Similar to buprenorphine and includes cardiovascular effects (QT prolongation and arrhythmias) Johnson RE, Chutuape MA, Strain EC. A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence. N Engl J Med 2000;343:1290-7

36. Buprenorphine Partial opioid agonist Onset within 15 minutes Available as monotherapy (subutex) or in combination with naloxone (suboxone) Naloxone provides deterrent for abuse Dose Induction: (depends on type of opioid and time since last dose) Day 1: 8 mg SL Day 2: 16 mg SL ≥ Day 3: 16 mg SL and titrate to response Maintenance : 12 - 16 mg/day; suboxone preferred Adverse effects: Sedation, dizziness, hypotension, nausea and respiratory depression

37. Naltrexone Opioid antagonist Blocks pleasurable effects of opioids Must be opioid free for a minimum of a week before treatment initiation Pretreatment with clonidine can be used to alleviate withdrawal symptoms Adverse effects: Abdominal pain, diarrhea, nausea, vomiting, anxiety Dose Induction: 25 mg PO initially and then 50 mg daily Maintenance: Oral 50 mg daily 50 mg on weekdays and 100mg on Saturday 100 mg every other day 150 mg every 3 days IM 380 mg once a month American Psychiatric Association. Treatment of Patients with substance use disorders. 2006

38. Comparison of treatment Volkow ND, Frieden TR, Hyde PS et al. Medication-Assisted Therapies — Tackling the Opioid-Overdose Epidemic N Engl J Med 2014; 370:2063-2066

39. Summary of management Buprenorphine Methadone Naltrexone Acute overdoseWithdrawal VentilationBuprenorphine NaloxoneMethadone Clonidine Supportive therapy Maintenance therapy

40. PATIENT CASE CC “My husband is confused shaky, agitated and sweating a lot” CJ is a 48 year old man who presents to the ED with tremors, vomiting and altered mental status. His wife states that his symptoms started this morning and she thinks it’s because he tried to quit drinking “cold turkey”. He had been drinking about 9 bottles of beer per day since he lost his job last year and has not had a drink since yesterday morning. She also reports that he had a seizure on the way to the hospital. Vitals BP: 170/90 mmHg P: 106 bpm RR: 25 bpm T: 38.4 0 C Wt: 55 kg Ht: 5’9 ft CIWA score: 11 Pertinent labs Na 137 mEq/LAST 300 IU/L K 3.0 mEq/LALT 275 IU/L Cl 90 mEq/lT. Billi 1.8 mg/dL BUN 15 mg/dLGGT 200 U/L SCr 1.1 mg/dLAlb 2.4 g/dL Glu 80 mg/dLINR 1.20 Mg 1.5 mg/dLPT 17 sec Phos 3.0 mg/dLETOH negative

41. PATIENT CASE What is CJ’s diagnosis? What information supports your diagnosis?

42. PATIENT CASE All of the following are laboratory abnormalities in this patient except? a)Elevated AST/ALT b)Elevated K c)Reduced Albumin d)Reduced Mg All of the following would be appropriate for the management of the patient except? a) IV lorazepam - control agitation b) Supplement K and Mg c)½ NS, D5W infusion with thiamine 100 mg and folic acid 1 mg d) Insulin glargine 10 units qhs

43. CNS STIMULANTS

44. METHAMPHETAMINES Can be smoked, snorted, injected or orally ingested Accounted for 103,000 ED visits in 2011 (4 th common illicit drug in ED cases) In 2012, over 12 million people reported that they had used methamphetamine and the average age of new users was 19.7 years old Nicknames: Meth, crank, ice, tweak, glass, speed etc. National Institute on Drug Abuse. Methamphetamine. 2013

45. Manufacturing Manufactured from common household ingredients: Pseudoephedrine, acetone, fertilizer etc. Methamphetamine act in 2005 : Limits the sale of ephedrine products to a max of 3.6 g/day and 9 g/30 days Pharmacies are required to keep a log of every pseudoephedrine product sold

46. Pathophysiology Increased release in catecholamines (dopamine, norepinephrine and serotonin) Increased production of tyrosine hydroxylase, enzyme responsible for dopamine synthesis Redistribution of catecholamines to the cytosol Blocked activity of monoamine transporters Inhibition of monoamine oxidase activity Barr AM, Panenka WJ, MacEwan GW et al. The need for speed: an update on methamphetamine addiction. J Psychiatry Neurosci. 2006 Sep;31(5):301-13.

47. Clinical presentation Acute intoxication Increased wakefulness Decrease appetite Dry mouth Dilated pupils Tachycardia Hypertension Hyperventilation Hyperthermia Convulsion Aggressive behavior Hallucinations and delusions (insects creeping under skin) Withdrawal Intense cravings Depression Fatigue Long term effects Anorexia Changes in brain structure and function Memory loss Severe dental problems National Institute on Drug Abuse. Methamphetamine. 2013

48. Acute intoxication management American Psychiatric Association. Treatment of Patients with substance use disorders. 2006 Buxton JA and Dove NA. The burden and management of crystal meth use. CMAJ 2008; 178(12): 1537 - 1539 Agitation Benzodiazepines IV lorazepam or diazepam Can be used for seizure control Antipsychotics: IV or IM haloperidol Used as adjunct therapy to BZD Hypertension Nitroprusside Caution with beta blocker therapy due to unopposed alpha vasoconstriction Hyperthermia and Hyperventilation Neuromuscular blockade agents Temporary paralysis to control hyperthermia Avoid succinylcholine due to increased risk of rhabdomyolysis Ensure patient has adequate ventilation support and analgesia Cooling blankets

49. COCAINE Can be inhaled, smoked or injected In 2012, 1.6 million Americans used some form of cocaine Accounted for 4.6 million ED visits in 2009 Nicknames: Crack, coke, blow, snow, snow white, rock, blanca etc. National Institute on Drug Abuse. DrugFacts: Cocaine. 2013

50. Manufacturing Made from coca plant Two forms: Water soluble HCl salt (powder) Water insoluble base (solid) Cocaine powder is mixed with ammonia or baking soda and water and heated to remove the HCL to produce the crystal rock “crack” National Institute on Drug Abuse. DrugFacts: Cocaine. 2013

51. Pathophysiology Increased catecholamines (norepinephrine, serotonin and dopamine) and glutamate activity Blockade of monoamine oxidase Norepinephrine stimulates alpha receptors Sodium channel blockade O’Connor PG. Drug Use and Dependence: Cocaine. Merck Manual. 2013

52. Clinical presentation Acute intoxication Increased wakefulness Decrease appetite Abdominal pain Dilated pupils Constricted blood vessels Chest pain Tachycardia Hypertension Hyperthermia Aggressive behavior Myocardial infarction Strokes Withdrawal Intense cravings Depression Fatigue Long term effects Bowel gangrene Paranoia Anorexia Infections and blood borne diseases like HIV National Institute on Drug Abuse. Cocaine. 2013

53. Management Acute intoxication Same as amphetamine therapy Nitroglycerin for cocaine induced chest pain Maintenance Disulfiram 250 mg daily Mixed efficacy data Modafinil 200 – 400 mg daily Abuse potential Tiagabine 12 – 24 mg daily Topiramate 200 – 300 mg daily American Psychiatric Association. Treatment of Patients with substance use disorders. 2006

54. Summary of management Disulfiram Modafinil Tiagabine Topiramate Acute overdose Benzodiazepines Antipsychotics Nitroprusside Neuromuscular blockade agents Cooling blankets Supportive therapy Cocaine maintenance therapy

55. POP QUIZ Appropriate therapy for the management of methamphetamine overdose includes? a)Benzodiazepines b)Naloxone c)Acamprosate d)Warming blanket The sale of ephedrine products has been limited to? a)5.6 grams per day b)7 grams per 30 days c)There is no limit on the sale of ephedrine products d)9 grams per 30 days

56. SUBSTANCE ABUSE AND PREGNANCY Survey conducted by the National Survey on Drug Use and Health in 2008 – 2009: 15.8% of pregnant women aged 15 to 17 years old reported illicit drug use 7% of pregnant women aged 18 to 25 years old reported illicit drug use. National institute on drug abuse. Prenatal exposure to drugs of abuse- May 2011.

57. Neonatal abstinence syndrome Jones HE, Kaltenbach K, Heil SH et.al. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. N Engl J Med 2010;363:2320-31. Medline Plus. Neonatal abstinence syndrome Withdrawal syndrome in babies exposed to opioids in utero Severity evaluated by the modified Finnegan Scale Symptoms CNS hyperirritability GI dysfunction Respiratory distress Metabolic disturbances Vasomotor disturbances Complications Diarrhea Feeding difficulties and weight loss Seizures Death

58. Management Non-opioid therapy* Clonidine 0.5 to 1 mcg/kg PO q4 - 6 hrs Wean by 0.25 mcg/kg q6hrs Phenobarbital 5 mg/kg/day PO or IV divided every 12 hours Wean by 20% every 48 hours DOC for non narcotic related withdrawal or polydrug abuse * Adjunct to opioid therapy Opioid therapy Morphine 0.03 mg/kg PO q3 -4hrs, MAX dose of 0.2 mg/kg/dose Wean by 10 – 20% every 48 to 72 hrs Methadone 0.05 – 0.2 mg/kg PO or IV q12hrs Wean by 10 – 20% every 5-7 days Buprenorphine 5.3 mcg/kg SL q8hrs Wean by 10% per day Siu A and Robinson CA. Neonatal Abstinence Syndrome: Essentials for the Practitioner. J Pediatr Pharmacol Ther. 2014 Jul-Sep; 19(3): 147–155.

59. POP QUIZ Which of the following is a CNS stimulating substance? a)Alcohol b)Cocaine c)Heroin d)Morphine Which of the following medications cannot be used to effectively manage neonatal abstinence syndrome? a)Buprenorphine b)Clonidine c)Morphine d)Naltrexone

60. ROLE OF THE PHARMACIST Identifying patients with problems related to substance abuse and prescription medication misuse Providing pharmaceutical care to these patients Participating in multidisciplinary efforts to manage patients recovering from substance abuse Utilizing the prescription monitoring programs to help deter prescription medication abuse American Society of Health-System Pharmacists. ASHP Statement on the Pharmacist’s Role in Substance Abuse Prevention, Education, and Assistance. Medication Therapy and Patient Care: Specific Practice Areas-Statements. 2013: 305-308

61. RESOURCES National Institute on Drug Abuse www.drugabuse.gov National Institute on Alcohol Abuse and Alcoholism www.Niaaa.nih.gov Substance Abuse and Mental Health Services Administration www.samhsa.gov

62. Questions Aatanda@valleyhealthlink.com

63. REFERENCES Substance Abuse and Mental Health Services Administration. Substance Use and Mental Health Estimates from the 2013 National Survey on Drug Use and Health-Overview of Findings. The NSDUH Report. Sept 2014. National Institute on Drug Abuse. Drug-Related Hospital Emergency Room Visits. Drug Facts. May 2011. U.S. Department of Health and Human Services: Office of Adolescent Health. Virginia Adolescent Substance Abuse Facts. Nov 2014. The Office of National Drug Control Policy-The White House. Virginia Drug Control Update. Jan 2013. Department of Health Professions- Virginia Board of Pharmacy. The pharmacy act and the drug control act with related statues. 2013 Diagnostic and statistical manual of mental disorders, 5th ed., text revision. Washington, DC: American Psychiatric Association, 2013. Friedmann PD. Alcohol Use in Adults. N Engl J Med 2013;368:365-73. Anton RF. Naltrexone for the management of Alcohol Dependence. N Engl J Med 2008;359:715-21. Schuckit MA. Recognition and Management of Withdrawal Delirium. N Engl J Med 2014;371:2109-13. Thompson W, Lande GR, kalapatapu RK. Alcoholism workup. Medscape. 2014

64. REFERENCES Manasca A, Chang S, Larriviere J et.al. Alcohol Withdrawal. Southern Medical Journal. 2012; 105(11): 607-612 American Psychiatric Association. Treatment of Patients with substance use disorders. 2006 Kalra G, Sousa A and Shrivastava A. Disulfiram in the management of alcohol dependence: A comprehensive clinical review. Open Journal of Psychiatry, 2014, 4, 43-52 Witkiewitz K, Saville K and Hamreus K. Acamprosate for treatment of alcohol dependence: mechanisms, efficacy and clinical utility. Ther Clin Risk Manag. 2012; 8: 45–53. Anton RF. Naltrexone for the management of Alcohol Dependence. N Engl J Med 2008;359:715-21. Dart RD, Surratt HL, Cicero TJ et.al. Trends in Opioid Analgesic Abuse and Mortality in the United States. N Engl J Med 2015;372:241-8. Goldstein, A. Heroin addiction: neurobiology, pharmacology, and policy. J Psychoactive Drugs 23(2):123–133, 1991. National Institute on Drug Abuse. Heroin. National Institute on Drug Abuse. Bethesda, MD: November 2014 Wesson DR and Ling W. The Clinical Opiate Withdrawal Scale (COWS). Journal of Psychoactive drugs. 2003; 35(2): 253-259 Boyer EW. Management of Opioid Analgesic overdose. N Engl J Med 2012;367:146-55. Johnson RE, Chutuape MA, Strain EC. A comparison of levomethadyl acetate, buprenorphine and methadone for opioid dependence. N Engl J Med 2000;343:1290-7

65. REFERENCES Volkow ND, Frieden TR, Hyde PS et al. Medication-Assisted Therapies — Tackling the Opioid-Overdose Epidemic N Engl J Med 2014; 370:2063-2066 National Institute on Drug Abuse. Methamphetamine. 2013 Barr AM, Panenka WJ, MacEwan GW et al. The need for speed: an update on methamphetamine addiction. J Psychiatry Neurosci. 2006 Sep;31(5):301-13. Buxton JA and Dove NA. The burden and management of crystal meth use. CMAJ 2008; 178(12): 1537 - 1539 National Institute on Drug Abuse. DrugFacts: Cocaine. 2013 O’Connor PG. Drug Use and Dependence: Cocaine. Merck Manual. 2013 National institute on drug abuse. Prenatal exposure to drugs of abuse- May 2011. Jones HE, Kaltenbach K, Heil SH et.al. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. N Engl J Med 2010;363:2320-31. Medline Plus. Neonatal abstinence syndrome Siu A and Robinson CA. Neonatal Abstinence Syndrome: Essentials for the Practitioner. J Pediatr Pharmacol Ther. 2014 Jul-Sep; 19(3): 147–155. American Society of Health-System Pharmacists. ASHP Statement on the Pharmacist’s Role in Substance Abuse Prevention, Education, and Assistance. Medication Therapy and Patient Care: Specific Practice Areas-Statements. 2013: 305-308