Respect Reason Recognition Resolution Referral Respect

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#FSHP2019 Disclosure #FSHP2019

I do not have (nor does any immediate family member have): Shining Light on the MATter: – a vested interest in or affiliation with any corporate organization offering financial support or grant monies Emergency Department Management of Opioid Withdrawal for this continuing education activity – any affiliation with an organization whose philosophy Nick Scaturo, PharmD could potentially bias my presentation Sarasota Memorial Hospital

#FSHP2019 #FSHP2019 Pharmacist Objectives Technician Objectives • Review the history of the opioid epidemic and the resulting implications for emergency departments (ED) • Explain the pathogenesis of AOW • Explain the pathogenesis of acute opioid withdrawal • List traditionally used treatments options for AOW (AOW) • Describe newer treatment options for AOW • Appraise literature surrounding different treatment options for AOW • Describe limitations to classical treatment modalities for AOW • Create evidence-based strategies for the treatment of AOW in the ED

#FSHP2019 #FSHP2019 The 5 R’s of Opioid Withdrawal

Respect Reason Recognition Resolution Referral Respect

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#FSHP2019 #FSHP2019

“No one dies from opioid withdrawal”

#FSHP2019 #FSHP2019 Drug-Related Poisoning Death Risk by Intervention 2.5

2 Naloxone Administration by EMS 1.5 = 1 10% mortality within 1 year 0.5

Adjusted Hazard Ratio 0 No Treatment Psychological Psychological Intervention Only Intervention & Opiod Agonist Treatement Intervention Weiner SG et al. Ann Emerg Med 2017;70:S158. Pierce et al. Addiction 2015;111:298-308. 910

#FSHP2019 #FSHP2019 Timeline of Important Events

NEJM letter Oxycontin CMS JACHO HCAHPS claiming low risk hits the institutes removes pain revision 2009 2007 1980 1997 of addiction market HCAHPS management 2017 with opioid use standards

Reason 1980 1990 2000 2010 2015

JACHO 2007 1986 2012 2017 Portenoy’s 2001 institutes Purdue pleads Portenoy case report pain guilty to retracts Bibliometric published standards misbranding statements analysis

NEJM: New England Journal of Medicine; JACHO: Joint Commission on Accreditation of Healthcare Organizations; CMS: Centers for Medicare and Medicaid Services; HCAHPS: Hospital Consumer Assessment of Healthcare Providers and Systems 11 12

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#FSHP2019 #FSHP2019 NEJM Letter Bibliometric Analysis

Porter J, Jick H. NEJM 1980;302(2):123. Leung P et al. NEJM 2017; 376:2194-2195. 13 14

#FSHP2019 #FSHP2019 Portenoy’s Case Series Purdue Pharma’s OxyContin • Aggressive marketing • Retrospective review of 38 non-malignant, chronic pain • All expenses paid conferences patients • Targeting highest opioid prescribers • 2/38 patients had problems with management, but noted • that these patients had a history of drug abuse Bonus system for sales reps • Branded promotional items • Conclusion: opioids are a safe and more humane alternative than surgery or no treatment in patients with • Misrepresentation of addiction risk intractable, non-malignant pain and no history of drug • “Risk of addiction less than 1%” abuse • Package insert: • “Delayed absorption is believed to reduce abuse liability of the drug” Portenoy RK et al. Pain 1986; 25(2):171-86. Van Zee, A. Am J Public Health 2009; 99(2):221-227. 15 16

#FSHP2019 #FSHP2019 Purdue Settlement Joint Commission

• $634.5 million dollar settlement • Pain Management Standards introduced in 2001 • Estimated sales of OxyContin total $35 billion • Necessitated quantitative pain assessments in all patients • Additional settlement in 3/2019 with state of Oklahoma for $270 million • Unintended consequences • Increased opioid prescribing • 1600 additional cases have been filed against the • Fear of decreased federal funding if benchmarks not met company • Increased opioid over-sedation and fatal respiratory • Potential for bankruptcy of company depression • Standards removed in 2009 Van Zee, A. Am J Public Health 2009; 99(2):221-227. Jones MR. Pain Ther 2018; 7:13-21. https://www.npr.org/sections/health-shots/2019/03/26/706848006/purdue-pharma-agrees-to-270-million-opioid-settlement-with-oklahoma Baker DW. The Joint Commission 2017: 1-10. 17 18

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#FSHP2019 #FSHP2019 HCAHPS HCAHPS Revisions

• Patient satisfaction survey required by CMS • Medication-based questions Old • Did you need medicine for pain? established in 2006 • How often was your pain well controlled? • How often did the hospital staff do everything they • Impacts (2006) could to help you with your pain? • Results are publically reported • Patient’s perception impacts institution’s reputation • Communication-based questions • CMS reimburses based on results • Did you have any pain? New • How often did hospital staff talk with you about • Valued-based purchasing how much pain you had? • How often did hospital staff talk with you about (2017) how to treat your pain?

Thompson CA. Am J Health-Syst Pharm 2017; 74(23):1924-26. Thompson CA. Am J Health-Syst Pharm 2017; 74(23):1924-26. 19 20

#FSHP2019 #FSHP2019 Roots of the Opioid Epidemic Definitions Tolerance

Dependence

Low-quality Misguided evidence regulatory Addiction perpetuated Aggressive pressure pharmaceutical industry marketing Withdrawal

Kosten TR et al. Sci Pract Perspect 2002; 1(1):13-20. 21 22

Opioids in the Brain #FSHP2019 #FSHP2019 Opioid PFC

PFC Addiction PFC: Prefrontal cortex Addiction VTA: Ventral tegmental area Simplified NAc: Nucleus accumbens VTA PFC: Prefrontal cortex (Psychological D: Dopamine Symptoms) VTA: Ventral tegmental area NAc: Nucleus accumbens NAc LC: Locus ceruleus

LC Dependence NAc (Physical Symptoms)

Kosten TR et al. Sci Pract Perspect 2002; 1(1):13-20. 23 24

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Opioid Withdrawal Simplified #FSHP2019 #FSHP2019

NE NE NE Mu NE NE NE NE NE NE NE Recognition NE NE NE NE NE NE NE NE NE NE NE

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#FSHP2019 #FSHP2019 Screening: Opioid Dependence Signs and Symptoms Physiological RODS MINI Psychological - Restlessness -Pain - Nausea/Vomiting • Specific screen for opioid • Screens for 17 -Anxiety - Diarrhea dependence psychological disorders - Stress Intolerance - Autonomic • 11-question section specific • 8-item questionnaire - Irritability Hyperactivity to opioid use • Takes < 2 minutes - Drug Craving - Gooseflesh skin • Takes 15-20 minutes, if - Diaphoresis • Proven high sensitivity and whole MINI preformed - Yawning specificity compared to • Weeks to -Mydriasis Days to MINI Gold-standard • Used in most study protocols Months Weeks

Wickersham JA et al. J Correct Health Care 2015;21(1):12-26. Herring AH et al. Ann Emerg Med 2019;18:S1482-1483. 27 28

#FSHP2019 #FSHP2019 COWS Score

Signs or Symptoms Assessed Resting Pulse Rate (0-4) Sweating (0-4) Total Level of Withdrawal Restlessness (0-5) Score Pupil Size (0-5) <5 None Bone or Joint Aches (0-4) Add it Up 5-12 Mild Resolution Runny Nose or Tearing (0-4) 13-24 Moderate GI Upset (0-5) 25-36 Moderately Severe Tremor (0-4) >36 Severe Yawning (0-4) Anxiety or Irritability (0-4) Gooseflesh Skin (0-5) 29 30

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#FSHP2019 Supportive Care Measures #FSHP2019 Treatment Options Symptom Medication Common/ Dangerous Adverse Effects Abdominal Dicyclomine Anticholinergic, dizziness, nausea • Supportive Care Cramps Anxiety/ Diazepam, Over-sedation; use caution if giving mu agonists • Central Alpha2 Agonists Restlessness Hydroxyzine • Clonidine Diarrhea Loperamide QT-interval prolongation and cardiac arrest with • Lofexidine large doses Dyspepsia Famotidine QT-interval prolongation • Opiate Agonists Myalgias Methocarbamol Dysphoria, suicidal thoughts • Methadone Nausea/ Ondansetron QT-interval prolongation • Buprenorphine (BUP) Vomiting Pain APAP, Ibuprofen Allergic reaction Insomnia Trazodone Orthostatic hypotension

Duber HC et al. Ann Emerg Med 2018; 72(4):420-431. 31 32

#FSHP2019 Lofexidine Study #FSHP2019 Clonidine/Lofexidine Study Design • 8-day, randomized, double-blind, placebo controlled, parallel group • Outcomes: subjective opiate withdrawal scale (SOWS) on Day 3 and time- • Central alpha agonists to-dropout 2 • Lofexidine 3.2 mg daily in four divided doses vs matching placebo days 1- • Decrease norepinephrine 5, followed by 2 days of placebo release Patient Population • 264 patients dependent on short acting opioids with withdrawal signs Exclusion: medical/psych illness, AIDS, dependence on other substances, • Address physiologic hyper- or hypotension, bradycardia, use of methadone or BUP in last 14 days, use of psychotropics, prescription analgesics, anticonvulsants, symptoms of withdrawal antihypertensives, antiarrythmics in last 4 weeks, pregnancy or lactation only Results • Day 3 SOWS: 6.32 vs 8.67 (p=0.0212) • Early Terminators: 59 vs 80 • Lofexidine FDA approved Limitations • Not compared to opiate agonist therapy for opioid withdrawal • Limited to those withdrawing from short acting opioids

Conclusions • Lofexidine significantly decreased SOWS scores and demonstrated higher retention rates in participants undergoing opioid withdrawal Toce MS et al. J Med Tox. 2018;14:306-322 Gorodetzky CW et al. Drug and Alc Depend. 2017;176: 79-88 33 34

#FSHP2019 #FSHP2019 Effectiveness: Alpha2 Agonists Dosing • 26 RCTs1728 patients • Clonidine • Compared to placebo: • Higher success of completing • 0.1-0.2 mg every 6-8 hours titrated to symptoms treatment and less severe and blood pressure withdrawal symptoms • Maximum: 0.3 mg/dose or 1.2 mg/day • Compared to tapering methadone: • Lofexidine • As effective; similar treatment completion rates • 0.54 mg every 6 hours for peak withdrawal, then • More adverse effects and tapered based on symptoms by decreasing by withdrawal occurred earlier • Lofexidine causes less hypotension 0.18 mg every 1-2 days than clonidine • Maximum: 0.72 mg/dose or 2.88 mg/day

Gowing L et al. Cochrane Database Syst Rev. 2009;8(3):1-73 35 36

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#FSHP2019 #FSHP2019 Concerns? • Hypotension/Bradycardia • Less with lofexidine • Cost • Lofexidine: 0.18mg tab= $24.83 • Clonidine: 0.1mg tab= $0.30 • Do not address psychological symptoms • Place in Therapy: opioid alternative requested or mild symptoms expected

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#FSHP2019 #FSHP2019 Methadone Methadone Pharmacology • Long acting, full mu agonist and NMDA antagonist • Long, variable half-life • FDA approved for pain and opioid use disorder • Metabolism primarily via • Restricted prescribing CYP2B6 1. DEA registration as a narcotic treatment program • Minor routes: CYP3A4, + CYP2C9, CYP2C19 2. Registration with Center for Substance Abuse • Blockade of cardiac Treatment Image from: https://www.pbs.org potassium channels + 3. Registration with any state methadone authority

Drug Enforcement Administration. www.deadiversion.usdoj.gov/pubs/manuals/pract/section6.htm Toce MS et al. J Med Tox. 2018;14:306-322 39 40

#FSHP2019 #FSHP2019 Issues with Methadone Ideal Candidates • Chronic pain patient on high dose of opioids • Drug Interactions • Insurance coverage issues • Illicit Use/Respiratory Depression • Florida Medicaid covers methadone, but only covers • Cardiac abnormalities BUP for induction • Inconvenient follow-up • May be easier to enroll in methadone clinic if no benefits • Daily travel to clinic • Availability concerns in suburban/rural areas • Closer supervision • Usually requires daily dosing at methadone clinic • In special circumstances, patients may receive take home doses Toce MS et al. J Med Tox. 2018;14:306-322 41 42

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#FSHP2019 #FSHP2019 Summary: Methadone Buprenorphine Brand Name Formulation Generic Cost • FDA indication for opioid Available? • Once the gold standard, now second line dependence Subutex® BUP SL Tab Y $$ • Not an ED initiated therapy due to risks Suboxone® BUP/NAL SL Y$$ • Multiple formulations Film available • Full agonist Zubsolv® BUP/NAL SL N$$ • Patient specific dosing • With or without naloxone Tab • Drug interactions • Highly regulated Bunavail® BUP/NAL N$$ • Cardiac concerns prescribing rights Buccal Film • Drug Addiction Treatment Probuphine® BUP SQ N $$$ • Certain patients may be more fit for methadone Act Implant clinic referral than BUP • “X”-waiver Sublocade® BUP SQ N $$$ Injection • 3-day rule Toce MS et al. J Med Tox. 2018;14:306-322 43 44

Buprenorphine Pharmacology #FSHP2019 Buprenorphine Efficacy #FSHP2019

• Partial mu agonist • 38/102 (37%) engaged in treatment at 30 • High binding affinity Referral to Treatment • Long half life (~37 hours) days • Ceiling effect

• Antagonism at opiate-receptor-like Brief Intervention + receptor • 50/111 (54%) engaged in treatment at 30 Referral to Treatment days • Blocks rewarding and anti-nociceptive actions of opioids Brief Intervention + • CYP3A4 metabolism to active • 89/114 (78%) engaged in treatment at 30 ED-Initiated BUP + metabolite days • Further eliminated via glucoronidation Referral to Treatment Toce MS et al. J Med Tox. 2018;14:306-322 Dahan A et al. Br J Anaesth. 2005;94:825-834 D’Onofrio et al. JAMA. 2015;313: 1636-1644 45 46

#FSHP2019 #FSHP2019 France & Baltimore Comparison of Therapies

• BUP vs Methadone • Similar rates of treatment completion • BUP vs Alpha-2 Agonists • BUP=lower overall withdrawal scores and more days in treatment

Emmanueli J et al. Addiction 2005;100(11):1690-1700. Schwartz RP et al. Am J Public Health 2013; 103(5):917-922. Gowing L et al. Cochrane Database Syst Rev. 2017;2:1-80 47 48

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#FSHP2019 #FSHP2019 Buprenorphine COWS≥7? Dosing Y Abuse potential? Complicating Y Complicating Factors Factors N • Possible, but not probable • Acute liver failure Give 8 mg Address SL BUP Complicating • >20 weeks pregnant Factors • Combination with naloxone would deter IV use • Intoxicated/altered • If diverted, generally to prevent withdrawal in • Withdrawal due to naloxone Symptoms Y Improved? others • Taking methadone or long N • Rather this, than IVDU? acting opioid Give 2nd dose Symptomatic 8-24 mg SL Treatment • Chronic pain patient BUP • Borderline COWS score (6-8) or recent opioid use Rx, if X Treatment waivered Referral Toce MS et al. J Med Tox. 2018;14:306-322. Cisewski DH et al. Am J Emerg Med 2019; 37:143-150. Genberg BL et al. Addict Behav. 2013;38(12):2868-2873. 49 50

#FSHP2019 #FSHP2019 Summary: Buprenorphine

• Long acting opioid like methadone, but without the risks • Can initiate in ED • No X-waiver: 72 hour rule Referral • X-waiver: prescription • Not all withdrawal patients are good candidate, screen appropriately • Proven to keep patients in treatment, off opioids, and alive

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#FSHP2019 #FSHP2019 Linkage to Treatment Peer Recovery Specialist

• Goal should be within 72 hours of ED evaluation • Individual with history of OUD present to discuss • Champions in the ED/Waivered MDs recovery options with patients • Know your local/state resources • Aids in education about treatment options and • Opioid Treatment Programs harm reduction • Primary Care Practices • Helps to facilitate follow-up after patients leave the • Residential Clinics ED • Federally Qualified Health Centers • Bridge Clinics

Duber HC et al. Ann Emerg Med 2018;72(4):420-431. Reif S et al. Psychiatric Services 2014;65:853-861. 53 54

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#FSHP2019 Final Word

• Respect the suffering a patient with opioid withdrawal is going through, they are seeking your help • Keep in mind the reason behind how we got to this point • Knowing the reason behind how withdrawal and addition occur can help you make sense of the therapies we use • Recognize the symptoms and timeline of withdrawal • Resolve your patients symptoms • Referral to outpatient therapy should be a priority and a process should be established