12/8/18. Is your patient an Uber driver? Why you should ask. I have nothing to disclose NEJM. Outline. Treatment models Brief Updates

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1 Is your patient an Uber driver? Why you should ask. I have nothing to disclose A clinical review of substance use disorders: opiates, benzodiazepines, and alcohol Katherine Grieco DO DABAM Medical Director HAVEN Health Assistance InterVention & Education Network Connecticut Outline NEJM Treatment models Brief Updates Opiates Benzodiazepines Alcohol October 18 th, 2018

2 Addiction Treatment Models Harm reduction set of practical strategies and ideas aimed at reducing negative consequences associated with drug use a movement for social justice built on a belief in, and respect for the rights of people who use drugs Moderation Management Abstinence complete cessation of alcohol and drugs. Individualized approach Safety sensitive occupations Healthcare professionals Airline pilots Construction workers Risk/benefit ratio Opiates As opioid epidemic levels off, stimulant use rises. 2017: 47,944 OD deaths 2018: 46,655 OD deaths ~2.8% drop CDC: Opioid Overdose Deaths Age-adjusted drug overdose death rates, by state: United States, 2016 Opioid overdoses are not declining, rather, are increasing at a slower rate than they have previously.

3 CDC: Drug Overdose Deaths, Drug overdoses are now the leading cause of death among Americans under klkl ,000 to 65,000 people died from drug OD in US in 2016 Peak car crash deaths 1972 Peak HIV deaths 1995 CDC: Fentanyl Deaths in 2016:Up 540% in 3 Years (provisional data) Worse than HIV Deaths involving synthetic opioids, mostly fentanyl, jumped from 3,000 to 20,000 in 3 yrs. Peak gun deaths : >72,000 deaths from drug OD Increase in deaths from Cocaine & meth use (often involve opiates) WARNING: Crisis has not peaked (?) Number of Deaths Overdose Deaths by Opioid, SF Phillip O. Coffin, MD MIA Chris Rowe, MPH San Francisco Dept of Public Health Total Opioids Heroin Rx Opioids (not fent) Fe ntanyl Fentanyl Test Strips Detects presence of fentanyl in drug sample not percentage. Test drug residue Brown University study young adults reduced overdose risk by using less, going slower or using with someone else present. SF DOPE Project survey 8/17-1/18, Harm Reduction Coalition Positive response Available at syringe-exchanges Use of rapid fentanyl test strips among young adults who use drugs; Maxwell S Krieger et al. International Journal of Drug Policy, Oct 18, 2018,

4 Kratom Tropical tree in Southeast Asia Eat leaves raw, crush or brewed in tea, tablets, capsules, liquid Acts on opioid receptors Small amounts -> stimulant Larger amounts -> sedative Users claim it helps with pain & opioid withdrawal Symptoms (via case report) withdrawal seizures psychosis Kratom DEA 2017: Drugs of Concern List FDA NOT approved for any therapeutic use Legal buy online Banned in several states, not CA FDA working with DEA to block shipments into USA. Send-out test in urine CDC link to Salmonella, CA 13 cases (4/17) 44 Kratom-related deaths DSM-5 Criteria for ANY Substance Use Disorder 11 Criteria Presence of at least 2 for OUD Missing work or school Using in hazardous situations Using despite social or personal problems Craving for the drug Build up of tolerance Withdrawals when trying to quit Using more than intended Trying to quit without success Increased drug-seeking behavior Interference with important activities Continued use despite health problems Pharmacotherapy for OUD Mild: 2-3; Moderate: 4-5; Severe: 6 or >

5 33 yo male with h/o poor engagement in care/? reliability, using illicit oxycodone pills daily and occasional heroin, unable to stop without significant w/d and cravings. Wants to discuss treatment options. If he took time off to enter detox, he fears he would lose his job. What is the best tx option for him? 1) Buprenorphine/naloxone 2) Methadone maintenance 3) Recommend he use Kratom to help with w/d sxs. 4) Naltrexone Tx for Opiate Use Disorder Options Buprenorphine/naloxone 1st Partial opioid agonist Ceiling effect resp depression, sedation Films/Pills/Injectable Office based tx requires federal waiver to Rx Stable pts no poly drug use, support system in place, psychiatrically stable MUST be in withdrawal to start Robust data to support efficacy Methadone maintenance (MMTP) 1st Full opioid agonist Higher risk for OD, sedation Liquid form, daily dosing Federally qualified OTP (opiate tx program) Highly regulated, structure Counseling mandated Naltrexone 2nd Opioid blocker NO risk for OD from Nal; risk trying to override blockade Pill or injection (Vivitrol) Office based Pts w/cravings, not experiencing withdrawal, not currently using Stable pts - no poly drug use, Pts in need of monitoring, lack of support system in place, support system, psychiatrically psychiatrically stable (? for pts unstable, Failed bupe who have failed MMTP/bupe) Withdrawal not necessary to start MUST be in withdrawal to start Robust data to support efficacy Limited data Opiate replacement treatment is associated with reduced mortality, lower HIV transmission, improved social functioning, and reduced criminal behavior. Injectable Buprenorphine Extended-release bupe, subcutaneous abdominal monthly injection Moderate to Severe OUD Stabilize on 8-24mg oral bupe for at least 7 days prior to starting Induction dose (first 2 months) followed by maintenance dose California MediCal covers as of 10/18 Only available via REMS certified pharmacies/clinics - Sacramento Medication for OUD after opiate overdose Retrospective cohort study n= 17,568 Methadone, buprenorphine, naltrexone Minority received MOUD, ~12% Buprenorphine and methadone tx associated with reduced allcause, opioid-related mortality Larochelle MR ; Bernson D ; Land T; et al. Medication for opioid use disorder after nonfatal opioid overdose and association with mortality: a cohort study. Ann Intern Med. 2018; 169:

6 XR Naltrexone vs Buprenorphine JAMA Psychiatry 10/18/17 Open-label, randomized clinical trial x 12 wks N=159, Norway Noninferior to buprenorphine/naloxone The Lancet 1/27/18 Open-label, randomized controlled trial x 24 wks N= 570, USA Both medications equally safe and effective Extended-Release Naltrexone Improves Viral Suppression in HIV+ Prisoners 2 Double-blind placebo controlled randomized trials AUD, OUD Incarcerated PLH released into community XR-NTX can improve or maintain HIV viral suppression better than placebo after release to the community. Enrollment followed detox Avg buprenorphine dose ~ 11mg No follow up data re: overdose after stopping the medication Ease of induction remains problematic for XR Nal Higher relapse rate upfront No follow up data re: overdose after stopping the medication Sandra Springer et al, Extended-Release Naltrexone Improves Viral Suppression in HIV+ Prisoners. CROI Abstract Number 96, Boston MA 3/18. XR Naltrexone Guidelines SAMHSA - Clinical Use of Extended-Release Injectable Naltrexone in the treatment of OUD: A Brief Guide Office based addiction tx Comprehensive tx approach Counseling Psychiatric treatment as needed OUD suicide risk: 10% vs 1.3% in the gen population Social support: AA, NA, mutual-help programs Same case but 33 yo male with active OUD. Wants to discuss treatment options. If he took time off to enter detox, he fears it would impact his employment/income. He works as an Uber driver. What is the best tx option for him? 1) Buprenorphine/naloxone 2) Methadone maintenance 3) Recommend he use Kratom to help with w/d sxs. 4) Strongly recommend detox, followed by naltrexone

7 BZDs and HIV - Studies BZD use independent risk factor for HIV seroconversion Benzodiazepines Benzodiazepine use as an independent risk factor for HIV infection in a Canadian setting; Drug and Alcohol Dependence. Volume 155, Oct 1st 2015 HIV infection itself is significant predictor of BZD & Z-drug use 76.4% of the HIV pts had BZD or Z-drug Rx; psych illness substantial risk factors Primarily prescribed by nonpsychiatrists; only 31.1% sought mental health support and received Rx from psychiatrists. Benzodiazepines and Z-Drug Use among HIV-Infected Patients in Taiwan: A 13-Year Nationwide Cohort Study; BioMed Research International, Volume 2015 BZD use is associated with a low quality of life and high HIV-risk behaviors among patients with SUD. Substance abuse and psychiatric disorders in HIV-positive patients: epidemiology and impact on antiretroviral therapy, Drugs, vol. 66, BZD Categories/Equivalencies Epidemiology 80% of pts w/ sedative use disorder use other drugs 30-50% of pts w/ EtOH use disorder who have presented to detox, use BZDs 44% IV drug users use BZDs to offset opiate w/d, common practice to come down from a cocaine high Ratio of 2:1, women:men Use increases with age Most frequently abused Rx drug, 2nd to opioids Rarely the initial or primary substance of abuse

8 Overdose Use of BZDs alone rarely cause overdose Combination of other sedatives can be fatal EtOH, opiates (esp MTD) Opioids + BZDs = synergy (?) vs additive effect Users: a more intense high More research needed September 2017 The combined use of these drugs increases the risk of serious side effects; however, the harm caused by untreated opioid addiction can outweigh these risks. BZDs & Dementia Use of sedative-hypnotics and the risk of Alzheimer's dementia: A retrospective cohort study; Lee, Joonki et al. N = 268,170 PLoS One. 9/18 risk of AD significantly associated with sedative-hypnotics use regardless of prescribed dosage, drug type, or half-life of benzodiazepine. Association between Benzodiazepine Use and Dementia: A Meta- Analysis; Zhong G PLoS One. 5/15. Long term BZD use is associated w/ dementia Causal? More prospective cohort studies with long term f/u are needed. BZDs & Dementia 2014: older adults using BZDs for longer than 3 months - 51% greater risk of Alzheimer s. Anxiety & insomnia often sxs of AD - still found independent risk 4 other prior studies ( ) similar results Increased risk of dementia, cognitive decline Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study BMJ; 2/16, N = 3400 Risk of dementia slightly higher w/ minimal exposure to BZDs but not w/ the highest level of exposure. Results do not support a causal association between BZD and dementia. BMJ September 9, 2014; BMJ 2012;345:e6231; Am J Geriatr Psychiatry Jul;17(7):614-20; Psychological Medicine / Volume 35 / Issue 03 / April 2005, pp ; Journal of Clin Epi Volume 55, Issue 3, March 2002, Pages

9 What we DO know about BZDs Dementia? research on risk of heavy use is mixed. Evidence overall suggests an increasing risk with cumulative exposure. Cognitive effects Review of 68 studies, Tannenbaum et al. Review of 19 studies, Crowe et al., 2018 BZDs associated w/both amnesiac and non-amnesiac cognitive impairment. Affect memory storage, impact attention, reaction time, and other psychomotor functions American Geriatric Society Avoid sedative-hypnotics in age > 65 Tolerance Hypnotic effects Few days to weeks Common to increase dosage Anxiolytic effects Months Longterm use does little to control anxiety; may aggravate Often 2 BZDs taken; just prevents w/d, rather than reduce anxiety Anticonvulsant & muscle relaxant effects Few weeks Cognitive deficits/dementia/amnesic effects Very little tolerance How long is too long? (before w/d occurs) Therapeutic dose: ~ 10 days insomnia ~ 2 weeks rebound anxiety Anxiety sxs worse than prior to treatment ~ 2 months mild withdrawal Recommendation: Short term Rx only Prescribe no longer than 2-4 wks Cap maximum dose (2mg in 24 hrs) BZD Withdrawal Historically w/d has been poorly managed -> acquired reputation as a traumatic process for both patient AND provider. Management of BZD w/d extensively reviewed: all agree Gradual dosage taper Longterm users: 6 mos to 1 year Psychological support! Exception: illicit use, high-risk abuse, on opiates Inpt detox average 5-10 days, long acting BZD taper

10 Outpatient Taper Switch to long-acting agent Clonazepam, Chlordiazepoxide Decrease dose by 10-25% weekly Taper up to 6 months to a year(s) Add supportive meds San Francisco Health Network Behavioral Health Services Medication Use Improvement Committee Safer Prescribing of Sedative-Hypnotics Guideline Hypnotic-Guideline.pdf Supportive meds For use during taper/detox Insomnia Trazodone 50mg PO QHS PRN Mirtazapine 15 mg QHS Diphenhydramine 50mg PO PRN Anxiety SSRIs/antidepressants first line! Clonodine 0.1mg TID PRN Buspirone 5mg TID Hydroxyzine 100mg PO every 8 hrs PRN anxiety Propranolol 10 mg TID (can increase dose as needed) Use with caution Quetiapine Gabapentin Interactions with HIV meds Protease Inhibitors/NNRTIs Integrase Inhibitors Midazolam, triazolam Same concerns as PIs/NNRTIs Significant BZDs Do NOT coadminister Exception: RAL ok Alprazolam, diazepam BZD levels may Alt: lorazepam, oxazepam, temazepam (LOT) Non-CY P450 pathways Preferred in liver dx & elderly Zolpidem, Eszopiclone CY P450 3A4 pathway May increase levels of Z drugs Same case but 33 yo male with active OUD, and h/o anxiety, currently prescribed alprazolam 1mg TID PRN, admits he often takes more than prescribed. Wants to discuss treatment options. If he took time off to enter detox, he fears this would impact his employment/income. He works as an Uber driver. How would you approach this pt? 1) Start buprenorphine/naloxone 2) Methadone maintenance 3) Start slow benzodiazepine taper, and initiate tx for OUD 4) Strongly encourage inpt detox for both opiates and BZDs

11 Alcohol & HIV Alcohol Rate of Alcohol Abuse general population: 4.6%, VS HIV: 8% (2x) Increases viral replication May increase immune activation, inflammation May increase concentration in semen and vaginal secretions Increase in unhealthy drinking associated with poorer outcomes: lower CD4, higher VL EtOH effects on ARV Liver damage Adherence Pts who drink 9 more times likely to fail to adhere to regimen vs sober Interactions?: 1 in 4 HIV pts believe this; skip doses while drinking NIAAA; Alcohol Alert Number 80; Williams EC, McGinnis KA, Bobb JF, et al. Changes in alcohol use associated with changes in HIV disease severity over time: a national longitudinal study in the Veterans Aging Cohort. Drug Alcohol Depend. 2018;189: Safety-sensitive workers Persistent impairment in surgeons after alcohol consumption Drank to intoxication, still impaired 4pm following day during simulated laparoscopic procedures Cognitive, perceptual, visuospatial abilities Gallagher AG, Boyle E, Toner P, et al. Persistent Next-Day Effects of Excessive Alcohol Consumption on Laparoscopic Surgical Performance. Arch Surg. 2011;146(4): doi: /archsurg Hangover effects on aircraft pilots Pilots did poorly in hangover conditions not intoxicated, but impaired Yesavage JALeirer VO Hangover effects on aircraft pilots 14 hours after alcohol ingestion: a preliminary report. Am J Psychiatry 1986;143 (12) Uber drivers drug testing, CA requires

12 Alcohol Screening Tools At-risk Drinking CAGE: Cut down, Annoyed, Guilty, Eye-opener AUDIT: 10 questions CRAFFT Adolescents Single question screen: On any single occasion during the past 3 months, have you had more than 5 drinks containing alcohol? identifies patients who meet criteria for at-risk drinking or alcohol abuse or dependence specified in DSM IV. p Standard Drink 12 fl oz = 8-9 fl oz of = 5 fl oz of regular malt liquor table beer (12-oz glass) wine = 1.5 fl oz shot 80-proof spirits ("hard liquor") ~ 5% alcohol ~ 7% alcohol ~ 12% alcohol ~ 40% alcohol Biochemical Tests PEth Test TEST CDT AST/ALT GGT EtG Use Detects >60g/day of alcohol in >2wks Detects inflammatory liver damage Detects >60g/day of drinking in > 4 wks Advantages High specificity Uses routine labs See prior to liver damage Sensitivity 26%-83% 56% 61% 76% Specificity 92% Low 11%-50% 93% Cost $30 $10 $10 $14-75 Detects any exposure to ethanol for 1-3 days High specificity PhosphatidylEthanol blood test direct biomarker phospholipid formed in the RBC membrane exclusively in the presence of ethanol Detection period of up to 3-4 wks Peterson K. Alcohol Research & Health, 28: 30-35, 2005 Stewart SH. Alcohol Clin Exp Res. 37:150-5, 2013

13 PEth Test High diagnostic sensitivity and specificity for detecting active chronic excessive drinking behaviors regular daily alcohol intake of ~3 drinks in men, ~2 in women one standard drink contains gms of EtOH, & is equivalent to one ordinary beer, a small glass of wine (100 mls) or a nip of spirits (30 mls) PEth levels above 20 ng/ml are typically indicative of moderate to heavy ethanol consumption. DUI # DUI Arrests Medical Criminal 1 50% chance SUD Alcohol Education Program* 2 90% chance SUD Misdemeanor Conviction 3 Diagnostic SUD Felony ** Second Conviction * Estimate driven approx 60 times under influence before arrested. ** May be considered a second first conviction. By the time there is a felony conviction, there are at least 3 arrests. Remember to ask about DUIs when screening. STAGE Symptoms Management Notes I Mild Shaking, elevated Outpatient Pt should be Within 24 hrs pulse & BP, GI management; monitored by upset, agitation daily visits (RN) family/friend who 5 days will stay w/ pt throughout detox II-Moderate hrs III Severe > 48 hrs Stages of Alcohol Withdrawal Stage I sxs PLUS hallucinations with insight Stage I sxs PLUS Inpatient hallucinations Detox/ICU without insight- Delirium Tremens Outpatient Very difficult to management if diagnose; pt reverts to Recommend Stage I in 3 hrs inpatient detox 5-10 day detox Principles of Addiction Medicine, Ries, Fiellin et al Hallucinations when to be concerned Alcohol Hallucinosis ~ 24 hrs after last drink, lasts for 24 hrs. 25% of pts with prolonged h/o EtOH abuse Tactile, visual hallucinations most common Otherwise sensorium is clear; insight Not necessarily followed by DTs Delirium Tremens ~48-72 hrs after last drink Profoundly altered sensorium Disorientation, agitation, hallucinations Severe autonomic derangements BP, HR, RR, diaphoresis, hyperthermia

14 Withdrawal seizures ~24 hours after last drink Withdrawal Seizures 23%-33% of pts w/ severe EtOH withdrawal Brief, generalized, tonic-clonic, no aura 30%-50% progress to DTs Acute Tx benzodiazepine lorazepam 2mg Diazepam 10mg send to ER Withdrawal Tx (Detox)- Outpatient Benzodiazepines mainstay Short-acting Oxazepam, lorazepam (preferred in liver dx, geriatric) Longer-acting Chlordiazepoxide Rarely abused Supportive Tx Clonidine mg TID Combats adrenergic discharge: HTN, tachycardia, tremor Anti-diarrheal, antacid, NSAIDs Chlordiazepoxide Outpatient Taper Schedule Day 1 Day 2 Day 3 Day 4 Rigid mg QID mg TID Flexible mg Q 4-6 hrs PRN Front loading mg Q 2-4 hrs until sedation is achieved; then 50 to 100 mg Q4-6 hrs PRN mg Q 6-8 hrs PRN mg Q 4-6 hrs PRN mg BID mg Q 12 hrs PRN mg Q 4-6 hrs PRN mg QHS mg QHS PRN None * For uncomplicated withdrawal Gabapentin Outpatient Taper 400mg TID x 3 days 400mg BID x 2 days 400mg Q daily x 1 day Vitamin Deficiencies MVI: one daily Thiamine (Vit B1): 100mg daily Folate (Vit B9): 1 gm daily Insomnia, anxiety Trazodone mg QHS Hydroxyzine mg QID Outpatient Meds Propranolol 20-40mg BID Monitor BP, HR; caution in asthma, cocaine users No concerning interactions with HIV meds

15 AUD Pharmacotherapy Naltrexone (PO and IM)-blocks mu receptors. Nausea, HA, dizziness, LFTs. Acamprosate-increases GABA and effects glutamate neurotransmission. Decreases cravings, GI, pruritis Disulfuram blocks aldehyde dehydrogenase. 2 nd line, avoid in CAD, pregnancy, cognitive impairment, severe liver disease Gabapentin off label, helps with cravings Topiramate off label, requires dose titration, side effects Baclofen off label, GABA receptor, helps with cravings Varenicline off label, nicotinic receptor, helps reduce EtOH consumption San Francisco Health Network Behavioral Health Services Medication Use Improvement Committee Approaches to Alcohol Use Disorder Medication Assisted Treatment Guideline ToAlcoholUseDisorder.pdf Comprehensive Treatment Approach Counseling Psychiatric treatment as needed 30-40% of pts with AUD have major depression EtOH + depression: suicide rate 11% Depression alone: suicide rate 0.5% Social support: Alcoholics Anonymous Narcotics Anonymous Refuge Recovery Recovery Yoga Pts who attend AA are 50% more likely to be abstinent vs non-attendees. (Hoffman, 1992) Efficacy remains controversial more data needed to determine; anecdotally, efficacy appears real. Resources for Clinicians ASAM - American Society of Addiction Medicine AAAP American Academy of Addiction Psychiatry SAMHSA Substance Abuse Mental Health Services Administration NIDA National Institute on Drug Abuse CDC up-to-date data Opioidprescribing.org Boston University SOM PrescribeToPrevent.org PCSS website: Providers Clinical Support System Thank you Thank you for your attention, and for your commitment to treating those patients with substance use disorders.