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Is your patient an Uber driver? Why you should ask.

A clinical review of substance use disorders: opiates, benzodiazepines, and alcohol

Katherine Grieco DO DABAMMedical DirectorHAVEN – Health Assistance InterVention & Education NetworkConnecticut

I have nothing to disclose

Outline

• Treatment models • Brief Updates–Opiates–Benzodiazepines–Alcohol

NEJM

• October 18th, 2018

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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

• Opioid overdoses are not declining, rather, are increasing at aslower rate than they have previously.

CDC: Opioid Overdose DeathsAge-adjusted drug overdose death rates, by state: United States, 2016

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klklCDC: Drug Overdose Deaths, 1980-2016

Drug overdoses are now the leading cause of death among Americans under 50.

59,000 to 65,000 people died from drug OD in US in 2016

Peak car crash deaths1972

Peak HIV deaths 1995

Peak gun deaths 1993

2017: >72,000 deaths from drug OD

WARNING: Crisis has not peaked (?)

CDC: Fentanyl Deaths in 2016:Up 540% in 3 Years (provisional data)

Worse than HIV

2000 2015

Increase in deaths from Cocaine & meth use (often involve opiates)

Deaths involving synthetic opioids, mostly fentanyl, jumped from 3,000 to 20,000 in 3 yrs.

Overdose Deaths by Opioid, SF

5 3 5 8 6 10 6 6 8 1122 26

0

50

100

150

200

250

2006 2008 2010 2012 2014 2016

Num

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TotalOpioidsHeroinRx Opioids (not fent)Fentanyl

Phillip O. Coffin, MD MIAChris Rowe, MPHSan Francisco Dept of Public Health

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-exchangesUse of rapid fentanyl test strips among young adults who use drugs; Maxwell S Krieger et al. International Journal of Drug Policy, Oct 18, 2018, https://doi.org/10.1016/j.drugpo.2018.09.009

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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 2014-2017

DSM-5 Criteria for ANY Substance Use Disorder11 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

Mild: 2-3; Moderate: 4-5; Severe: 6 or >

• 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

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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• Pts in need of monitoring, lack of

support system, psychiatrically unstable, Failed bupe

• Withdrawal not necessary to start • Robust data to support efficacy

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,

support system in place, psychiatrically stable (? for pts who have failed MMTP/bupe)

• MUST be in withdrawal to start• 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 all-

cause, 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: 137-145

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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

–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

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.

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

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Benzodiazepines

BZDs and HIV - Studies• BZD use independent risk factor for HIV seroconversion

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 supportand 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 impacton antiretroviral therapy, Drugs, vol. 66, 2006.

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

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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 (2002 -2012) similar results– Increased risk of dementia, cognitive decline

• Benzodiazepine use and risk of incident dementia or cognitivedecline: 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. 2009 Jul;17(7):614-20; Psychological Medicine / Volume 35 / Issue 03 / April 2005, pp 307-315; Journal of Clin Epi Volume 55, Issue 3, March 2002, Pages 314–318

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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

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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– https://www.sfdph.org/dph/files/CBHSdocs/Sedative-

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– Midazolam, triazolam

• Significant ↑ BZDs

• Do NOT coadminister

– 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

• Integrase Inhibitors

– Same concerns as PIs/NNRTIs

– Exception: RAL ok

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

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Alcohol

Alcohol & HIV• 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;189:21–29.

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

• Hangover effects on aircraft pilots – Pilots did poorly in hangover conditions – not intoxicated, but impaired

• Uber drivers – drug testing, CA requires

Gallagher AG, Boyle E, Toner P, et al. Persistent Next-Day Effects of Excessive Alcohol Consumption onLaparoscopic Surgical Performance. Arch Surg. 2011;146(4):419–426. doi:10.1001/archsurg.2011.67

Yesavage JALeirer VO Hangover effects on aircraft pilots 14 hours after alcohol ingestion: a preliminary report. Am J Psychiatry 1986;143 (12) 1546- 1550

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Alcohol Screening Tools

• 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 hadmore than 5 drinks containing alcohol?”– identifies patients who meet criteria for at-risk drinking or alcohol abuse or

dependence specified in DSM–IV.

“At-risk” Drinking

• p

12 fl ozregular

beer

= 8-9 fl oz ofmalt liquor(12-oz glass)

= 5 fl oz oftable wine

= 1.5 fl oz shot 80-proof spirits("hard liquor")

~ 5% alcohol

~ 7% alcohol

~ 12% alcohol

~ 40% alcohol

Standard Drink

Biochemical TestsTEST 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

Detects any exposure to ethanol for 1-3 days

Advantages High specificity Uses routine labs See ↑ prior to liver damage

High specificity

Sensitivity 26%-83% 56% 61% 76%

Specificity 92% Low 11%-50% 93%

Cost $30 $10 $10 $14-75

Peterson K. Alcohol Research & Health, 28: 30-35, 2005Stewart SH. Alcohol Clin Exp Res. 37:150-5, 2013

PEth Test

• 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

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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 10-14 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 MisdemeanorConviction

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 – MildWithin 24 hrs

Shaking, elevated pulse & BP, GI upset, agitation

Outpatient management; daily visits (RN)5 days

Pt should be monitored by family/friend who will stay w/ ptthroughout detox

II-Moderate24-36 hrs

Stage I sxs PLUS hallucinations with insight

Outpatientmanagement if pt reverts to Stage I in 3 hrs

Very difficult to diagnose; Recommend inpatient detox

III – Severe> 48 hrs

Stage I sxs PLUS hallucinations without insight-Delirium Tremens

Inpatient Detox/ICU

5-10 day detox

Stages of Alcohol Withdrawal

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

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Withdrawal Seizures

• Withdrawal seizures– ~24 hours after last drink– 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 0.1-0.2 mg TID

• Combats adrenergic discharge: HTN, tachycardia, tremor

– Anti-diarrheal, antacid, NSAIDs

Schedule Day 1 Day 2 Day 3 Day 4

Rigid 50-100mg QID 50-100mgTID

50-100mgBID

50-100mgQHS

Flexible 50-100mg Q 4-6 hrs PRN

50-100mg Q6-8 hrs PRN

50-100mg Q12 hrs PRN

50-100mgQHS PRN

Front loading

100-200 mg Q 2-4 hrs until sedation is achieved; then 50 to 100 mg Q4-6 hrs PRN

50- 100 mgQ 4-6 hrsPRN

50-100 mg Q4-6 hrs PRN

None

ChlordiazepoxideOutpatient Taper

Gabapentin Outpatient Taper

• 400mg TID x 3 days• 400mg BID x 2 days• 400mg Q daily x 1 day

* For uncomplicated withdrawal

Outpatient Meds

• Vitamin Deficiencies– MVI: one daily– Thiamine (Vit B1): 100mg daily– Folate (Vit B9): 1 gm daily

• Insomnia, anxiety– Trazodone 50-100mg QHS– Hydroxyzine 50-100mg QID– Propranolol 20-40mg BID

• Monitor BP, HR; caution in asthma, cocaine users

• No concerning interactions with HIV meds

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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. 2nd 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

https://www.sfdph.org/dph/files/CBHSdocs/CBHS_MedicationApproaches 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.