Interactions between opioids and alcohol Dr. Andriy V. Samokhvalov, MD, PhD Staff Psychiatrist / Scientist Addictions Program / Social & Epidemiological Research Centre for Addiction and Mental Health

Objectives

• To review the prevalence of alcohol use disorders both in general population and in people with opioid dependence

• To analyze the effects and potential interactions between alcohol, opioids and other drugs of abuse

• To learn the pharmacological approaches to treatment of comorbid alcohol and opioid dependence

Prevalence of alcohol use disorders in Canada

• According to 2012 Canadian Community Health Survey among Canadians:

• Lifetime prevalence of AUD is 18.1%

• 12-month prevalence is 3.2%

• To compare it with all other substances:

• Lifetime prevalence of SUD (excl. cannabis) is 4.0%

• 12-month prevalence is 0.7%

Drinking patterns in Canada

Drinking category Women Men

Abstention or very light drinking (<0.25 g/day) 66.9% 40.4%

Low consumption (F: 0.25-<20 g/d; M: 0.25-<40 g/d) 24.9% 46.8%

Hazardous consumption (F: 20-<40 g/d; M: 40-<60 g/d) 6.3% 6.5%

Harmful consumption (F: ≥40 g/day; M: ≥60 g/day) 1.9% 6.3%

Taylor et al., 2006; Data for 2002

Low-Risk Drinking Guidelines

• Limits:

• 10 drinks a week for women, with no more than 2 drinks a day most days

• 15 drinks a week for men, with no more than 3 drinks a day most days

• No more than 3 drinks a day for women or 4 drinks a day for men on any single occasion

• No drinking in situations when increased alertness is required

• “A drink” means: • 341 ml (12 oz.) bottle of 5% alcohol beer, cider or cooler

• 142 ml (5 oz.) glass of 12% alcohol wine

• 43 ml (1.5 oz.) serving of 40% distilled Butt et al., 2011

Alcohol consumption in opioid users

• Chart review of 229 new admissions at CAMH Addictions Clinic

• Primary diagnosis of alcohol dependence

• Majority are men (65% vs. 35%)

• Average age of 37±11 years

• Data on alcohol consumption is available for 211 patients:

• 46% are abstainers

• 54% drink regularly

• 9% drink every day

• 17% (one third of all drinkers) exceed low-risk drinking guidelines

Identification of AUD

• Screening tools

• CAGE+2+Y

• AUDIT

• Clinical tools

• DSM-IV/V Criteria

• History taking

• Laboratory tools

• Breathalyzer

• Urine Drug Screening

• Bloodwork

NIAAA

Screening tools

• Used in general practice and in surveys

• Usually have high sensitivity and relatively low specificity

• Require further investigation

• Two of the most common tests used are CAGE and AUDIT

• There are also modifications of CAGE: CAGE+2+Y and T-ACE

NIAAA

CAGE and variants

• CAGE (and CAGE+2+Y): • C: Have you ever felt you should cut down on your drinking? • A: Have people annoyed you by criticizing your drinking? • G: Have you ever felt bad or guilty about your drinking? • E: Eye opener: Have you ever had a drink first thing in the morning to steady

your nerves or to get rid of a hangover? • Two positive answers are considered a positive test • +2 extra questions:

• How many drinks do you consume on a typical drinking day • How many days a week do you consume alcohol

• Y: If the answer is positive to any of the questions, ask if it has occurred in the past year

• T-ACE • T: Tolerance: How many drinks does it take to make you feel high? • A.C.E. – same questions as in CAGE • Affirmative answers to questions A.C.E. give 1 point, reporting tolerance of

more than 2 drinks in T question give 2 points. • A score of 2 or more is considered positive

NIAAA

AUDIT

• AUDIT = Alcohol Use Disorders Identification Test

• More structured than CAGE

• Serves both as an identification tool and as an alcohol consumption quantification tool in some surveys

• Contains 10 questions related to patterns of drinking and associated problems

• Scores range between 0 and 40 points

• Scores of 8+ on the AUDIT indicate hazardous or harmful drinking

NIAAA

Clinical Tools

• DSM-IV/V Criteria for Alcohol Use Disorders:

• Alcohol Dependence (DSM-IV):

• 3 out of 7 criteria met in the past 12 months

• Alcohol Abuse (DSM-IV):

• 1 out of 4 criteria met in the past 12 months

• Criteria for Alcohol Dependence were never met

• History taking:

• Current patterns of alcohol consumption

• History of alcohol use

• Sequelae of alcohol consumption: medical, social, vocational, legal, financial etc.

• Previously received treatments

NIAAA

Laboratory tools

• Breathalyser: • The easiest way to document very recent alcohol consumption • Can only be informative if alcohol is still in bloodstream • Also, might be quite useful in patients who are in denial or do

not fully understand the extent of their drinking problem (readings higher than allowed driving limits etc.)

• Should be documented as evidence of alcohol consumption

• Urine Drug Screening: • Usually used in patients who use opioids in any case • Ethanol itself is quickly eliminated from bloodstream and

cannot be identified after 6-8 hours • Ethyl glucuronide is alcohol metabolite identifiable in UDS

• Identifiable within 3-4 days

• UDS with some limitations can be used to monitor medication compliance (e.g. disulfiram)

Clinical Case: Alexander

Alexander is a 53 y.o. man, married, has two grown up children, engineer, self-employed with high income. Long history of alcohol consumption, started drinking problematically in his early thirties, during professional conventions, business parties etc. Also, suffers from mild anxiety disorder and anxiety is one of the major triggers for alcohol consumptions, specifically in situations when he has to make a presentation or in negotiations. Two years ago Alexander had seizures on the peak of alcohol withdrawal and his driver’s license was revoked. He receives treatment for alcohol dependence and reports significant reduction of alcohol consumed. Effectively, he is drinking within low-risk drinking guidelines and compliant with his medications. His laboratory test results are gradually normalizing over the course of the last 4 months.

Today Alexander’s breathalyzer reading is 0.168 at 11 am. He states that he only had 2 glasses of wine yesterday. Similar situation was observed on 3 out of 7 previous visits.

Quiz:

Why, in your opinion, Alexander’s BAC is so high?

A) The breathalyser is not functioning properly

B) Alexander used alcohol-containing mouthwash

C) Alexander is deceiving you – he actually drinks way more than he discloses

D) The information is not accurate (more than a half of a bottle of wine with higher alcohol content and had his last drink closer to 2 am)

E) Alexander is on ketogenic diet

Laboratory tools cont’d

• Blood work: • Liver enzyme levels:

• AST: usually takes around 7 days to normalize, but there is considerable variability in declines with abstinence

• ALT: the least sensitive one, but still used traditionally • GGT: most sensitive one, it takes 2-6 weeks to return to normal values

• CDT: normalizes within 2-4 weeks, sensitive, specific (rare false positives)

• MCV: elevated in chronic users, slowly returns to normal values

• Blood work test results indicate chronic consumption, can be used to monitor relapses and, most importantly, to track progress.

• Also, the choice of medications might be based on bloodwork results

Clinical case: Simon, part 1

New admission in outpatient clinic. 43 y.o. man, works part-time (handyman, some electrical works without license). History of extensive use of opioids, alcohol, benzodiazepines and cocaine. Currently consumes around 10-15 drinks per day, mostly beer, sometimes hard liquor. Mostly drinks throughout the day. Has hangovers in the morning, moderate alcohol withdrawal symptoms during the day if doesn’t drink in the morning, so he usually starts drinking at 10-11 a.m. Also uses opioids daily: Oxycontin 160-240 mg per day, sometimes substitutes it with percocets and Tylenols #1 (OTC) or #3/#4 (street). No recent cocaine use, though uses benzodiazepines occasionally, primarily to help with anxiety, which in majority of cases is observed when he fails to secure opioids. Lives with his partner who is also a polysubstance user. Presents very emotional, cries and demands immediate assistance with all his problems, as he is “sick and tired of such living”.

Quiz:

What in your opinion is the best therapeutic approach in Simon’s case?

A) Abstinence-based approach, inpatient withdrawal management

B) Abstinence-based approach, outpatient withdrawal management

C) Harm reduction, Suboxone maintenance

D) Harm reduction, methadone maintenance

E) Other

Treatment options

Abstinence-based approach:

Available for both alcohol and opioids

Disulfiram

Naltrexone

High relapse rate

Harm reduction approach:

Available for both alcohol and opioids

For opioids methadone or buprenorphine maintenance options are available

For alcohol number of medications can be used to curb the cravings and reduce amounts of alcohol consumed and number of drinking days and heavy drinking days

Psychotherapy is advised in any case

Pharmacokinetic interactions between alcohol and opioids • Acute alcohol consumption (binge)

• General inhibitor of CYP 3A4

• Slows down metabolism of buprenorphine, methadone, oxycodone, tramadol and fentanyl

• Increases the risk of overdose

• Chronic alcohol consumption

• General inducer of CYP 3A4

• Diminishes effects of opioids/-ates metabolised by CYP 3A4

• Higher doses might be required for achieving same effects

• Especially important for opioid maintenance therapy with buprenorphine and methadone

• Irregular alcohol consumption makes interactions unpredictable

• Excessive alcohol consumption eventually leads to liver impairment that in turn can significantly affect metabolism of any opioids, not only those metabolised by CYP 3A4, but also by CYP 2D6 and via glucuronidation (UGT 2B7)

Smith, 2009

Pharmacodynamic interactions between alcohol and opioids

Sedation and respiratory depression

additive life-threatening effect of opioids, alcohol and benzodiazepines as well as numerous medications with sedative properties (e.g. barbiturates, non-benzodiazepine sleeping aids, antihistamines, antipsychotics etc.)

Effects on cardiovascular system

QT-interval prolongation during withdrawal – might be additive with methadone and some other commonly prescribed medications (e.g. quetiapine, TCA)

Clinical considerations

Alcohol used disorders in opioid users have several clinical implications:

• Cravings and consistent often uncontrollable alcohol consumption that will:

• Include both chronic and acute alcohol consumption

• Interfere with opioids on pharmacokinetic and pharmacodynamic levels

• Require pharmacotherapy that must be compatible with the treatment of main substance use disorder

• Potential for development of alcohol withdrawal

Alcohol intoxication

Erratic behaviour, impaired judgement – lost carries, lost prescriptions; missed appointments, confrontational.

Treatment non-adherence

Nausea and vomiting – vomited doses

Tend to use OTC medications like dimenhydrinate to cope with nausea. These medications may have additional sedative effects

Alcohol withdrawal

Alcohol withdrawal is often treated with benzodiazepines, use of which in opioid-dependent individuals might be quite dangerous and require inpatient settings.

Special attention should be paid to potential alcohol withdrawal in those on high doses of methadone or buprenorphine

CIWA-Ar protocol is normally used in inpatient settings

In cases of relatively stable patients who will likely experience mild-to-moderate withdrawal symptoms home detoxification or day detoxification might be considered

Opioid maintenance therapy

• Harm reduction approach

• Two medications can be used (methadone or Suboxone)

• Similar principles:

• Gradual titration

• Number of checks and balances

• Frequent visits and urine drug tests

• Carries

• Both medications cannot be combined with naltrexone

Methadone maintenance

In case of concurrent alcohol use disorder:

Alcohol withdrawal management with benzodiazepines is complicated

Lower initiation dose (5-20 mg)

Slower and smaller increments (5-10 mg every 3, preferably 5 days)

There are indications that methadone might suppress cravings for alcohol to certain extent

Special considerations to QT-interval as alcohol consumption / withdrawal is associated with increased risk of QT-interval prolongation

Carries should be provided only if patient is clinically stable (=alcohol consumption is under control)

Clinical case: Simon, part 2

Simon is receiving methadone maintenance therapy for 5 months, receives 45 mg of methadone daily, level 2 carries. Presents in the clinic due to recent relapse - 10 days ago started drinking and quickly progressed to 10-15 beers per day in the past week. Usually starts drinking at 10-11 am and finishes at 2-3 am next day. Manages to conceal his drinking when attending pharmacy. Experiences alcohol withdrawal symptoms when not drinking. During the visit appears intoxicated, his BAC=0.278. He is emotionally labile, cries, states that he is “hopeless”, that his partner is not contributing to their relationship, that he is broke and a “failure”. Doesn’t have any withdrawal symptoms at the moment, had his methadone dose early in the morning today. States that he cannot stop drinking on his own and requests help with his condition.

Quiz:

• In your opinion, what is the best course of action in Simon’s case now:

• Supportive counselling, no changes in medications

• Supportive counselling, cancel carries

• Same dose of methadone, cancel carries, diazepam on outpatient basis

• Reduction of methadone dose / quick taper, cancel carries, diazepam on outpatient basis

• Same dose of methadone, cancel carries, day detoxification

Suboxone maintenance

• As partial agonist of μ-opioid receptors Suboxone is generally safer than methadone due to ceiling effects, though alcohol use disorder effectively makes it as dangerous as methadone.

• Most of the deaths in Suboxone users are associated with the use of either alcohol or benzodiazepines or combination of thereof (Kintz, 2001)

• Similarly to MMT initiation and titration should be done carefully and provision of take-home doses should be initiated when patients are clinically stable

• There are indications that Suboxone might reduce alcohol consumption

Clinical case: Sean

• Sean is 43 y.o. man, who uses Tylenol #1; 80-100 tabs per day; He also drinks 3-5 times per week, various quantities of alcohol (from 3-5 drinks to a 375 ml bottle of vodka per occasion). Last drink was 2 days ago. Last use of opioids was today in the morning (90 minutes before the visit). Liver enzymes are elevated (GGT>1000), likely due to combination of acetaminophen from Tylenol and alcohol.

• Sean was prescribed Suboxone, maximum dose was 10 mg/day. Successfully tapered off in less than 4 months. Did not require any special treatment for alcohol. Currently is abstinent from both alcohol and opioids for more than a year.

Treatment of AUD

• Three medications approved by Health Canada:

• Naltrexone (and other opioid receptor antagonists)

• Acamprosate

• Disulfiram

• Other medications showing potential

• Topiramate

• Baclofen

• Sertraline

• Gabapentin

• Pregabalin

• Ondasetron

• Metadoxine Aubin & Daeppen, 2013

Naltrexone

First-line treatment for alcohol dependence

Opioid receptor antagonist

Recommended dosage is 50 mg PO OD

Two major contraindications:

Opioid use

Incompatible with opioid maintenance therapy

Cannot be used in cases when opioids are prescribed for pain

Liver impairment

common among people with AUD

Still can be a solution for both opioids and alcohol use

Strong genetic influence

Adherence might be an issue (similar to disulfiram)

Clinical Case: Simon, Part 3

After having received several months of methadone maintenance and then Suboxone maintenance therapy, Simon relapsed to drinking again. Currently he receives 16 mg of Suboxone daily, no carries. Consumes 10+ drinks almost every day. Suboxone doesn’t seem to have any significant effect on his alcohol consumption. When considering the use of disulfiram in Simon’s case, he recalled that several years ago he received disulfiram though he manged to drink while taking this medication. By the moment Simon has attended medical withdrawal services multiple times with a pattern of quick relapse, primarily to alcohol. Hi current opioid maintenance therapy significantly reduced the safety and feasibility of home detoxification.

Simon was provided with day detoxification at the clinic and minimal amounts of diazepam to be taken on the next two days, to be dispensed daily with Suboxone. He was tapered off Suboxone during next several weeks and switched to naltrexone treatment 3 weeks ago. At the moment he doesn’t use

opioids and reduced his alcohol consumption.

Vivitrol

• Depot formulation of naltrexone

• Injectable form

• Effects last for 1 month

• Designed to solve the issue with non-adherence

• Expensive ($750-1000 per 1-month vial)

• Not yet approved in Canada

Nalmefene

• Newer medication, very similar in structure to naltrexone

• Longer duration of action

• Safer profile (no liver impairment associated)

• Same mechanism of action and indications as for naltrexone

• Not yet approved for use in Canada (but soon will be)

• Several large clinical trials showed its effectiveness (similar to naltrexone)

Acamprosate

• Approved for use in Canada

• Modulates the neurotransmission of glutamate

• Major clinical effect – reduction of cravings

• Shown to be effective in several clinical trials

• Clinical evidence suggest that for better results acamprosate should be used after patient stopped drinking for several days

• Recommended dosage is 666 mg PO TID

• Can be used along with opioids

Disulfiram

• Approved for use in Canada

• Oldest medication for alcohol use disorders

• Classical abstinence-based approach medication

• Blocks the effects of acetaldehyde dehydrogenase thus drastically increasing the acetaldehyde levels

• Compounded by few pharmacies

• Recommended dosages 125-500 mg PO OD

• Dangerous if alcohol consumed

• Seems to have no effect in some patients

Baclofen

• GABA-B receptor agonist

• Used for treatment of spastic disorders

• Was shown to decrease cravings and alcohol consumption in several studies

• No effects on liver function

• No interactions with opioids

• Recommended dosages: 5-15 mg PO TID

• Available in Canada

• Used off-label

Clinical case: Michael

• 34 y.o. male

• Highly functioning

• Hx of polysubstance use and mood disorder

• Alcohol dependent, 2 years ago stopped drinking using phenibut (precursor of baclofen, manufactured in Soviet Union as an anxiolytic, can be bought online)

• Also currently uses kratom (opioid agonist, sold online as herbal supplement)

• Alcohol withdrawal symptoms if stops using phenibut, opioid withdrawal symptoms if stops using kratom

• Successfully switched to and tapered off baclofen

• Was able to stop using kratom on his own • Samokhvalov et al., 2013

Topiramate

• Antivonvulsant

• Complex mechanism of action

• Shown to be effective in several studies

• Available in Canada

• Used off-label

• Associated with weight loss

• Recommended dosages: 100-150 mg PO BID

• Pregnancy: teratogenic effects, decreases effectiveness of oral contraceptives

Gabapentin

• GABA analog

• Used as an antiepileptic drug

• Also used to treat neuropathic pain

• Helps to curb the withdrawal symptoms

• Shown to reduce the number of drinks per day, number of heavy drinking days

• In the studies is used in doses of up to 1200 mg/day

• Recommended dosage 600-900 mg/day (300 mg PO BID/TID)

Pregabalin

• Successor of gabapentin

• Similar to gabapentin in many ways

• Used in seizure disorders, neuropathic pain and anxiety disorders

• Curbs withdrawal symptoms

• Dosages: 25 mg PO TID gradually increasing by 75 mg once a week

Guglielmo et al., 2012

Sertraline

• Selective Serotonin Reuptake Inhibitor

• Studies show reduction of number of drinking days, HDDs, increased time to relapse compared to placebo in non-depressed patients

• Recommended (tested) dosage: 200 mg PO OD

• Available in Canada

• Can be used off-label or prescribed to people with alcohol use disorder and concurrent mood disorder

Ondasetron

• 5-HT3 receptor antagonist

• Used mostly as an antiemetic

• In three studies was shown to be effective medication to reduce alcohol consumption

• Specific mechanisms are unknown

Metadoxine

• Facilitates elimination of alcohol

• Used in dosages of up to 3000 mg/day

• Abstinence rates are twice higher in patients receiving metadoxine compared to placebo

Clinical case: Eugene

56 y.o. man, married, lives with his spuse. Long history of alcohol (over 30 years) and opioid (over 15 years) use. Uses mostly oxycodone in various quantities (20-80 mg/day). Doesn’t use opioids every day, though if he doesn’t use them, experiences withdrawal symptoms; last use was yesterday in the evening. Also binges, mostly liquor, though not in extremely high quantities – up to 375 ml of vodka that he consumes throughout a day. If he doesn’t drink, he might experience mild withdrawal symptoms. Uses lorazepam or diazepam to cope with both opioid and alcohol withdrawal symptoms (prescribed to his wife). Patient agreed to stop taking opioids and was prescribed naltrexone which he was supposed to start taking 48 hours past the last time he used opioids.

Quiz:

Which treatment option is the most appropriate in Eugene’s case?

A) Opioid maintenance (Suboxone or methadone)

B) Opioid maintenance in combination with one of the medications used for treatment of alcohol dependence

C) Monotherapy with naltrexone

D) Monotherapy with acamprosate

E) Monotherapy with another medication used for treatment of alcohol dependence

Some other medications

• Fluvoxamine – no evidence supporting efficacy

• Aripiprazole – no evidence supporting efficacy

• Flupenthixol – no evidence supporting efficacy

• Zonisamide – improvements in one open-label study, no differences in an double-blind RCTs

• Oxcarbazepine – no evidence supporting efficacy

• Tiagabine – no evidence supporting efficacy

• Escitalopram – effective in combination therapy, but not as monotherapy

• Olanzapine – no evidence supporting efficacy

• Tiapride – no evidence supporting efficacy

• Amisulpride – no evidence supporting efficacy

• Galantamine – no evidence supporting efficacy • Aubin & Daeppen, 2013

Summary

• UP to 25% of opioid-dependent people are using alcohol in a way that may interfere with effects of opioids or opioid maintenance treatment

• Use of opioids in turn precludes administration of opioid receptor antagonists and complicates the treatment of alcohol withdrawal

• There are abstinence-based and harm reduction approaches for treatment of both alcohol and opioid dependence

• There are three medications approved by Health Canada for treatment of alcohol use disorders (naltrexone, disulfiram and acamprosate).

• Naltrexone is a first line treatment for alcohol dependence (harm reduction), but can also be used to negate the effects of opioids

Summary (cont’d)

• There is also a number of medications that were shown to have effects on alcohol consumption and do not interfere (not contraindicated) with opioid maintenance treatment: Topiramate, Gabapentin, Pregabalin, Baclofen, Sertraline, Ondasetron, Metadoxine

• There are genetic influences at least for several medications

• There are some indications that both methadone and buprenorphine might reduce alcohol consumption

• Patients should be informed about interactions between alcohol and opioids

• Therapeutic approaches vary depending on severity of alcohol and opioid use, concomitant medications, concurrent disorders and treatment settings

• Existing arsenal of medications in combination with psychotherapy and genetic testing (when possible) allow for creation of individualized interventions

Thank you!

Discussion and Q&A

References

• Butt P, Beirness D, Cesa F, Gliksman L, Paradis C, Stockwell T. (2011). Alcohol and health in Canada: A summary of evidence and guidelines for low-risk drinking. Ottawa, ON: Canadian Centre on Substance Abuse.

• National Institute on Alcohol Abuse and Alcoholism. Assessing Alcohol Problems: A Guide for Clinicians and Researchers, 2d ed. NIH Pub. No. 03–3745. Washington, DC: U.S. Available at: http://pubs.niaaa.nih.gov/publications/AssessingAlcohol/index.htm

• Smith HS. Opioid metabolism. Mayo Clinic Proceedings 2009; 84(7):613-24.

• Guglielmo R, Martinotti G, Clerici M, Kaniri L. Pregabalin for alcohol dependence: a critical review of the literature. Adv Ther 2012; 29(11):947-57.

• Kintz, P., 2001. Deaths involving buprenorphine: a compendium of French cases. Forensic Sci. Int. 121, 65-69.

• Aubin HJ, Daeppen B. Emerging pharmacotherapies for alcohol dependence: A systematic review focusing on reduction in consumption. Drug and Alcohol Dependence 2013; 133(1):15-29.

• Samokhvalov AV, Paton-Gay CL, Balchand K, Rehm J. Phenibut Dependence. BMJ Case Reports 2013. doi: 10.1136/bcr-2012-008381