PSYCHIATRY'S ROLE IN TACKLING THE OPIOID CRISIS: HOW TO OPTIMIZE MEDICATION-ASSISTED TREATMENT

Learning Objectives

•Distinguish between the treatment options for opioid use disorder in terms of their mechanisms and clinical profiles

•Optimize strategies to reduce adverse effects during medically-supervised withdrawal

•Apply maintenance strategies for opioid use disorder that minimize the risk of relapse

Epidemic: Prescribing Opiates for Pain

• Opiate prescriptions: 76 million in 1991 to 207 million in 2013• 15.3 million opiate prescriptions in 2013 for Medicare patients • 2 million Americans addicted to prescription opiates, annually• Physicians blamed for opiate addiction “as much as public holds

individuals responsible for abusing the medications”• FDA: “should forbid marketing opiates for chronic pain”• CDC: limits opiates to 7 days of treatment for short-term pain• Chronic opiates amplify pain through tolerance, hyperalgesia, and

inflammation • Fentanyl is the new threat of overdose & death because current

addiction treatments do not block this class of opiate analgesics

Pattern of Opioid Addiction

Stahl SM, Grady MM. Stahl's Illustrated Substance Use and Impulsive Disorders 2012; Koob GF, Le Moal M. Annu Rev Psychol 2008;59:29-53.

Compulsivity

anticipation/ preoccupation

Profound craving

Tolerance to intoxication

binge/ intoxication

Profound dysphoria and physical and emotional pain

abstinence

DSM-5 Criteria for Diagnosis of Opioid Use Disorder (OUD)

1. Take more/longer than intended2. Desire/unsuccessful efforts to quit opioid use3. A great deal of time taken by activities involved in use4. Craving, or a strong desire to use opioids5. Recurrent opioid use resulting in failure to fulfill major role obligations6. Continued use despite having persistent social problems7. Important activities are given up because of use8. Recurrent opioid use in situations in which it is physically hazardous

(e.g., driving)9. Use despite knowledge of problems10. Tolerance11. Withdrawal

At least two criteria must be met within a 12-month period

Severity

Mild: 2-3 symptomsModerate: 4-5 symptomsSevere: 6 or more symptoms

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.

Known Risk Factors for Opioid Misuse

• Age ≤45 years• Psychiatric disorder• Substance use disorder• History of:

• Legal problems• Motor vehicle accidents• Preadolescent sexual abuse (in women)

• Family history of:• Substance use disorder

• Poor support

Katz NP et al. Clin J Pain 2007;23(2):103-18; Manchikanti L et al. J Opioid Manage 2007;3(2):89-100; Webster LR, Webster RM. Pain Med 2005;6(6):432-42.

Recent Annual US Prevalence of Opioid-Related Behavior70,000,000

60,000,000

50,000,000

40,000,000

30,000,000

20,000,000

10,000,000

0Used opioids not

as prescribed

In one year…− 11.5 million people in the US

used opioid pills in a manner that was not as prescribed

− 2.6 million people in the US were addicted to opioid pills or heroin

− 62.3 million people in the US filled at least one prescription for opioids

− 20.7% reported having shared pills

− estimated 3.27% become iatrogenically addicted

Had no RX

Had own RX

Addicted to opioids

Pills

Heroin

Filled an opioid prescription

Other than medical use Medical use

Ever shared pills

iatrogenically addicted

Adapted from Epstein DH et al. Trends Pharmacol Sci 2018;39(11):911-916.

• Rates of iatrogenic addiction can be drastically lower than 3.27% if clinicians attend to patients’ histories

• For pain patients with no history of alcohol or drug problems, the rate is only 0.19%

• This knowledge is now reflected in guidelines for prescription, and the annual number of prescriptions written in the US has decreased by 16% since peaking in 2012

Epstein DH et al. Trends Pharmacol Sci 2018;39(11):911-916.

Science-Based Actions Can Help Address the Opioid Crisis: Complete Patient History

Drug Overdose Deaths Involving Specific Drugs and Drug Classes in the United States

Heroin

Natural & semi-synthetic opioids

Methadone

Synthetic opioids*

*excluding methadone

0

4,000

8,000

12,000

16,000

20,000

2012 2013 2014 2015 2016

9,580 deaths

19,413 deaths

Dru

g ov

erdo

se d

eath

s

Year

Hedegaard H et al. NCHS Data Brief, no 294. Hyattsville, MD: National Center for Health Statistics. 2017.

Endogenous Opiate Neurotransmitters

Stahl’s Essential Psychopharmacology 4th Ed; 2013.

The Opioid System

Nucleus accumbens

GABA

Endogenous opioid

Dopamine

Agonist Actions at Mu Opioid Receptors

Endogenous Opioid

Heroin

Prescription Opioids

Norepinephrine and Side Effects

NaltrexoneBuprenorphineMethadone

Medication-Assisted Treatment (MAT)

Methadone

• First approved MAT for opioid use disorder• Full agonist at mu opioid receptors• Does not elicit the same euphoric high

experienced after using heroin or Rx opioids• Allows individuals with opioid use disorder to

discontinue use of heroin without experiencing the withdrawal symptoms

• Only available through specialty clinics • Patient must make daily visits• Restriction to access• Stigma

• Increased risk for respiratory depression• Available in both liquid and tablet formulation

Fullerton et al. Psychiatric Serv 2014;65(2):146-57; Ngyuen et al. CNS Spectr 2013;18:289-95; Patel, Kosten. CNS Spectr2019;1-7; Salsitz, Wiegland. J Med Toxicol 2016;12:58-63.

Methadone

Buprenorphine

• Partial agonist at mu opioid receptors• Acts as an antagonist in the presence of a mu opioid receptor

agonist, blocking its effects• May precipitate active withdrawal symptoms in individuals

currently using heroin or Rx opioids• Patients should be experiencing at least some mild withdrawal

before initiating buprenorphine• Does not need to be administered at specialty clinics (although

specialty licensing for the prescriber is required) • Less risk for respiratory depression compared to methadone• Available as a sublingual tablet and a film as well as a long-

acting implant

Buprenorphine

Alderks CE. CBHSQ Report 2017; Ayanga D et al. Exp Opin Pharmacother 2016;17(17)2307-18; Blanco-Gandia MC, Rodriguez-Arias M. Eur J Pharmacol 2018;836:89-101; Dematteis M et al. Exp Opin Pharmacother 2017;18(18):1987-99; Kosten TR, Baxter LE. Am J Addiction

2019;28:55-62; Mannelli P et al. Curr Drug Abuse Rev 2012;5:52-63; Nguyen TA et al. CNS Spectr 2013;18:289-95; Parida S et al. Exp Clin Rev Clin Pharmacol 2019;12(8):791-803; Salsitz E, Wiegand T. J Med Toxicol 2016;12:58-63; Soyka M. Dialogues Clin Neurosci 2017;19:299-

308; Zoorob R et al. Am Fam Physician 2018;97(5):313-20.

Maintenance Using Buprenorphine: Efficacy

•Numerous outpatient clinical trials comparing efficacy of buprenorphine to placebo and to methadone

•Expect average daily dose to be somewhere between 8/2 and 24/6 mg of buprenorphine/naloxone

•Depot buprenorphine—lasts a month; full-dose range• Equivalent efficacy to sublingual film; enhanced compliance

•These studies conclude that:• Buprenorphine is more effective than placebo• Buprenorphine is as effective as moderate doses of methadone (e.g., 60 mg/day)

Mattick RP et al. Cochrane Database Syst Rev 2008;(2):CD002207.

Buprenorphine Implant

• Four implants are inserted subdermally and are removed by the end of the 6th month

• Examine insertion site after 1 week for signs of infection

• After one insertion in each arm, transition back to transmucosal

• FDA approved for maintenance treatment of opioid dependence

• Patients should:• Be stable on ≤8 mg transmucosal

buprenorphine for ≥3 months without need for supplemental dosing or adjustment

• NOT have dose reduced for the purpose of transitioning

• NOT be prescribed as-needed transmucosal buprenorphine

Methadone and Buprenorphine Efficacy

• More effective than placebo• Efficacy of the medication is related to the dose • Controlled studies have tested doses as high as 100 mg/day

methadone and 16 mg/day buprenorphine• Good treatment retention• Decreased illicit opiate use (urines, self-reports)• Improvements in other areas included increased employment,

decreased criminal activity, and psychological adjustment (depression)

Stotts AL et al. Expert Opin Pharmacother 2009;10(11):1727-40;Dole VP et al. JAMA 1965;193:646-50.

Buprenorphine-Naloxone Combination

• Naloxone is a mu opioid receptor antagonist that can block the actions of mu opioid receptor agonists or partial agonists

• Buprenorphine-naloxone combination• Prevents diversion of buprenorphine• Taken sublingually, naloxone has little effect =no withdrawal• Diverted into inhaled or injected form, naloxone actions dominate =withdrawal

BuprenorphineNaloxone BuprenorphineNaloxone BuprenorphineNaloxoneNaloxone

Opiate Abuse + Pain: Buprenorphine

• Advantages of buprenorphine + naloxone compared to other opiates• Medical safety – overdose prevented• Diversion very unlikely – precipitated withdrawal• Readily discontinued – mild withdrawal• Does not cause hyperalgesia – sustained pain relief• Prevents “doctor shopping” – blocks other opiates• Divided daily dosing for pain – 2 mg SL 4 × daily

Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration,

2004. http://buprenorphine.samhsa.gov/Bup_Guidelines.pdf.

Discontinuing Opioids or MAT

With

draw

al S

ever

ityHeroin or Rx Opioids

Methadone

Buprenorphine

Drug Interactions With Buprenorphine

•Few clinically significant interactions compared with methadone

•Benzodiazepines, or sedating drugs in combination with buprenorphine, can lead to overdose

•Medications metabolized by cytochrome P450 3A4

•Methadone also interferes with 2D6 metabolism

•Opiate antagonists: few effects

•Opiate agonists: mostly blocked; fentanyl

Lutfy K et al. Curr Neuropharmacol 2004;2(4):395-402.

Naltrexone

• Mu opioid receptor antagonist• Binding of naltrexone to mu opioid receptors results in no

effect yet blocks the actions of opioid agonists• Individual should be free of opioid agonists for 7-10 days

before initiating naltrexone• May precipitate withdrawal in those actively using opioids

• Does not require specialty facilities or licenses• Relatively little risk of respiratory depression or

overdose• Available as both oral and 30-day depot formulations

Naltrexone

Alderks CE. CBHSQ Report 2017; Ayanga D et al. Exp Opin Pharmacother 2016;17(17)2307-18; Mannelli P et al. CurrDrug Abuse Rev 2012;5:52-63; Nguyen TA et al. CNS Spectr 2013;18:289-95; Bart G. J Addict Dis 2012;31(3):207-25;

Bisaga A et al. Am J Addictions 2018;27:177-87; Noble F, Marie N. Front Psychiatry 2019;9(742):1-8; Patel B, Kosten TR. CNS Spectr 2019;1-7; Rodriguez-Arias M, Aguilar MA. Exp Opin Invest Drugs 2015;24(11):1459-72; Sigmon SC et al. Am J

Drug Alcohol Abuse 2012;38(3):187-99; Stahl SM. CNS Spectr 2018;23:113-6.

What Happens If an Individual on Naltrexone Uses Heroin (or Rx Opioids)?

Naltrexone

• Euphoric effects• Reinforcement

• No euphoric effects• Extinction learning

Relapse to heroin/Rx opioid use while on

naltrexone may actually HELP with abstinence

Naltrexone’s Pharmacokinetic Profile

Galloway GP et al. BMC Psychiatry 2005;5:18.

0

5

10

15

20

Naltrex

one (ng

/ml)

0

2

4

6

8

10

12

14

Plasm

a Conc

entrat

ion (ng

/ml)

Plasma levels from daily dose

Fluctuations each monthTime (Hours)

Days0 4 8 12 16 33

0 4 8 12 16 2420

Plasma Concentration: 50 mg (PO), 0–24 Hours

Depot Naltrexone

Johnson BA. Expert Opin Pharmacother 2006;7(8):1065-73.

Provide sustained naltrexone release following injection

• Avoid daily loss of therapeutic plasma levels, maintaining levels for 30 days

• Eliminate need for daily dosing by patient

• Reduce repetitive high plasma peaks

• Eliminate first pass metabolism

Depot Naltrexone Pharmacokinetics

Dunbar JL et al. Alcohol Clin Exp Res 2006;30(3):480-90.

30

20

Nal

trexo

ne m

ean

plas

ma

leve

ls (n

g/m

L)

10

5

0 30

25

15

2520151050Time (Days)

Naltrexone 380 mg IM injection

Oral naltrexone 50

Oral vs. Depot Naltrexone: Opiates

•Retention and urine results compared between oral (n = 69) and long-acting injectable naltrexone (n = 42); retention in treatment and opiate use in the first 8 weeks post-detoxification were compared

•Long-acting injectable naltrexone produced significantly better outcome than oral naltrexone on days retained in treatment and proportion of opiate-free urines

•Days retained: depot 42 vs. oral 32•Opiate-free urines: depot 0.52 vs. oral 0.37

Brooks AC et al. J Clin Psychiatry 2010;71(10):1371-8.

Depot Naltrexone:Study Design and Outcomes

•Randomized, placebo-controlled 6-month outpatient clinical trial in 250 opiate-addicted patients

•Assigned to depot naltrexone vs. placebo after 7 days opiate-free while at inpatient setting

•Dose of about 25 mg daily from monthly injection•6-month outcome

• 1.6 × more abstain completely on depot naltrexone: 36% vs. 23%• Average depot naltrexone patients attain 90% opiate-free weeks vs. average

placebo patients attain 40% opiate-free weeks

Krupitsky E et al. Lancet 2011;377(9776):1506-13.

Sustained Complete Abstinence With Depot Naltrexone

Abstinence: opiate-free from weeks 5–24Krupitsky E et al. Lancet 2011;377(9776):1506-13.

40

30

Patie

nts

(%)20

10

0 Naltrexone (n = 126)

Placebo(n = 124)

36%

23%

P = .0002

Adverse Events: Depot Naltrexone

Krupitsky E et al. Lancet 2011;377(9776):1506-13.US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Depot naltrexone was well tolerated in opiate-dependent patientsDepot naltrexone

n = 126Placebo n = 124

Alanine aminotransferase increased 13% 6%Aspartate aminotransferase increased 10% 2%Gamma-glutamyltransferase increased 7% 3%Nasopharyngitis 7% 2%Insomnia 6% 1%Influenza 5% 4%Hypertension 5% 3%Injection site pain 5% 1%Toothache 4% 2%Headache 3% 2%

Depot Naltrexone: Rare Severe Adverse Events

•Precipitated withdrawal, if not detoxed• Injection site reactions (mild mostly)

•Sterile abscess from injection into fatty tissue•Eosinophilic pneumonia (rare)•Large increase in LFT (doses > 300 mg daily)

LFT = liver function test.

US Food and Drug Administration. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

Effectiveness of Extended-Release Naltrexone vs. Buprenorphine-Naloxone for Opioid Relapse Prevention

• In a 12-week study from Norway, extended release injectable naltrexone was as safe and effective as buprenorphine-naloxone in maintaining short-term abstinence from illicit opioids1

• In a 24-week, open-label, randomized controlled study in the US, buprenorphine-naloxone was superior to injectable naltrexone in preventing relapse in the entire population studied2

• However, more than ¼ of participants dropped out of naltrexone treatment before it had even begun due to failure to get through detoxification and start treatment

• When treatment was successfully initiated in the US study, both medications were comparably safe and effective in preventing relapses

1 Tanum L et al. JAMA Psychiatry 2017;1(12):1197-1205; 2 Lee JD et al. Lancet 2018;391(10118):309-318.

Tips and Tricks for MAT

Mitigating Withdrawal Symptoms During Transition to MAT or Between MATs

Symptoms

Opiate Detoxification:New Ways to Transition to Depot Naltrexone

• Needed to reduce tolerance and hyperalgesia• Stops pro-inflammatory opiate effects• Detox fails unless patient is transitioned to sustained antagonist or

maintenance: buprenorphine• Innovative approaches:

• Clonidine or lofexidine• Lofexidine/naltrexone – rapid• Buprenorphine

The rapid naltrexone protocol is not FDA approved.

Clonidine vs. Lofexidine

•Both adrenergic antihypertensives

•Non-abusable, oral use

•Dose titration not needed with lofexidine

•Lasts 7 days (except methadone)

•Targets autonomic symptoms

•Anxiety; diarrhea not well relieved

•Side effects: sedation, orthostatic hypotension

Kosten TR et al. N Engl J Med 2003;348(18):1786-95.

Lofexidine

Clonidine

Clonidine vs. Lofexidine

•Lofexidine has been widely used in Europe for >20 years

•Recently FDA approved – effective as clonidine; fewer side effects, greater patient acceptance

•Fixed dosing from 2.4 mg to 3.2 mg daily

•Treatment strategy very similar to clonidine

•Can use rapid detoxification variations with naltrexone

Stotts AL et al. Expert Opin Pharmacother 2009;10(11):1727-40; Kosten TR et al. N Engl J Med 2003;348(18):1786-95.

Severity of WithdrawalAfter Methadone Discontinuation

Seve

rity

of W

ithdr

awal

Days since last methadone dose

With lofexidine

Abrupt discontinuation

0 5 10 15

With lofexidine + naltrexone

Severity of WithdrawalAfter Buprenorphine Discontinuation

Days since last buprenorphine dose

With lofexidine

Abrupt discontinuation

With lofexidine + naltrexone

Kosten TR et al. N Engl J Med 2003;348(18):1786-95.

Seve

rity

of W

ithdr

awal

0 3 5 7

Overdoses Now From Fentanyl:Need for Anti-fentanyl Vaccination

• Methadone, naltrexone, or buprenorphine do not block fentanyl overdoses or “high”

• A vaccine against fentanyl is effective in animals, and needs to move into humans

Summary

• Opioid use disorder (OUD; including heroin and prescription opioids) is an epidemic we are currently faced with

• Medication-assisted treatment (including methadone, buprenorphine, and naltrexone) may be our best option in treating OUD

• The 3 MATs have differing mechanisms of action with varying effects on the opioid system

• There are several strategies for transitioning patients from opioid use to MAT and from one MAT to another

• Mitigating withdrawal symptoms using MAT and non-opioid therapies may provide patients with OUD the best opportunity for maintained abstinence and recovery

Posttest Question

Francine is a 42-year-old patient addicted to oxycodone. She has recently begun treatment with naltrexone. At mu opioid receptors, naltrexone acts as a/an:

1. Agonist2. Partial agonist3. Antagonist

Posttest Question

Which of the following interact with mu opioid receptors as full agonists?

1. Endogenous opioids2. Heroin3. Rx opioids (e.g., oxycodone)4. 1 and 2 only5. 1 and 3 only6. All of the above

Posttest Question

Ivan is a 25-year-old with OUD. He is concerned that the heroin he is obtaining on the streets may be laced with fentanyl. Which of the following MATs is effective against fentanyl overdose?

1. Methadone2. Buprenorphine3. Naltrexone4. All of the above5. None of the above