Medications for opioid use disorder

Objectives

Explain the physiology of addiction.
Compare and contrast the different types of medication for opioid use disorder.
Report confidence in initiating someone on MOUD.
Acknowledge the risks factors of precipitated withdrawal.

Addiction is a chronic, relapsing, and treatable brain disease.

*Source: Volkow ND, Koob GF, McLellan AT. N Engl J Med. 2016.*

“During intoxication, drug-induced activation of the brain’s reward regions (in blue) is enhanced by conditioned cues in areas of increased sensitization (in green). During withdrawal, the activation of brain regions involved in emotions (in pink) results in negative mood and enhanced sensitivity to stress. During preoccupation, the decreased function of the prefrontal cortex leads to an inability to balance the strong desire for the drug with the will to abstain, which triggers relapse and reinitiates the cycle of addiction. The compromised neuro-circuitry reflects the disruption of the dopamine and glutamate systems and the stress- control systems of the brain, which are affected by corticotropin-releasing factor and dynorphin. The behaviors during the three stages of addiction change as a person transitions from drug experimentation to addiction as a function of the progressive neuroadaptations that occur in the brain.”
Volkow et al, NEJM 2016

Individuals with addictive disorders engage in maladaptive decision-making.

Suboptimal choices can reflect impairment in subjective evaluation of rewards.
Various factors (delay, uncertainty, emotion, cues, peers) affect valuation.
Valuation relies on a distributed network of brain regions.
These regions show impaired function in addicts during decision-making.

“Drugs belonging to different pharmacological classes but sharing the characteristic of being rewarding in animals and humans share the properties of preferentially increasing synaptic dopamine concentrations in the mesolimbic dopaminergic system and of stimulating behavior… The drugs showing these properties include central stimulants (e.g., amphetamine and cocaine), opiates (e.g., morphine, methadone, and fentanyl), central depressants (e.g., ethanol), and cholinergic agonists (e.g., nicotine). Whereas amphetamine and cocaine increase extracellular dopamine by displacing it from presynaptic sites and by blocking dopamine reuptake, respectively, opiates, ethanol, and nicotine increase extracellular dopamine by stimulating the firing of dopaminergic neurons.”
Di Chiara et al, Proc Natl Acad 1988

Dopamine receptors are down-regulated with chronic drug use. They become sensitized and it requires higher doses to stimulate the receptors in the same way.

*Source: Clinical Addiction Research and Education (CARE) Unit*, *Boston University*

Dependence leads to physical withdrawal, persistent cravings, maladaptive behaviors, and long-term neurological changes.

Treatment of OUD

Data demonstrates Medication for Opioid Use Disorder (MOUD) can

Increase abstinence from opioid us
Decrease injection drug use
Improve social functioning
Improve quality of life
Decrease HIV and Hepatitis C rates
Reduce mortality by 50%

Medication for opioid use disorder (MOUD) can

Lower rates of opioid use
Improve social functioning
Decrease injection drug use
Reduce HIV transmission
Reduce Hepatitis C transmission
Improve quality of life
Reduce mortality

Opioid agonist therapy (OAT)

*Source: The Pew Charitable Trusts. Medication-Assisted Treatment Improves Outcomes for Patients With Opioid Use Disorder*. 2016

Methadone

Liquid
Can treat withdrawal (low dose: 30 mg)
Titrate to effect (sometimes >200 mg)
For addiction, must be dispensed by federally-regulated Opioid Treatment Program (OTP)
- Heavily restricted
- ”Take homes”
For pain: anyone can prescribe
Pharmacokinetics:
- Half-life: 24-36 hr; 5-7 days steady state
- CYP-450 metabolism
DDIs: Be wary of AEDs, TB meds particularly
- Overdose possible, particularly with BZDs, polysubstance use
Serum methadone level available (peaks and troughs)
INCREASE dose in pregnancy
ADE:
- Prolonged QTC at high dose
- Constipation
- Insomnia
- Hypogonadism

Buprenorphine

Sublingual tablet or film
- Standard dose: 8 mg (1-3x per day)
Can be prescribed in an office
- Office-Based Agonist Therapy (OBAT)
For addiction, must have X-waiver
- Sign up online; must have medical license
For pain, anyone can prescribe

Question: Which of the following is a CONTRAINDICATION for Buprenorphine?

a) Cirrhosis
b) End-stage renal disease (ESRD)
c) Prolonged QTc
d) Concurrent prescription of benzodiazepines
e) Cocaine use
f) Pregnancy

Buprenorphine is safe!

Very few adverse affects
- No prolonged QTc
Few non-opioid medication interactions
- Rare exceptions: TB treatment, HAART, AEDs
No renal or hepatic dosing changes
- Rare hepatitis in underlying risk factors
Safe in pregnancy
Ceiling effect

Philosophy of Low Threshold

“Initial U.S. recommendations for buprenorphine treatment were unintentionally restrictive. These restrictions have been associated with a shortfall of prescribers and barriers to care for patients. Recent evidence-based recommendations more readily support initial and ongoing individualized care. Practices and policymakers should update their approaches on the basis of this evidence.”
Martin et al, Ann Intern Med 2018

*Source: Martin et al. Ann Intern Med. 2018*

Multiple formulations:

Sublingual (MAT):
- Film (Suboxone): buprenorphine + naloxone
- Tablets (Zubsolv): buprenorphine + naloxone
- Tablet, monoproduct (Subutex): buprenorphine
Buccal (pain):
- Bunvail: buprenorphine + naloxone
- Belbuca: buprenorphine
Implant (6 months)
Transdermal patch (pain):
- Butrans
Injectable (MAT):
- Sublocade

What happens if you take buprenorphine right after injecting heroin / fentanyl / methadone / other opioid?

Precipitated withdrawal is when withdrawal symptoms are caused by medications or MAT used in substance abuse treatment rather than absence or abstinence from the chosen drug of abuse.

Partial agonist opioid with high affinity for mu-receptors replaces the full opioid agonist rapidly over a short period of time causing a massive change in the net mu-receptor activation leading to rapid precipitated withdrawal. Source: Ghosh et al. Canadian Journal of Addiction. 2019

Precipitated withdrawal is rare, but we should know about it. Risks include the level of physical dependence (e.g., heavy use), the half-life of current opioid use (fentanyl, methadone), recent opioid use, and high initial dose of buprenorphine.

“Buprenorphine’s partial mu opioid agonist profile and low intrinsic activity contribute to its good safety profile, decreased abuse potential, and its ability to suppress opioid withdrawal while limiting the physical dependence produced by buprenorphine maintenance treatment. At the same time, buprenorphine’s ability to block the effects of concurrently administered opioids, either through cross-tolerance or pharmacological an- tagonism, reduces the risk of relapse in buprenorphine- maintained patients who may self-administer opioids during treatment. Finally, buprenorphine’s high recep- tor affinity and slow dissociation from its receptor may prolong its agonist action and allow less-than-daily dosing for clinic-enrolled patients, which may enhance its acceptability to some individuals.
However, some of these same clinical laboratory studies reveal that, because of buprenorphine’s some- times paradoxical pharmacodynamic effects, clinicians must use caution when planning buprenorphine main- tenance treatment with their patients. For example, methadone-maintained patients interested in transfer- ring to buprenorphine maintenance risk experiencing precipitated-withdrawal if the transfer is not carefully planned. Also, despite its lower abuse potential, ther- apeutic buprenorphine doses can produce prototypic mu agonist effects, especially when administered parenter- ally, and studies have shown that it is self-administered in non-dependent individuals with opioid abuse his- tories. The likelihood of parenteral abuse in opioid- dependent individuals will likely be reduced by combin- ing buprenorphine with naloxone in a single, sublin- gually administered combination medication. The clinical laboratory experience with buprenorphine in combination with naloxone indicates that this combined product will deter the likelihood of illicit diversion to parenteral routes, and the combination will have a very low potential for abuse by opioid-dependent subjects.”
Walsh et al, Drug Alcohol Depend 2003

Question: Which of the following is associated with high likelihood of precipitated withdrawal?

a) Diarrhea, yawning, chills before taking
b) Methadone use yesterday
c) Illicit use of buprenorphine
d) Current cocaine and benzodiazepine use
e) Remote history of heavy drug use

How do you start buprenorphine in a safe way?

It’s easy!

1) Wait until you start feeling withdrawal symptoms.
- Taking buprenorphine while “high” or with opioids in system can cause precipitated withdrawal
- If patient has not had opiates in >72 hours, generally safe.
2) Start with a low dose.
- Half a strip or 4 mg is usually a good “tester” dose.
3) If tolerating low dose, OK to go to regular dosing.
- Typically 16-24 mg/day; either once daily or BID
4) Follow-up in 1-2 weeks

Quick script: “Please wait until you start feeling sick. Once the withdrawal is really bothersome: take the first dose (half a strip). Wait a couple of hours then take the second strip. In the morning, starting taking the full 8 mg strip: you’ll take it twice a day for the next week. Keep it under your tongue and let it dissolve. Also, do you know about naloxone?”

What dose should a patient be on?

8-16 mg per day
- With fentanyl, more people now on 24 mg/day
- Minimal data supporting benefits >24 mg/day
Discussion continues on optimal dosing frequency
- once daily recommended by SAMHSA TIP 63
- Alternative day dosing is effective
- Analgesia improved with more frequent dosing (QID)

How long should a patient be on OAT treatment?

“Risk of acute care service use and overdose were high following buprenorphine discontinuation irrespective of treatment duration. Superior outcomes became significant with treatment duration beyond 15 months, although rates of the primary adverse outcomes remained high.”
Williams et al, Am J Psychiatry 2020

Unadjusted 6-month outcomes following discontinuation among Medicaid beneficiaries ages 18–64 retained on buprenorphine for ≥180 days, by treatment duration cohort.
Source: Williams et al. Am J Psychiatry. 2020

What if someone diverts the medication?

In one study, of 602 individuals with IV drug use, 90% were aware of buprenorphine and 5% used it to get high.

In another study of 356 patients with OUD, 91% reported using street-obtained buprenorphine to manage withdrawal symptoms.

Diversion is common
Non-prescribed buprenorphine is mainly used for treatment of withdrawal, not euphoria, and is likely due to inadequate treatment access
Expanding access to buprenorphine will help minimize presence of the illicit market.

What about urine drug screens?

“Testing should be a routine part of initial and ongoing patient assessment.“
“Not used as sole determinant”
Unclear if regular tox screen is effective
- Associated with increased opioid abstinence
- Associated with increased drop out

How do we treat precipitated withdrawal?

1) Frequent small doses of buprenorphine
- Give 2 mg of buprenorphine every 2 hours for up to 8- 12 mg on the first day
2) Symptomatic management
- Anxiety? Try hydroxyzine
- Muscle aches? NSAIDs
- Abdominal cramps? Dicyclomine
- Insomnia? Melatonin, trazodone, mirtazapine
- Nausea/vomiting? Ondansetron
3) Reassure patient that this will pass

Buprenorphine: Other Considerations

Things We Do For No Reason: Don’t discontinue buprenorphine when treating acute pain!

Don’t stop buprenorphine in the perioperative setting!

Are some groups at high risk for opioid overdose?

Incarceration is associated with 41x greater overdose death (Gan et al. Addiction. 2021)
Within 2 weeks of release, individuals are 129x more likely to die of opioid overdose (Binswanger et al. NEJM. 2007)
Nearly half of fatal opioid overdoses occur in people with criminal justice involvement (Saloner et al. JAMA Psych. 2020)
75% of individuals using heroin report criminal justice involvement (Winkelman et al. JAMA Net Open. 2018)
33% of individuals with OUD have encountered the criminal justice system within the prior year (Boutwell et al. J Opioid Manag. 2007)

MOUD in a Correctional Setting

Increased community engagement
Decreased substance use and overdose
Decreased criminal behavior and recidivism
Decreased HIV risk behaviors (Malta et al. PLoS Med. 2019)
In RI: Initiation of MOUD while incarcerated is associated with a 61% reduction in post-release overdose deaths (Green et al. JAMA Psych. 2017)