Module 1: Epidemiology of Opioid Use – Topic K Recognize the person-specific and environmental factors that may influence the selection of a specific type of opioid agonist treatment for opioid use disorder.

Learning Objectives

By the end of this topic, the student should be able to:

• Compare and contrast the two common opioid agonist therapies: buprenorphine and methadone.
• Describe the pharmacological agents used to treat opioid withdrawal symptoms.
• Compare and contrast regulations for prescribing buprenorphine and methadone.
• Describe factors that affect the choice of OAT.
• Identify barriers to accessing medications for opioid use disorder.

Key Concepts

• The main pharmacotherapy for problematic opioid use is opioid agonist therapy (OAT).
• Buprenorphine-naloxone and methadone are the two most common pharmacotherapies for opioid use.
• For many clients, symptoms of withdrawal may occur before initiation of opioid agonist therapy.
• Additional pharmacotherapies for withdrawal management include both prescription and over-the-counter drugs.
• In 2018, regulatory barriers, in particular the requirement of physicians to obtain an exemption under the Controlled Drugs and Substances Act to prescribe methadone, were removed/amended by Health Canada.
• To dispense methadone in most jurisdictions, pharmacists are required to obtain additional certification/training.
• Multiple barriers to OAT exist, including inadequate support, accessibility challenges, and stigma.

Treatment of Opioid Use Disorder - OAT

Opioid agonist therapy or treatment (OAT) is the primary treatment for opioid use disorder or problematic opioid use.

• The goals of therapy include replacing problematic opioid use with regular use of specific opioids and doses, prescribed by a physician, and avoiding symptoms of withdrawal.

Compounds Used For OAT

Methadone

Methadone is a full agonist at the opioid receptor, and a longer-acting opioid.

Buprenorphine

Buprenorphine is a partial agonist at the opioid receptor meaning that it activates the receptor, but not maximally. Thus, in the presence of a full agonist, it actually acts as an opioid receptor blocker, and can even induce opioid withdrawal symptoms.

• The most commonly used buprenorphine is formulation in a sublingual tablet mixed with naloxone called Suboxone to prevent injection of the product. If it were to be injected, the naloxone would block the effects of buprenorphine. But because naloxone is not well absorbed orally, when taken as directed, it does not interfere.

Methadone Versus Buprenorphine

Effectiveness

• Both methadone and buprenorphine are effective therapies.
• Some data suggest that methadone may be slightly more efficacious than buprenorphine in opioid use disorder.
• Methadone does better by some measures in clinical trials.
• 73 percent retention in treatment versus 22 percent given placebo, compared to buprenorphine/naloxone, which had 64 percent retention in treatment versus 39 percent given placebo.
• A 2014 Cochrane review and meta-analysis (Mattick et al., 2014) found that flexible-dose and low-dose buprenorphine had a lower rate of retention in treatment compared to flexible-dose and low-dose methadone.

Initiation

• Initiation of buprenorphine treatment requires patients to be in withdrawal for at least 12–24 hours. Methadone can be started immediately.
• Despite the possible increased efficacy of methadone over buprenorphine, some prescribers favour buprenorphine because methadone has a significantly higher risk of a lethal overdose.
• The increased risk of a lethal overdose from methadone can be explained by its full agonist action compared with buprenorphine’s partial agonist action.

Administration

• Buprenorphine-naloxone is placed under the tongue for 10 minutes to absorb the buprenorphine sublingually; buprenorphine long-acting is given subcutaneously on a monthly basis.
• Methadone is available as oral tablets and liquids. Dosing of liquid formulations is often observed by a pharmacist.
• Although OAT can be tapered to reduce or cease opioid use, OAT is often long-term and there is no maximal duration of therapy.
• Client contracts, treatment agreements, and urine drug screening may be mandated by the prescriber, or in some cases, by provincial and territorial regulations.

Withdrawal Management

In addition to OAT, which can be initiated immediately (methadone) or 12–24 hours after withdrawal symptoms (buprenorphine), additional pharmaceutical agents are used to manage the symptoms of opioid withdrawal.

NOTE: See Module 1 Topic I for a list of withdrawal symptoms.

• clonidine, an alpha2-adrenergic receptor agonist, for anxiety
• quetiapine, an atypical antipsychotic, for anxiety
• trazodone, an antidepressant and antihistamine, for sleep
• ibuprofen, a cyclo-oxygenase inhibitor, for pain
• dimenhydrinate, an antihistamine, for nausea
• ondansetron, a serotonin blocker, for nausea
• loperamide, a peripheral opioid, for diarrhea

In addition to the agents listed above, other drugs may also be used to treat specific withdrawal symptoms.

Methadone and Buprenorphine-Naloxone Regulations

Methadone prescribing has been more extensively regulated in Canada compared to other opioids. Originally, the use of methadone as an opioid agonist therapy was overseen at the federal level, by Health Canada. In 1995, much of that authority was passed to the provinces and territories. Now, there is variability across provinces and territories with respect to obtaining methadone prescribing authority, requirements for urine drug screening, documentation, and so on.

Pharmacists who want to dispense methadone often need additional certification or training, depending on the jurisdiction.

• For example, the College of Pharmacists of British Columbia (CPBC) runs a methadone maintenance treatment (MMT) training program. In BC, pharmacists must “have successfully completed the mandatory CPBC MMT training program,” and “have implemented all necessary practice requirements identified in the CPBC Methadone Maintenance Treatment Policy Guide” (College of Pharmacists of British Columbia, 2013).
• In Ontario, a designated manager and at least one staff pharmacist must receive additional training. Specific resources and guidelines must be available in the pharmacy.

Individual Factors That Affect the Selection of OAT

Methadone and Heart Function

Methadone is associated with a type of abnormal heart functioning called QT prolongation. Thus, a choice between methadone and buprenorphine necessitates investigation into client risk factors for QT prolongation, including other medications with QT prolonging potential and cardiac risk factors.

• An electrocardiogram (ECG) can be ordered in clients with significant risk factors.
• Buprenorphine may be a better option in clients with QT prolongation or those at high risk of a specific type of abnormal heart rhythm called Torsades de Pointes

Methadone and Respiratory Depression

Methadone poses a greater risk of respiratory depression compared with buprenorphine. This is because methadone is a substrate of multiple CYP enzymes including CYP2B6, CYP3A4, CYP2C19, CYP2C9, and CYP2D6. These pharmacokinetic interactions, when combined with methadone’s full agonist mechanism of action results in the greater risk of respiratory depression.

Drug Interactions

Buprenorphine has fewer and less severe drug interactions compared with methadone. Therefore, clinicians should review the client’s medications to identify any potential interactions.

• If clinically significant drug interactions are present, buprenorphine may be preferred over methadone.

Other Considerations

In pregnancy, detoxification should be avoided. Both methadone and buprenorphine/naloxone are safe to use in pregnancy.

NOTE: Age may matter. Methadone is less studied in youth under age 25.

Although differences between male and female OAT clients have been described, there is insufficient information on gender, including the LGBTQ2 population, to guide the choice of OAT.

The presence of concurrent mental health disorders may lead to issues with OAT adherence; thus, there is an enhanced need for additional support to be available to the persons receiving this therapy.

The presence of additional, non-opioid substance use disorders also negatively impacts OAT adherence.

HCV/HIV status is a factor affecting the selection of OAT because both methadone and buprenorphine/naloxone have interactions with antiviral medications, particularly older medications for HIV.

Methadone is available as oral tablets and liquids. Therefore, buprenorphine is preferred for clients with difficulty swallowing (dysphagia).

Lived Experience

Barriers to OAT Access and Treatment

Stigma

Stigma around the diagnosis of opioid use disorder, as well as OAT and other treatments, is a barrier to accessing treatment. Stigma exists:

• in the general population,
• among families and those supporting individuals with opioid use disorder,
• in law enforcement, and
• among health and social service professionals.

Stigma can exacerbate concerns about medication diversion.

Lack of Health and Social Service Provider Support

There is a lack of training among health and social service providers regarding opioid use disorder.

• This can have a significant impact on smaller, rural, or remote communities if the prescriber is not authorized to prescribe methadone or the pharmacy does not offer methadone services.

Race

U.S. data suggest that White Americans are more often treated for opioid use disorder compared to non-White Americans (Wu et al., 2016).

In Canada, Indigenous Peoples are three times as likely to die from overdose as their non-Indigenous counterparts (Johnston, 2020).

Abstinence-Based Approaches

Residential treatment programs that use abstinence-based approaches may be a barrier to OAT.

• Abstinence-based programs use a top-down approach and take away the individual’s power to make decisions surrounding opioid use.

The harm reduction approach recognizes individuals with lived experiences are experts of their experience.

• As experts, individuals are given the power to decide what to do to reduce the harm experienced when using opioids.

Client Perspectives

A study by Teruya and colleagues (2014) investigated differences among OAT therapies from the client perspective and their reasons for preferring methadone or buprenorphine/naloxone.

• Clients reported a preference for methadone over buprenorphine/naloxone for the following reasons:
• adverse effects associated with the latter (restless legs, headaches, diarrhea)
• a reduced incidence of withdrawal symptoms
• the naloxone in buprenorphine/naloxone, blocked the effects of additional opioids they chose to use
• greater familiarity with methadone compared to buprenorphine/naloxone
• Others reported great success with buprenorphine/naloxone and without adverse effects.

Stop and Think

Now that you have reviewed this content, consider the following:

---

References