A3.3 Methadone-specific Guidance

A3.3.i Assessment

A3.3.ii Methadone Pharmacology

• Full opioid agonist, with action predominantly at the mu-opioid receptor and some action at the kappa and delta opioid receptors; antagonist at the NMDA receptor 
• Most frequently administered as an oral solution, generally given as a single daily dose
• Average plasma half-life is approximately 24 hours (with a range of 6–90 hours)
• The average time to peak plasma concentration and peak clinical effect is 3 hours (with a range of 2–6 hours)
   

A3.3.iii Formulations

There are 2 methadone options available as regular PharmaCare benefits in BC (Covered under Plans B, C, G, and Z):

• Methadose
• Metadol-D 

There are also 2 methadone options that are not covered under regular PharmaCare benefits and require a Special Authority Request: 

• Compounded methadone
  • Exceptional, last-resort
• Methadose Sugar-free

Methadose was introduced in 2014, replacing 1mg/mL pharmacy compounded methadone. Since this formulation change, many patients who had been stable on compounded methadone 1mg/mL have reported return to unregulated opioid use due to inadequate management of withdrawal symptoms.182-184 As a result, Metadol-D was added as a regular benefit in 2019.

In October 2019, compounded methadone became available as an exceptional, last-resort option for individuals who had trialed regular benefit formulations without success. For individuals who have not benefited from documented, reasonable trials of two methadone formulations, and for whom methadone remains the optimal OAT option, compounded methadone 10mg/mL may be considered.

Table 13. Summary of Methadone Options

For further information to support formulation selection and transition between formulations, see the BCCSU’s bulletin on Methadone Formulations Options and Interchangeability. For specific formulation for pharmacists and prescribers on requesting and prescribing compounded methadone as a last resort option, refer to the BCCSU’s Compounded Methadone Bulletin.

A3.3.iv Initiation

Initiation and dosing guidance provided in this guideline is applicable to all formulations of methadone.

During initiation, prescribers should see patients in person or virtually at least weekly to carefully monitor treatment response. Clinical assessment is necessary before adjusting methadone doses; this is due to the unique pharmacokinetic properties of methadone (long half-life, slow bioaccumulation) compared to other opioids, and the high degree of individual variability in absorption rates, metabolism, potency, and cross-tolerance with other opioids. 

Depending on the patient’s needs and circumstances, these assessments can be conducted virtually or in person. For example, patients with previous treatment experience with methadone face a lower risk of complications during initiation, and may be good candidates for virtual assessment. 

Due to risk of overdose from drug–drug interactions, current substance use, including alcohol and prescription medications, should be reviewed with patients at every visit and confirmed with PharmaNet records. Periodic check in with the dispensing pharmacy is encouraged, in order to collect collateral information on patient wellbeing (e.g., sedation) and adherence to daily witnessed ingestion requirements. 

Prior to initiation, review risks and benefits of treatment, determine starting dose based on patient-specific risk of opioid toxicity (see below), and obtain informed consent.
 

A3.3.v Rapid Titration in Monitored Settings

There is scant evidence on rapid methadone titration245,480; however, there is growing clinical need for, and experience with, safe and successful rapid titration in monitored settings. This is likely in response to the needs of patients who use fentanyl and other highly potent synthetic opioids, for whom existing methadone dosing and titration guidelines may be insufficient to address withdrawal symptoms or support treatment retention.188 To address the treatment needs of this population, META-PHI recommendations for Methadone Treatment for People Who Use Fentanyl emphasizes the need for measures to reach an optimal dose of methadone quickly and safely in order to avoid drop-outs and reduce concurrent unregulated opioid use which increases the risk of overdose in this population.188 

The sample rapid titration protocol presented in Table X is based on the St. Paul’s Hospital protocol featured in a 2019 case study.245 It is emphasised that a rapid titration schedule such as this one should be performed in monitored settings (e.g., hospital wards, inpatient detox facilities, bed-based treatment facilities) that can accommodate greater flexibility and the ability to monitor for early signs of opioid toxicity. This protocol starts patients at 30–40mg methadone per day, with up to 3 x 10mg methadone PRN per day. Additional doses should be at least 3 hours apart, with post-dose re-assessment at 3 hours after each dose (peak effect). On the 4th day, the lowest most consistently administered total daily dose should be consolidated into the new scheduled dose with a 10mg increase,  with up to 3 x 10mg q3h PRN doses in addition. Oral hydromorphone is also given 8–24mg q2h PRN to manage acute pain and withdrawal symptoms not managed by methadone. If the patient reports continued pain or withdrawal symptoms, consider increasing the morphine dosing during the OAT titration, as adequate OAT and analgesia dosing have a protective effect against unregulated opioid use in hospital and leaving against medical advice.481-483 In this sample protocol, the patient took all PRN doses.

Table 15. Sample Rapid Methadone Titration 

During rapid methadone titration, the patient should receive pre- and post-dose assessments—for both scheduled and PRN dosing, ensuring that they are alert and showing no signs of sedation.

An alternative rapid methadone titration protocol utilized in some North American jurisdictions is presented on the Ca Bridge website.
 

A3.3.vi Stabilization

The optimal therapeutic dose varies widely among patients. The range commonly cited in existing guidelines is 60mg–120mg. However, this is based on evidence collected before the emergence of fentanyl in the unregulated drug supply. While there is scant evidence around relative effectiveness or best practices for methadone prescribing in the fentanyl era, clinical experience suggests that doses of 150mg or higher may be required in some patients to meet therapeutic goals.

A3.3.vii Missed Doses

Tolerance is lost rapidly when methadone treatment is interrupted or discontinued. To avoid overdose as a result of lost tolerance, BC pharmacists are required to notify prescribers of missed doses and clinicians must review and document PharmaNet profiles. Under current regulations, the dispensing pharmacy is also required to cancel the prescription if the patient misses 4 consecutive days of methadone, and notify the prescribing clinician. 

In alignment with an increasing number of guidelines suggesting that most patients who are stable on their medication can safely resume their medication after 3 consecutive missed once-daily doses,188,192 this guideline endorses the resumption of the patient’s usual dose after 3 consecutive missed once-daily doses. An assessment for dose reduction should be conducted after 4 consecutive missed once-daily methadone doses, and titration should be restarted after 5 or more consecutive missed once-daily methadone doses, as outlined below. For split dosing (BID or more frequently), prescribers should count fully missed days rather than missed doses for assessments according to the missed dose protocol. However individualized clinical judgement should be exercised any dose adjustments for patients who have missed a part of their total daily dose over a number of days.  

• One to three consecutive once-daily doses missed: No change in dose is required, as long as there is no other reason to withhold methadone. The reasons for the missed doses should be discussed and documented at the next visit. 
• Four consecutive once-daily doses missed: Methadone should be held pending virtual or in-person reassessment, and the remainder of the prescription should be cancelled. Reasons for missed doses should be discussed and documented during the subsequent clinical visit, and patients should receive advice and support for removing barriers to taking methadone doses as prescribed. Following assessment, methadone may be restarted at 50% of previous dose or at 30¬–40mg, whichever is higher (see Table 16). 
• Five or more consecutive once-daily doses missed: Methadone should be held pending virtual or in-person reassessment, and the remainder of the prescription should be cancelled. Reasons for missed doses should be discussed and documented during the subsequent clinical visit, with attention to supporting the patient for better OAT retention. Restart at 30–40mg and titrate as needed according to guidelines. If clinical judgement indicates more aggressive re-titration (e.g., for patients who were on a high dose of methadone within the past 4–7 days), prescribers may seek specialist consultation.  Additionally, patients should discuss the risks of more rapid titration schedules with patients, obtain verbal consent, and plan for frequent re-evaluations until the patient is stable.
   

Table 16. Suggested Protocol for Managing Missed Methadone Doses* 

A3.3.viii Transitioning Patients to Different Commercial Methadone Formulations

1. Discuss potential risks and benefits of the transition with your patient
2. If a shared decision is made to switch to a different commercial methadone formulation, document the discussion, decision, and your clinical rationale carefully in the patient’s medical record
3. Call the patient’s pharmacy and discuss the switch to ensure the pharmacy is aware of the new transition and able to fill the prescription. This will allow for easier transition for your patient
    

The above appendix was developed to support clinical practice using a different methodology from the process utilized for the main body of the guideline. 

The clinical guidance provided in the appendix has been derived through guideline committee consensus following iterative discussions in reference to existing evidence and national and international evidence-based clinical practice guidelines. 

1. The content presented in the appendix is also informed by the opinion of expert reviewers, personal communication with study authors, and a review of position papers and practice bulletins issued by recognized addiction medicine professional organizations and authorities. In addition, where appropriate, Health Canada-approved drug product monographs, and previous and current guidance from the College of Physicians and Surgeons of BC (CPSBC) and Health Canada were consulted to ensure compliance with provincial and national safety regulations and standards for practice.