09.21.2023

Methadone, Beyond the Basics

This month’s case takes a deeper dive into methadone dosing, going beyond the basics to review the use of methadone “as needed,” for analgesia in patients with opioid dependence and as an adjuvant analgesic. For a review of dosing basics, refer to the prior cases: Methadone Conversion: Revisiting a Prior Case and Methadone and the Pediatric Patient: Dosing Guidance.

Enclara pharmacists provide methadone treatment recommendations in accordance with the Enclara Method, revised in early 2021. Adherence ensures consistency in the advice provided to our hospice partners. The Enclara Method aligns with consensus guidelines from pain management experts with some minor differences as outlined below:

Practice (#) Consensus Guidelines1 Enclara Method Comparison
1 Opioid-Naïve dosing for patients on <60mg OME per day Opioid-Naïve dosing for patients on <60mg OME per day Identical
2 Starting dose ≤30-40mg per day regardless of previous opioid dose Starting dose ≤30mg per day regardless of previous opioid dose Enclara uses lower end of range from consensus guidelines1
3 Conversion Ratios:

· <60mg OME: Opioid-naïve dosing

· 60-199mg OME & Age <65 – 10:1

· ≥200mg OME & Age >65 – 20:1

Conversion Ratios:

· <60mg OME: Opioid-naïve dosing

· 60-99mg OME – 4:1

· 100-299mg OME – 8:1

· 300-360mg OME – 12:1

· >360mg OME – Recommend total daily dose of 30mg per day

Enclara uses ratios based on extensive clinical experience dispensing methadone, and incorporates opioid-naïve dosing for <60mg OME and maximum starting dose of 30mg total per day from consensus guidelines1
4 Dose may be increased after 5-7 days of consistent use Dose may be increased after 5-7 days of consistent use or 10-14 days for patients with liver impairment Enclara accounts for longer times to achieve steady state in patients with liver impairment
5 Dose increases of no more than 5-10mg per day depending on total methadone dose Dose increases of no more than 5-10mg per day depending on total methadone dose Identical

Consensus guidelines1 suggest that experienced clinicians, in closely monitored settings, may use more aggressive titration methods. Various equianalgesic dose ratios for methadone conversion exist, ranging from 3:1 to 10:1 at lower doses, and 8:1 to 20:1 at higher doses. For patients on higher doses of opioids, experts recommend using conservative ratios (15:1 to 20:1). For all conversion methods, the higher the oral morphine equivalent (OME), the lower the percentage of methadone is required to provide an equianalgesic effect.

Using Methadone as Needed (PRN)

Methadone is not often recommended for breakthrough pain (i.e., as needed). This is due to the fact that methadone has a long and variable elimination half-life ranging from 5-130 hours and toxicity can result from accumulation. The Enclara Method prefers around-the-clock scheduled administration of methadone, limiting recommendations for as needed usage to scenarios where it is necessary (e.g., true allergy to other opioids). However, it is important to recognize there are several strategies that recommend methadone “as needed” which may be utilized by clinicians. Prescribers may use different strategies for dosing methadone, including the methods outlined in the below table. No methadone dosing method has been proven superior in both safety and efficacy.2

Mercadante Method2 Ayronrinde Method2 Morley-Makin (UK Method)2
1. Stop the current opioid.

2. Calculate the total daily oral morphine equivalent (OME).

3. Determine the oral methadone equivalent dose using the following ratios:

· OME <90mg/day – 4:1

· OME 90-300mg/day – 8:1

· OME >300mg/day – 12:1

4. Divide the calculated oral methadone equivalent by 3 and administer dose every 8 hours. Give 1/6th of the daily methadone dose for breakthrough pain.

5. Titrate based on breakthrough usage as needed based on patient response.

1. Stop the current opioid.

2. Calculate the total daily oral morphine equivalent (OME).

3. Determine the oral methadone equivalent dose using the following ratios:

· OME <100mg/day – 4:1

· OME 101-300mg/day – 5:1

· OME 301-600mg/day – 10:1

· OME 601-800mg/day – 12:1

· OME 801-1000mg/day – 15:1

· OME >1001mg/day – 20:1

4. Divide the calculated oral methadone equivalent by 3 and administer dose every 8 hours. Give 1/6th of the daily methadone dose for breakthrough pain.

5. Titrate based on breakthrough usage as needed based on patient response.

 

1. Stop the current opioid.

2. Calculate the total daily oral morphine equivalent (OME).

3. Determine oral methadone equivalent using a 10:1 morphine to methadone ratio, not exceeding 30mg/dose. This dose is offered every 3 hours as needed.

4. On day 6, the total methadone used on days 4 and 5 are averaged to convert to a twice daily schedule. Give 10-15% of the total daily methadone dose for breakthrough pain, offered every 3 hours as needed.

Methadone for Analgesia in Patients with Opioid Dependence

Methadone is typically dosed once daily for patients with opioid use disorder (OUD) to diminish opioid dependence. Patients taking methadone for OUD may require a higher dose of methadone and more frequent administration for pain management due to a higher level of opioid tolerance. A common strategy when managing pain in patients being treated with methadone for OUD is to administer the total daily dose of methadone in 3 divided doses and titrate the dose as needed.1

Methadone for pain management is dosed 2 or 3 times daily due to its duration of analgesia ranging from 6 to 12 hours. As a reminder, Enclara pharmacists may not dispense methadone for OUD, and may only dispense methadone when indicated for pain management. Patients taking methadone for OUD are commonly managed by the substance abuse treatment centers/clinics where they had previously been receiving care.

Using Methadone as an Adjuvant Analgesic

Methadone may be used as an adjuvant, or co-analgesic, to other opioids because of its unique mechanisms of action, including NMDA-receptor antagonism. Evidence suggest that activation of the NMDA receptor leads to development of opioid tolerance, opioid-resistant neuropathic pain, and hyperalgesia. Although the information is limited, studies suggest that the addition of low-dose methadone may be beneficial in these scenarios. Studies also suggest that patients with a life expectancy shorter than the time to reach steady state may benefit from this treatment strategy. In accordance with this information, the Enclara Method recommends adding doses of 2.5mg every 12 or every 8 hours to the existing pain regimen when utilizing methadone as an adjuvant analgesic.1-3

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References

  1. McPherson ML, Walker KA, Davis MP, Bruera E, et al. Safe and Appropriate Use of Methadone in Hospice and Palliative Care: Expert Consensus White Paper. J Pain Symptom Management. 2019; 57:635-645.
  2. McPherson ML. Demystifying Opioid Conversion Calculations: A Guide to Effective Dosing, 2nd edition. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2018.
  3. Chou R, et al. Methadone Safety: A Clinical Practice Guideline from the American Pain Society and College on Problems of Drug Dependence, in Collaboration with the Heart Rhythm Society. The Journal of Pain. 2014; 15(4): 321-327.