01.23.2025

Methadone as a Coanalgesic

This month’s case expands upon methadone as an adjuvant analgesic, or coanalgesic, a concept introduced in Methadone, Beyond the Basics and a common topic of clinical consultations with Enclara pharmacists. We will begin with a patient case and proceed with methadone considerations, connecting patient case attributes to the medication’s use as a coanalgesic. 

PATIENT CASE 

A hospice physician and pharmacist collaborate on treatment planning for a 68-year-old patient with a primary diagnosis of head and neck cancer with no other significant comorbidities or drug allergies. The patient is a readmission to hospice care, currently being discharged from the hospital to their daughter’s home on a continuous hydromorphone infusion with PCA pump.  

The patient is experiencing mixed pain (somatic and neuropathic) symptoms with partial relief of pain (rates 5 out of 10 on visual analog scale after a bolus dose) on the regimen below.  

  • Hydromorphone (Dilaudid®) solution for injection; infuse 18 mg intravenously via port every 1 hour continuously, with a 4.5 mg bolus every 15 minutes as needed  
  • The physician cannot quantify the number of boluses per day at this time 
  • No other analgesics have been prescribed except acetaminophen as needed for fever 

Considering the mixed pain assessed, partial pain relief, and preference for a comparatively easier method of administration (oral) for the patient and caregiver at home, the physician asks for a recommendation to convert the hydromorphone infusion to oral methadone. Before calculating a starting dose, the pharmacist asks about patient prognosis and learns that life expectancy is “days.” They also learn that the patient’s port is patent, and the caregiver/daughter is prepared to maintain the port and hydromorphone infusion at home if that is the recommended therapy. 

METHADONE COANALGESIA CONSIDERATIONS 

Methadone is a unique and useful analgesic however clinicians may hesitate to use it due to concerns of drug-drug and drug-disease interactions, and differing models for dosing. Careful consideration of patient-specific attributes and a thorough pain assessment is critical for safe and effective use as a coanalgesic.  

Unique & Useful 

  • Methadone is active at mu-opioid and NMDA receptors, positioning it as a useful addition for patients experiencing mixed pain with partial relief despite dose titration of the current opioid (e.g., morphine, hydromorphone) 
  • Unique pharmacokinetics make the use of oral methadone liquid formulations useful for patients with long-acting pain medication needs and difficulty swallowing as well as those with an enteral tube for medication administration 
  • When the current opioid causes adverse effects (e.g., hyperalgesia and myoclonus), methadone addition may allow for dose reduction, lessening the adverse effect without sacrificing pain control  
  • Methadone is inexpensive 

Concerns & Pearls 

  • Methadone use is associated with a risk for QTc interval prolongation, which may result in the fatal cardiac arrhythmia, torsades de points (TdP).¹ Although this adverse effect has the potential to occur at any dose, it is most prevalent at methadone doses greater than 200 mg per day.  
  • Methadone coanalgesic doses are much lower and mirror opioid-naïve dosing 
  • It is recommended to wait 5 to 7 days after methadone initiation or dose increase before adjusting the daily dose any further, allowing methadone to reach its steady state (i.e., full effect/benefit).2,3 Adjusting the dose earlier is associated with methadone accumulation and increased risk of adverse effects such as sedation and respiratory depression.  
  • Initiating methadone as the sole opioid analgesic is not appropriate for patients with life expectancies shorter than methadone’s time to steady state and is considered inadequate pain management. However, methadone use as a coanalgesic may complement an existing opioid regimen despite limited life expectancy, enhancing pain management. It does not replace the current opioid as the sole opioid, it is added on at a low dose. 

METHADONE COANALGESIA IN THE LITERATURE 

Some studies suggest that activation of the NMDA receptor leads to development of opioid tolerance, opioid-resistant neuropathic pain, and hyperalgesia.4,5 Although evidence is limited, it suggests that the addition of low-dose methadone may be beneficial in these scenarios due to its NMDA-receptor antagonism. (See example studies below6,7) Patients with a life expectancy shorter than the time to reach steady state may benefit from this treatment strategy although additional research is needed to determine ideal approaches for using methadone as a coanalgesic.2,3,8

  • Courtemanche F, et al (2016)6 evaluated the impact of methadone as a coanalgesic on pain control in 146 patients with cancer receiving chronic opioid therapy. The median oral morphine dose was 120 mg per day, and a median dose of 3 mg oral methadone was added to the medication regimen. Results showed that seventy-two of the 146 patients (49.3%) had at least a 30% reduction in pain intensity, with a median time of seven days to first significant response.2,3
  • Wallace E, et al (2013)7 evaluated oral methadone addition to the opioid regimen of 20 patients with cancer in an outpatient palliative care clinic. The mean daily routine oral morphine equivalent was 338 ± 217.8 mg/day at initiation of the study, and 332 ± 191 mg/day at evaluation. The mean dose of methadone at initiation was 4.4 ± 1.4 mg/day, and 15.5 ±5.9 mg/day at evaluation. Eight patients (40%) achieved a decrease in pain score of two or more points at one month, and an additional seven patients (35%) had a decrease in pain score of two or more points at their last assessment, prior to one month.2,3

RECOMMENDATIONS 

Coanalgesic Dosing 

Enclara pharmacists recommend adding low doses of methadone when indicated as a coanalgesic.2,3,8 This dosing approach is also used when methadone is initiated in opioid naïve patients.

  • Adult patients – 2.5mg orally every 8 or 12 hours (should not exceed 7.5 mg per day as a starting dose) 
  • Pediatric patients – 0.1mg/kg (maximum of 5 mg per dose) every 8 hours 

Patient Case Revisited 

The current hydromorphone infusion rate of 18 mg per hour equals 432 mg of intravenous hydromorphone per day. This is equivalent to 5,400 mg oral morphine equivalents (OME). Considering the mixed pain assessed, partial pain relief with high dose hydromorphone infusion, and life expectancy of “days,” the pharmacist recommends the following: 

  1. Do not convert the hydromorphone infusion completely to oral methadone. Methadone needs 5 to 7 days of routine dosing to reach steady state and patient prognosis is “days”. 
  2. Continue hydromorphone infusion 
  3. Add methadone around-the-clock as a coanalgesic using opioid naïve dosing 
  4. Quantify hydromorphone bolus doses over 48 hours and adjust basal rate of infusion accordingly 

The hospice physician continues the hydromorphone infusion at 18 mg per hour with 4.5 mg boluses every 15 minutes as needed for breakthrough pain and prescribes a methadone 10mg/ml oral liquid regimen of 2.5 mg every 8 hours.  

Two days later, the hospice nurse contacts the pharmacist for a calculation double-check for adjusting the hydromorphone infusion basal rate. The patient’s pain is “much improved” since starting methadone, using an average of four boluses of hydromorphone per day, and with a pain rating of 2 out of 10 on a visual analog scale after each bolus dose as opposed to a rating of 5 prior to methadone initiation. The infusion basal rate is increased to 19 mg per hour with the same bolus dosing regimen. Methadone oral liquid is continued unchanged. The patient passed away comfortably 4 days later. 

In cases in which life expectancy is longer (e.g., months) and after methadone reaches steady state, there may be consideration for empirically increasing the methadone dose in small increments while tapering down on the hydromorphone infusion. It is important to note that methadone as a coanalgesic should not exceed 7.5 mg per day at initiation or as a starting dose; if pain assessment dictates the need to increase the methadone daily dose, the other opioid dose must be decreased accordingly. 

LEARN MORE ABOUT METHADONE 

Enclara Palliative Pearls 

Palliative Care Network of Wisconsin Fast Facts 

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REFERENCES 

  1. CredibleMeds. Resources for Healthcare Providers: QT Drug Lists. Accessed Jan 10, 2025. Available from: https://crediblemeds.org/healthcare-providers/   
  2. McPherson ML. Methadone: A Complex and Challenging Analgesic, But It’s Worth It! In: Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing, 2nd ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2018.  
  3. 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 Manage 2019;57:635-645. 
  4. Reddy A, Yennurajalingam S, Bruera E. Dual opioid therapy using methadone as a coanalgesic. Expert Opin Drug Saf 2015;14:181-182. 
  5. Furst P, Lundstrom S, Klepstad P, Runesdotter S, Strang P. Improved pain control in terminally ill cancer patients by introducing low-dose oral methadone in addition to ongoing opioid treatment. J Palliat Med 2018;21:177-181. 
  6. Courtemanche F, Dao D, Gagne F, Tremblay L, Neron A. Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med 2016;19:972-978. 
  7. Wallace E, Ridley J, Bryson J, Mak E, Zimmermann C. Addition of methadone to another opioid in the management of moderate to severe cancer pain: a case series. J Palliat Med 2013;16:305-309. 
  8. 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.