This month, we revisit one of the first Palliative Pearls cases published in March 2016. We have incorporated guidance from recently published literature along with revisions for your enrichment.
CT is a 62-year-old woman with metastatic breast cancer experiencing aching pain in her chest with shooting pains down her arm that has become increasingly uncontrolled over the past 2 weeks. She also has oral thrush that developed a few days ago. She has a history of asthma, exacerbated by her breast cancer, and recently completed a 6-day steroid taper. You note that she was treated with fluconazole 2 months ago for a prior case of oral thrush. You decide to recommend methadone to better manage her pain and an antifungal course. What is your starting dose of methadone? Which antifungal do you recommend?
Current pain medications:
- Morphine sustained-release 160mg PO Q12H
- Morphine oral solution 20mg/mL; 1.5ml (30mg) PO Q4H PRN (~6 doses per day; pain decreases from 8 to 5 rating on VAS after each breakthrough dose)
Methadone is active at mu-opioid and NMDA receptors and inhibits the reuptake of serotonin and norepinephrine. These actions make methadone ideal for patients experiencing mixed pain, including somatic (muscle, bone, and tissue), visceral (organ) and neuropathic pain. Methadone therapy is also inexpensive, and its unique pharmacokinetics make routine use of even the oral liquid formulations useful for patients with long-acting pain management needs.
Specific enzymes are responsible for methadone metabolism and can be affected by a number of medications. Methadone is metabolized in the intestines as well as the liver by the cytochrome P-450 enzyme system (CYP450), primarily by enzymes CYP2B6 and CYP3A4. Medications that induce (speed up or increase) or inhibit (slow down or decrease) metabolism of methadone do so by affecting one of these enzymes. The Indiana University School of Medicine has a useful website listing medications considered inducers and inhibitors of specific CYP enzymes for reference.1,2
Methadone may prolong the QTc interval, resulting in a potentially fatal cardiac arrhythmia, torsades de points (TdP). This potential is increased when methadone is used in patients with risk factors for QTc interval prolongation and/or taking other medications that also prolong the QTc interval. The lists below are not all-inclusive however the CredibleMeds online resource hosts in-depth listings and may be referenced for additional information.3
Risk factors for QTc prolongation include:1,3
- Hypokalemia or hypomagnesemia
- Impaired liver function
- Structural heart disease
- Genetic predisposition
Examples of medications with known risk for TdP:3
- Conventional antipsychotics (e.g., haloperidol)
- Escitalopram (Lexapro®) and citalopram (Celexa®)
- Fluconazole (Diflucan®)
- Fluoroquinolone antibiotics (e.g., ciprofloxacin)
- Macrolide antibiotics (e.g., azithromycin)
- Ondansetron (Zofran®)
In opioid naïve patients, consider starting methadone at a low dose, 2.5mg orally every 8 hours.1,4 While this is conservative, and typically a safe starting dose, in older and debilitated patients, an extended frequency interval of “every 12 hours” may be necessary.
There are countless methods to estimate methadone dosing needs in patients taking other opioids. The method used in the case below is conservative and was developed for use as a standard method for a hospice pharmacy clinical consult service. Several published methods were incorporated in its development with the objective of producing consistent recommendations from the pharmacy team. This method is not superior to other methods that can be used. No matter the method chosen, the key steps for safe and effective methadone dosing include starting low with slow titration, allowing time for the initial dose or increase in dose to come to its full effect (about 5-7 days) before making a change and monitoring.
Methadone is not often recommended as the breakthrough medication to complement a scheduled methadone regimen as this has potential for excess methadone accumulation and unintentional overdose.1 Short-acting opioids such as morphine, oxycodone or hydromorphone are beneficial when initiating methadone, allowing methadone to come to steady-state (full effect) without the interference of unscheduled breakthrough medication.
- CT is experiencing uncontrolled, somatic pain (muscle aches and pain) and neuropathic pain (shooting). Methadone can manage different types of pain.
- CT has oral thrush likely due to corticosteroid use. A potential drug-drug interaction exists between azole antifungals, such as fluconazole (Diflucan®), which causes increased concentrations of methadone and additionally prolongs the QTc interval. Nystatin suspension is considered a safer alternative.
Total Daily Usage of Current Opioids: Morphine PO 500mg/day that, until recently, controlled her pain
New Opioid Requested: Methadone tablets
New Dose and Interval: Using a conversion ratio based on milligrams of oral morphine equivalents (provided below), 500mg/day of Morphine is deemed equivalent to 33mg/day of Methadone, using a 15:1 conversion ratio. Place an order for Methadone 10mg tablet; 1 tablet PO Q8H. Maintain current breakthrough regimen with Morphine concentrate with increased dose of 2ml (60mg) PO Q4H PRN.
- Daily Oral Morphine Milligram Equivalents (OME) = Morphine: Methadone
- <30mg OME = 2:1 (2mg morphine = 1mg methadone)
- 30-90mg OME = 4:1 (4mg morphine = 1mg methadone)
- 100-299mg OME = 8.1 (8mg morphine = 1mg methadone)
- 300-499mg OME = 12:1 (12mg morphine = 1mg methadone)
- 500-999mg OME = 15:1 (15mg morphine = 1mg methadone)
- 1,000-1,999mg OME = 20:1 (20mg morphine = 1mg methadone)
- 2,000-3,999mg OME = 30:1 (30mg morphine = 1mg methadone)
Oral thrush therapy: Nystatin suspension; Swish and swallow 5ml PO Q.I.D. x 10 days
Monitor for therapeutic effectiveness (pain severity rating, breakthrough doses used) and toxicity (increased sedation or confusion, difficulty arousing patient)
Assess, and Titrate dose if needed, after 5-7 days. Note: more frequent dose increases may result in adverse effects/overdose.
CONSIDERATIONS IN HOSPICE/PALLIATIVE CARE
Appropriate candidates for methadone include those with:1
- A true morphine allergy
- Financial constraints with other opioid therapy
- High pill burden or opioid-induced adverse effects due to high dose opioids (e.g., hallucinations, myoclonus)
- Uncontrolled pain despite increasing opioid doses and opioid rotation trials
- Significant renal impairment
- Neuropathic pain
- Difficulty swallowing or presence of a PEG tube in a patient that requires long-acting pain medication to manage pain (with routine dosing methadone can take on long-acting properties even with the liquid formulation).
Patients who may NOT be appropriate candidates includes those with:1
- Limited prognosis
- Taking several medications that interact with methadone
- A history of syncope, arrhythmias, QTc prolongation
- Poor cognition
- Adherence issues to medication
- No stable practitioner to oversee methadone titration and adjustments
- No caregiver or an unreliable caregiver to assist with monitoring
Hospice patients often present with mixed pain making methadone ideal in appropriate candidates. They have frequently changing medication profiles making it important to review often for potential drug-drug and drug-disease interactions and before initiating any new therapy.
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FOR ADDITIONAL INFORMATION ON THIS TOPIC, PLEASE REVIEW THE FOLLOWING:
Enclara Pharmacia’s On Demand Educational Webinar, “Methadone: A Review for Hospice Clinicians”. Click here to log in.
- McPherson ML. Methadone: A Complex and Challenging Analgesic, But It’s Worth It! In: Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing, 2nd Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2018.
- Indiana University School of Medicine, Department of Medicine. Clinical Pharmacology Drug Interactions: Cytochrome P450 Drug Interactions Flockhart Table™. Accessed June 4, 2019. Available from: https://drug-interactions.medicine.iu.edu/main-table.aspx
- Resources for Healthcare Providers: QT Drug Lists. Accessed June 4, 2019. Available from: https://crediblemeds.org/healthcare-providers/
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