Background:  Despite its complex pharmacology and its associated stigma from opioid addiction treatment, methadone remains a viable analgesic option for seriously ill adults and children (1-5). Oral methadone is the preferred route of administration and typically can be accomplished via methadone tablets, soluble tablets, or oral solutions of various concentrations.  Still, select patients may be unable to tolerate oral methadone.  This Fast Fact reviews non-oral formulations of methadone. See Fast Facts #75, 86, and 171 for additional methadone prescribing information.

Non-oral Routes:  Of note: methadone has a large volume of distribution and lipophilic properties that causes the medication to accumulate in tissues with repeated doses when administered via any route.  This contributes to its association with QTc prolongation and its notoriously long and variable half-life which can range from 8-59 hours. Clinical circumstances, access availability, and the care setting are important factors when selecting the most appropriate non-oral route of methadone administration. 

• Intravenous (IV): IV methadone can be delivered by intermittent injections, continuous infusion through an indwelling catheter, or a patient-controlled analgesia pump.  However, it has a higher incidence of QTc prolongation than oral methadone, likely due to its preservative, chlorobutanol (6).  Additionally, conversion from other opioids to IV methadone is complex.  Although published dose-conversion guidelines are available for IV methadone (see Table 1 for an example of a more conservative guideline), these guidelines vary and may not be reliable.  Because of these risks, the prescription of IV methadone, especially for opioid-tolerant patients being rotated to IV methadone, should be restricted to pain management or palliative care experts with significant methadone management experience (7,8). Other important clinical pearls about IV methadone include: 
  • IV onset of analgesia occurs in 10-20 minutes vs 30-60 minutes after oral administration.
  • For opioid-naïve patients, the starting dose of IV methadone is 1.25 to 2.5 mg every 8-12 hours.
  • Discontinue all other scheduled opioids when initiating IV methadone (7,8).
  • The oral to parenteral ratio is 2:1. Therefore 10 mg oral methadone = 5 mg IV methadone. Due to variations in bioavailability, there is no consensus to support one parenteral to oral ratio, although many experts recommend a ratio between 1:1 and 1:1.5.
  • The average wholesale price (AWP) of IV methadone is more expensive than oral tablets.  For example, the AWP of IV methadone is $420.09 for a 20-mL syringe (10 mg/mL) compared to $32.15 for 100 tablets of 5 mg of methadone (9).
• Rectal: When administered rectally, methadone tablets or capsules are typically used, but compounded suppositories and enemas have also been described (10,11). Although associated with local discomfort, especially with repeated dosing, rectal administration has the advantage of preventing the need for infusions systems.  Furthermore, rectal methadone is often absorbed within 30 minutes and has a simple and reliable oral to rectal dose ratio of 1:1.  Cost, duration of action, and half-life are essentially equivalent with oral methadone (10,11).
• Subcutaneous (SC): In palliative care or hospice settings, IV methadone solution can be given SC in patients without an indwelling IV catheter. SC methadone, therefore, has similar risks and costs as IV methadone. Additional considerations include:
  • SC lines should be primed with the concentration of methadone that is being infused.
  • SC methadone has been associated with subcutaneous erythema and edema.  However, if appropriate precautions are taken such as rotation of the infusion site every one or two days; diluting the intravenous solution to 5-10 mg/mL at a rate of 2-3 mL/hr; and/or a one-time co-administration of dexamethasone 1-2 mg or local hyaluronidase 150 units, these reactions are usually mild and manageable (12,13). 
• Enteric tubes:  Unlike many long acting opioids, methadone can be given as a solution or a crushed tablet via a nasogastric or gastronomy tube without compromising effectiveness or duration of action. 
• Transmucosal:  A feasibility study suggested that concentrated oral solution (10 mg/mL) can be used for sublingual or buccal administration effectively (14).  Larger studies are still needed and the dose may be limited by volume constraints (1-1.5 mL) (15,16).
• Other:  The use of preservative-free parental methadone has been described for epidural administration in the post-operative setting (17,18). However, it may not offer substantial advantage over other routes considering its rapid systemic accumulation.  There are also case reports of compounded topical methadone. Larger investigations are needed before either of these routes should be widely prescribed (19).

References:

1. Bruera E, Sweeney C.  Methadone Use in Cancer Patients with Pain: A Review.  J of Pall Med 2002; 5(1): 127-138.
2. Fisher K, Stiles C and Hagen NA. Characterization of the early pharmacodynamic profile of oral methadone for cancer-related breakthrough pain: a pilot study.J Pain Symptom Manage2004; 28: 619–625.
3. Vigano A, Fan D, Bruera E. Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators.  Pain 1996;67:115-119.
4. Anglhelscu DL, Faughnan LG, et al.  Methadone use in children and young adults at a cancer center: a retrospective study.  J Opioid Manag 2011; 7(5):353-361
5. Fife A, Posteier A, et al.  Methadone conversion in infants and children: retrospective cohort study of 199 pediatric inpatients.  J Opioid Manag 2016; 12(2):123-30.
6. Kornick CA, Kilborn MJ, Santiago-Palma, et al. QTc interval prolongation associated with intravenous methadone. Pain. 2003; 105(3):499-506.
7. Fitzgibbon DR, Ready LB. Intravenous high-dose methadone administered by patient controlled analgesia and continuous infusion for the treatment of cancer pain refractory to high-dose morphine. Pain. 1997; 73(2):259-261.
8. Santiago-Palma J, et al.  Intravenous methadone in the management of chronic cancer pain: safe and effective starting doses when substituting methadone for fentanyl. Cancer 2001;92:1919-25.
9. Wolters Kluwer Clinical Drug Information, Inc. “Methadone”. Lexi‐Comp online database. Jan. 2018, https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7262. Accessed Jan. 2018.
10. Ripamonti C, et al.  Rectal methadone in cancer patients with pain.  A preliminary clinical and pharmacokinetic study.  Ann Oncol 1995;6:841-3
11. Wantaanabe S; Belzile M, et al.  Capsules and suppositories of methadone for patients cancer pain: clinical and economic considerations. Cancer Treat Reve 1996;22:131-6
12. Makin M, Morley J.  Subcutaneous methadone in terminally ill patients. J Pain Symptom Manage 2000;19:237. 
13. Mathew P. Storey P.  Subcutaneous methadone in terminally ill patients: manageable local toxicity. J Pain Symptom Manage 1999; 18:49-52
14. Hagen NA, Mouline DE, et al.  A formal feasibility study of sublingual methadone for breakthrough cancer pain. Palliative Medicine 2010;24(7): 696-706
15. Spaner D. Effectiveness of the buccal mucosa route for methadone administration at the end of life. Journal of Palliative Care Medicine. 2014:17(11): 1262-1265.
16. Hagen N, Fisher K, Stiles C. Sublingual methadone for the management of cancer-related breakthrough pain: a pilot study. Journal of Palliative Medicine. 2007:10(2):331-337.
17. Shir Y, Shapira SS, et al. Continuous epidural methadone treatment for cancer pain.Clin J Pain 1991;7:339–341
18. Wang JM, Knarr DC, et al. Continuous epidural methadone for management of postoperative pain after lower abdominal surgery. Reg Anesth 1992; 17:26–28
19. Love R, Bourgeois K. Topical methadone: an alternative for pain control in end-of-life management. Journal of Palliative Medicine. 2014;17(2): 128.

Author Affiliations: Ohio Health, Columbus, OH; Medical College of Wisconsin, Milwaukee, WI

Version History: First electronically published in June 2018

Conflicts of Interests: None reported