Despite its complex pharmacology and its associated stigma from opioid addiction treatment, methadone remains a viable analgesic option for seriously ill adults and children. Oral methadone is the preferred route of administration and can be achieved via methadone tablets, soluble tablets, or oral solutions of various concentrations. However, limited patients may not tolerate oral methadone.

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.

Non-oral routes.
• Intravenous (IV): it can be delivered by intermittent injections, continuous infusion through an indwelling catheter, or a patient-controlled analgesia pump. It has a higher incidence of QTc prolongation than oral methadone. Dose-conversion guidelines available for conversion from other opioids to IV methadone vary and may not be reliable. Because of these risks, the prescription of IV methadone should be restricted to experts with significant methadone management experience. Important clinical tips:
- IV onset of analgesia occurs in 10-20 minutes or 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.
- The oral to parenteral ratio is 2:1 - 10 mg oral methadone = 5 mg IV methadone.

• Rectal: tablets or capsules are typically used, but also compounded suppositories and enemas. Rectal administration prevents the need for infusions systems; rectal methadone is often absorbed within 30 minutes and has a reliable oral to rectal dose ratio of 1:1

• Subcutaneous (SC): IV methadone solution can be given SC in patients without an indwelling IV catheter. Considerations:
- SC lines should be primed with the concentration of methadone that is being infused.
- SC methadone has been associated with subcutaneous erythema and edema. If the infusion site is rotated every one or two days; the intravenous solution is diluted to 5-10 mg/mL at a rate of 2-3 mL/hr.; and/or dexamethasone 1-2 mg or local hyaluronidase 150 units are co-administered, these reactions are usually mild and manageable.

• Enteric tubes: it can be given as a solution or a crushed tablet via a nasogastric or gastrostomy tube without compromising effectiveness or duration of action.

• Transmucosal: Concentrated oral solution (10 mg/mL) can be used for sublingual or buccal administration effectively.

• Other: The use of preservative-free parental methadone has been described for epidural administration in the post-operative setting. There are also case reports of compounded topical methadone.

See reference for more information about dose conversion guidelines

Adapted from Elsass K, Marks S, Malone N. Non-oral routes of methadone for analgesia in Palliative Care. Palliative Care Network of Wisconsin. Fast facts and concepts #358. Internet. Accessed on December 27, 2018.