FROM: END OF LIFE/PALLIATIVE EDUCATION RESOURCE CENTER

#240 Levorphanol

Author: Jane Loitman MD

Pharmacology: Levorphanol is a unique opioid, with both similarities to and important differences from methadone (See Fast Facts #75, 86, 171).

- Levorphanol is an agonist at the mu, kappa and delta opioid receptors, an NMDA antagonist, and a monoamine reuptake inhibitor of norepinephrine and serotonin.

- Similar to methadone, levorphanol has a long half-life, and an elimination half-life which is longer than its analgesic duration of action (patients can still have significant tissue and serum levels of levorphanol even after its analgesic effects has waned). Levorphanol’s analgesic half-life is comparable to methadone’s (6-8 hours), however its elimination half-life of ~11 hours is more predictable than methadone’s. Accumulation and toxicity can occur if levorphanol’s dose is increased too quickly, without waiting for steady-state to occur (at ~5 elimination half-lives or 2-3 days).

- Drug concentrations peak 30 minutes after parenteral injection and one hour after oral doses.

- An oral dose undergoes approximately 50% first-pass clearance.

- Levorphanol is metabolized via conjugation to a 3-glucuronide; the cytochrome P450 system does not appear to be involved. It has no known active metabolites. Side effects are similar to other opioids. There are not documented studies showing QT interval prolongation or Torsades de Pointes.

Clinical uses: Several properties of levorphanol make it of interest as an analgesic.

- Similar to methadone, levorphanol’s longer duration of action is not affected by crushing, and it can be safely administered down a gastrostomy tube.

- Levorphanol lacks the stigma associated with methadone and its use in addiction medicine.

- Levorphanol is a strong NMDA receptor antagonist which has generated interest in it as a treatment for neuropathic pain. Limited research has supported its role as an effective treatment for neuropathic pain, allodynia, and hyperalgesia.

Dosing: Parenteral levorphanol is twice as potent as the oral formulation. Published oral morphine: oral levorphanol equianalgesic ratios range from 30:4 to 12:1. The most recent case series looking at switching from other opioids to levorphanol used a staggered morphine:levorphanol ratio, similar in concept to switching to methadone. Available data indicate there rations are reasonably safe and effective. The medication start with 6mg orally a day, divided. Levorphanol is available in 2 mg tablets and 2m/ml or 2mg/10ml parenteral formuations.

TABLE: Conversion to Levorphanol

Baseline 24 hr oral morphine equivalent	Morphine:levorphanol ratio
<100 mg	12:1 (e.g. 60 mg PO morphine = 5 mg PO levorphanol/24h)
100-299 mg	15:1
300-599 mg	20:1
600-799 mg	25:1
>800 mg	No data

Cost: Levorphanol is relatively expensive. A 2 mg tablet is roughly 10 times more expensive than an equivalent dose table of methadone and 2 times more expensive than an equivalent dose of a sustained-release morphine tablet.

For references please go to: www.eperc.mcw.edu/fastFact/ff_240/htm