Abstract
Overview
Pharmacology
Levorphanol is a unique opioid, with both similarities to and important differences from methadone (see Fast Facts #75, 86, 171 about methadone pharmacology):
• It is an agonist at the mu, kappa, and delta opioids 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 that is longer than its analgesic duration of action (patients can still have significant tissue and serum levels of levorphanol even after its analgesic effect 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.
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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 1 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 no 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.3–6
Rowbotham and colleagues demonstrated a dose-response curve with oral levorphanol for patients with neuropathic pain; 9 mg daily was more effective than 3 mg.
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As with methadone, levorphanol has not been directly compared with other opioids or adjuvant analgesics for neuropathic pain. • McNulty showed in a recent case series of 31 patients (including hospice patients and chronic nonmalignant pain patients) that 74% of patients had improved pain relief when switching to levorphanol in the setting of inadequately controlled pain on other opioids.
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Dosing
Parenteral levorphanol is twice as potent as the oral formulation. Published oral morphine:oral levorphanol equianalgesic ratios range from 30:4 to 12:1.5,7 The most recent case series looking at switching from other opioids to levorphanol used a staggered morphine:levorphanol ratio, 7 similar in concept to switching to methadone (see Table 1). Available data indicate these ratios are reasonably safe and effective. The medication is dosed every 6 to 12 hours depending on an individual patient's duration of analgesia. Opioid-naïve patients can start with 6 mg orally a day, divided. Levorphanol is available in 2-mg tablets and 2-mg/mL or 2-mg/10mL parenteral formulations.
Cost
Levorphanol is relatively expensive. In 2007, a 2-mg tablet was roughly 10 times more expensive than an equivalent dose tablet of methadone and 2 times more expensive than an equivalent dose of a sustained-release morphine tablet. These relative cost relationships persist. 1
Conclusion
Levorphanol is a unique opioid analgesic, has pharmacologic properties that may make it particularly suited for patients with neuropathic pain, and recent data suggesting it is a safe and effective opioid in patients having inadequate response to other opioids.
Footnotes
Fast Facts and Concepts are edited by Drew A. Rosielle, M.D., Palliative Care Program, University of Minnesota Medical Center–Fairview Health Services, and are published by the End of Life/Palliative Education Resource Center at the Medical College of Wisconsin. For more information write to: 
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Disclaimer: Fast Facts and Concepts provide educational information. This information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Facts cite the use of a product in a dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.