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Letters to Editor
25 (
); 483-484

Levorphanol: Rewinding an Old, Bygone Multimodal Opioid Analgesic!

Department of Anaesthesiology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India
Address for correspondence: Dr. Abhijit S Nair, Department of Anaesthesiology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad - 500 034, Telangana, India. E-mail:

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

This article was originally published by Wolters Kluwer - Medknow and was migrated to Scientific Scholar after the change of Publisher; therefore Scientific Scholar has no control over the quality or content of this article.


Levorphanol is a synthetic opioid racemic mixture “levo-3-hydroxy-N-methylmorphinan,” which was developed in the 1940s as an opioid agonist [Figure 1]. It was approved for use in the United States in the year 1953. It is also referred to as “The Forgotten Opioid” as levorphanol is neither prescribed nor known to many physicians.[1] As per the WHO, levorphanol is a step 3 opioid and is considered eight times potent than morphine (2 mg levorphanol is equivalent to 15 mg morphine). Along with mu-receptor agonist properties, levorphanol has delta, kappa1, and kappa 3 receptor agonist properties. It is an N-methyl-D-aspartate (NMDA) receptor antagonist and also inhibits reuptake of norepinephrine and serotonin.

Figure 1: Chemical structure of levorphanol. (Figure source: National Center for Biotechnology Information. PubChem Compound Database; CID = 5359272, accessed January 26, 2019)

Pharmacologically, levorphanol appears similar to methadone. Pham et al. compared the basic and clinical pharmacology of methadone with levorphanol and found that levorphanol is more potent as an NMDA antagonist, has a greater affinity toward delta and kappa opioid receptors, has a shorter plasma half-life (11–16 h) with a longer duration of action (up to 11 h), and has no significant CYP450 interactions or risks of serious QTc prolongation.[2] Levorphanol bypasses first-pass metabolism in the liver as cytochrome enzymes have no role in its metabolism; therefore this does not lead to serious drug interactions such as methadone. It undergoes Phase II metabolism by glucuronidation to an active metabolite levorphanol-3-glucuronide which is excreted by kidneys. Therefore, in renal insufficiency/failure, it can accumulate and can lead to adverse events.

The issues with methadone are its unpredictable pharmacokinetics and pharmacodynamics and QTc prolongation, leading to life-threatening arrhythmias. Methadone is a racemic mixture of R-and S-enantiomers which is extensively metabolized by several isoforms of cytochrome 450 (CYP450) enzymes. Unpredictable genetic polymorphisms affect metabolism, clearance, and susceptibility to drug interaction, which leads to inadequate analgesia, respiratory depression, opioid withdrawal syndromes, drug accumulation, and toxicity.[3] Moreover, methadone does not have any significant effect on delta and kappa opioid receptors.

Reddy et al. felt that due to its multimodal mechanism of action, levorphanol is a drug which has been useful in treating chronic pain conditions such as phantom limb pain which is otherwise difficult to treat pharmacologically with regular medications.[4] Thus, levorphanol can be used in several chronic pain conditions such as cancer pain, chronic neuropathic pain, postherpetic neuralgia, spinal cord injury, central poststroke pain, fibromyalgia, and multiple sclerosis. It can be used orally, intramuscularly, and subcutaneously. Sublingual absorption is inconsistent and not recommended.[5] The recommended dosing is orally 6 mg/day in 3–4 divided doses, 1 mg every 6–8 h intravenously, and 1–2 mg subcutaneously/intramuscularly every 6–8 h. It has been used safely in elderly patients as well.[6] Due to its long half-life, the drug can get accumulated after prolonged use, especially in patients with compromised renal function.

In conclusion, levorphanol appears to be a potent, broad-spectrum analgesic with a better safety profile due to its predictive pharmacokinetics without the need of any monitoring. It can be used in patients who are suffering with chronic pain of any etiology who have not benefitted with morphine, antidepressants, gabapentinoids, and other miscellaneous group of drugs.

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Conflicts of interest

There are no conflicts of interest.


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