Indian Journal of Palliative Care
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Table of Contents 
Year : 2019  |  Volume : 25  |  Issue : 3  |  Page : 483-484

Levorphanol: Rewinding an old, bygone multimodal opioid analgesic!

Department of Anaesthesiology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India

Date of Web Publication17-Jul-2019

Correspondence Address:
Dr. Abhijit S Nair
Department of Anaesthesiology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPC.IJPC_11_19

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How to cite this article:
Nair AS, Upputuri O, Mantha SS, Rayani BK. Levorphanol: Rewinding an old, bygone multimodal opioid analgesic!. Indian J Palliat Care 2019;25:483-4

How to cite this URL:
Nair AS, Upputuri O, Mantha SS, Rayani BK. Levorphanol: Rewinding an old, bygone multimodal opioid analgesic!. Indian J Palliat Care [serial online] 2019 [cited 2020 Aug 9];25:483-4. Available from:


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)

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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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  References Top

Prommer E. Levorphanol: The forgotten opioid. Support Care Cancer 2007;15:259-64.  Back to cited text no. 1
Pham TC, Fudin J, Raffa RB. Is levorphanol a better option than methadone? Pain Med 2015;16:1673-9.  Back to cited text no. 2
Arora A, Williams K. Problem based review: The patient taking methadone. Acute Med 2013;12:51-4.  Back to cited text no. 3
Reddy A, Ng A, Mallipeddi T, Bruera E. Levorphanol for treatment of intractable neuropathic pain in cancer patients. J Palliat Med 2018;21:399-402.  Back to cited text no. 4
Gudin J, Fudin J, Nalamachu S. Levorphanol use: Past, present and future. Postgrad Med 2016;128:46-53.  Back to cited text no. 5
Prommer E. Levorphanol: Revisiting an underutilized analgesic. Palliat Care 2014;8:7-10.  Back to cited text no. 6


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