Levorphanol: Biological Mechanisms, Clinical Uses and Side Effects

Levorphanol is the only commercially available opioid agonist of the morphinan derivatives,¹ which include opioid analgesics, psychoactive drugs, dissociative hallucinogens and cough suppressants.² Pharmacologically, levorphanol is similar to morphine in its actions and analgesic profile.¹ Levorphanol was first approved for use in the United States in 1953, and it is used for moderate to severe pain where an opioid analgesic is indicated.³ Because of its efficacy in analgesia, anesthesia providers should understand the mechanisms of action, clinical uses and side effects of levorphanol.

As a morphine derivative, levorphanol mimics the actions of morphine; however, it is about eight times more potent than morphine.⁴ Levorphanol has agonistic activity mainly at the μ-opioid receptors and some effect at κ- and δ-receptors.¹ Additionally, it acts as a NMDA receptor antagonist and a serotonin-norepinephrine reuptake inhibitor.⁵ Its binding at opioid receptors in the brain and spinal cord cause altered perceptions of pain,⁶ while its antagonism of NMDA receptors make it useful for types of pain that other medications cannot treat, including neuropathic pain.⁵ Specifically, levorphanol’s actions at opioid receptors result in inhibition of intracellular adenylate cyclase, decrease in calcium influx and hyperpolarization of neurons with suppression of action potentials, all of which lower neuronal activity.⁷ Levorphanol undergoes extensive metabolism in the liver into levorphanol-3-glucuronide, an active metabolite,⁸ and is eliminated through urine and feces.⁶ Unlike many other opioids, levorphanol is not metabolized by enzymes of the CYP450 family,⁸ which means that it does not interact with other substances that use the CYP450 enzyme.⁹ While levorphanol’s pharmacokinetics remain slightly unclear, its actions at opioid and other receptors are closely linked to its analgesic effects.

Levorphanol can be used in a variety of clinical settings. It is available in forms that can be administered subcutaneously, intramuscularly, intravenously or orally.¹ Levorphanol’s primary medical use is pain management for moderate to severe pain.⁴ This includes use as a preoperative medication, as a postoperative analgesic and in the management of chronic pain, primarily due to cancer.¹⁰ Typical doses are two milligrams orally every six to eight hours and one to two milligrams parenterally every three to six hours.⁷ Levorphanol can be used as a first-line opioid or during opioid rotation,³ which entails shifting from an original opioid drug due to unfavorable side effects that come with increased dosing.¹¹ Levorphanol has some advantages over morphine, in that its analgesic effects are similar but it has a lower incidence of nausea and vomiting.¹ Additionally, though levorphanol is metabolized by the liver, it has not been linked to serum enzyme elevation or hepatotoxicity.⁷ That said, patients with extensive liver injury should use levorphanol with caution, as they may have increased sensitivity or impaired drug metabolism.⁴ Overall, levorphanol is useful for acute or chronic pain management.

Like other opioids, levorphanol is accompanied with several unpleasant side effects that can occur even in patients who do not have prior liver injury. Some common side effects include confusion, sedation, euphoria, pupil constriction, agitation, itching, sweating, abdominal bloating, nausea, vomiting and constipation.^4,7 More severe adverse effects include respiratory depression and bradycardia (slow heart rate).⁴ Patients who are pregnant should not take this medication, as it can cause fatal withdrawal symptoms in a newborn.¹² Levorphanol can interact with other drugs to create enhanced effects and overdose potential, including tricyclic antidepressants, phenothiazines and ranitidine.⁸ Additionally, levorphanol has a high potential for physical and psychological dependence; hence, it is a controlled substance that is classified as a Schedule II drug by the United States Drug Enforcement Administration (DEA).⁷ Due to its side effects, which range from uncomfortable to severe, anesthesia providers should be cautious when using levorphanol.

Levorphanol is a potent morphine derivative that has actions at opioid and NMDA receptors. It is primarily used to treat moderate to severe pain before or after surgery, or chronic pain due to cancer. Levorphanol is accompanied by several adverse effects, ranging from nausea and vomiting to respiratory depression and substance use disorders. Nonetheless, levorphanol appears to have many advantages over other opioid drugs, including lack of interaction with CYP450 enzymes, high potency and action at NMDA receptors for neuropathic pain.⁹ More research is needed to see if this “forgotten opioid” could be a useful replacement for other opioid drugs currently being prescribed.^3,13

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10.       Levorphanol Tartrate Tablets USP, 2 mg: Rx Only. Columbus, OH: Roxane Laboratories, Inc.; July 2011.

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12.       Healthwise. levorphanol (oral). Michigan Medicine December 12, 2017; https://www.uofmhealth.org/health-library/d00825a1.

13.       Prommer E. Levorphanol: The forgotten opioid. Supportive Care in Cancer. 2007;15(3):259–264.