Is levorphanol an opioid? A comprehensive look at this unique analgesic

October 7, 2025 •

4 min read

Yes, levorphanol is a potent synthetic opioid, first developed in the 1940s as an alternative to morphine. It is used to manage moderate to severe pain and is classified as a Schedule II controlled substance in the U.S. due to its high potential for abuse and dependence. Beyond its role as an opioid, the pharmacology of levorphanol is distinct and offers unique benefits for certain patients and pain conditions.

Quick Summary

Levorphanol is a powerful synthetic opioid that works as a potent analgesic for moderate to severe pain. Its unique pharmacology includes agonistic activity at multiple opioid receptors, NMDA receptor antagonism, and inhibition of neurotransmitter reuptake, making it especially effective for neuropathic pain. Its controlled substance classification and comparison to other opioids highlight its specific uses and safety considerations.

Key Points

Is levorphanol an opioid? Yes, it is. It functions as a potent synthetic opioid analgesic for treating moderate to severe pain.
Levorphanol has a unique multimodal mechanism. It is not only an agonist at multiple opioid receptors (µ, κ, δ) but also an NMDA receptor antagonist and a serotonin-norepinephrine reuptake inhibitor.
Its unique pharmacology makes it effective for neuropathic pain. The combination of opioid action, NMDA antagonism, and reuptake inhibition provides broad-spectrum pain relief, particularly for difficult-to-treat neuropathic pain.
It offers advantages over some other long-acting opioids. Unlike methadone, levorphanol does not rely on the variable CYP450 enzyme system for metabolism, minimizing drug-drug interaction risk and avoiding QTc prolongation.
Levorphanol is a Schedule II controlled substance. Like other potent opioids, it carries a high risk for abuse, dependence, and respiratory depression, requiring careful prescription and monitoring.
Administration requires careful consideration due to its long half-life. The potential for accumulation means healthcare providers must adjust administration cautiously to avoid overdose and serious adverse effects.
It is considered an underutilized or 'forgotten' opioid. Despite its unique benefits, its use has declined due to the prevalence of other long-acting opioids.

Understanding levorphanol's mechanism as an opioid

As an opioid, levorphanol's primary mechanism of action involves binding to and activating opioid receptors in the central nervous system, particularly the mu (µ), kappa (κ), and delta (δ) receptors. This agonistic activity alters the perception of pain, leading to its powerful analgesic effects. However, its opioid action is only one part of a more complex pharmacological profile that makes it distinct from many other narcotics.

The broader pharmacological profile

Beyond its function as a multi-receptor opioid agonist, levorphanol also acts as a potent N-methyl-D-aspartate (NMDA) receptor antagonist. The NMDA receptor is a type of glutamate receptor involved in the nervous system's excitability. Its antagonism by levorphanol can contribute to pain relief, particularly in cases of neuropathic pain, which may not respond as effectively to opioids that only target opioid receptors.

Furthermore, levorphanol inhibits the reuptake of serotonin (5-HT) and norepinephrine (NE). This dual action increases the levels of these neurotransmitters in the brain and spinal cord, activating descending pain-inhibitory pathways. This mechanism is thought to further contribute to levorphanol's effectiveness in treating neuropathic pain syndromes.

Comparison of levorphanol with other opioids

Levorphanol's multifaceted mechanism sets it apart from more common opioids like morphine and methadone. While all three are potent, long-acting opioids for moderate to severe pain, their pharmacokinetics and additional receptor activity differ significantly.


Feature	Levorphanol	Morphine	Methadone
Mechanism of action	Agonist at µ, κ, and δ opioid receptors; also NMDA receptor antagonist and inhibits serotonin/norepinephrine reuptake	Primarily an agonist at the µ opioid receptor	Agonist at µ opioid receptors; also NMDA receptor antagonist and inhibits serotonin/norepinephrine reuptake, but with a more complex and unpredictable metabolic profile
Potency (vs. oral morphine)	Approximately 7 times more potent	Baseline for comparison	Can be more potent than morphine, but with highly variable conversion ratios
Half-life	Long (11–16 hours), can accumulate with repeated dosing	Shorter than levorphanol, requires more frequent administration for sustained effect	Long and highly variable, potentially leading to dangerous accumulation and drug interactions
Neuropathic Pain	Highly effective due to its multimodal action, particularly NMDA antagonism and reuptake inhibition	Less effective than levorphanol for this type of pain	Can be effective due to NMDA antagonism, but carries higher risk due to variable metabolism
Metabolism	Metabolized via glucuronidation; not dependent on CYP450 enzymes	Primarily metabolized by CYP450 enzymes and glucuronidation	Extensively metabolized by CYP450 enzymes, leading to significant potential for drug-drug interactions
Cardiac Risk	No known risk of QTc prolongation	Not associated with QTc prolongation	Associated with a risk of QTc prolongation, requiring closer monitoring

The “forgotten opioid” and its clinical relevance

Despite its potent and multidimensional pharmacology, levorphanol is often referred to as the “forgotten opioid” and remains underutilized in modern clinical practice. The decline in its use began with the introduction of long-acting formulations of more familiar opioids like morphine, oxycodone, and fentanyl. However, its unique properties offer significant advantages in specific clinical situations.

Potential clinical advantages of levorphanol

Levorphanol's multi-modal analgesic profile, particularly its effectiveness against neuropathic pain, makes it a valuable option for patients with complex pain syndromes that have proven refractory to other treatments. Its lack of dependence on the cytochrome P450 enzyme system for metabolism also minimizes the risk of drug-drug interactions, which is a major concern with other long-acting opioids like methadone.

Reasons for considering levorphanol:

Neuropathic and mixed pain: Its NMDA antagonism and neurotransmitter reuptake inhibition provide broader pain relief than standard µ-opioid agonists.
Opioid rotation: In cases where patients have developed tolerance to other opioids or experience side effects, switching to levorphanol can provide renewed analgesic efficacy due to incomplete cross-tolerance.
Reduced drug interactions: The metabolism of levorphanol via glucuronidation instead of the CYP450 system reduces the potential for dangerous interactions with many commonly prescribed drugs.

Controlled substance and safe use

As with all potent opioids, levorphanol is a Schedule II controlled substance with a high potential for abuse and dependence. Its long half-life requires careful management to avoid drug accumulation, which can lead to life-threatening respiratory depression. Healthcare providers must exercise caution when prescribing and monitor patients closely. In case of an overdose, a rescue medication like naloxone should be readily available.

Potential side effects and warnings

Patients taking levorphanol may experience a range of side effects common to opioids, including constipation, nausea, vomiting, dizziness, and sedation. Due to its high potency and risk of accumulation, careful individualization of administration is essential. Abrupt discontinuation after chronic use can lead to withdrawal symptoms, so a gradual tapering schedule is recommended.

Conclusion

In summary, is levorphanol an opioid? Yes, and much more. While it is a potent synthetic opioid, its classification as a Schedule II controlled substance and its pharmacological profile extend beyond typical opioid agonism. Its multimodal activity, particularly NMDA receptor antagonism and neurotransmitter reuptake inhibition, provides a unique advantage in treating complex pain syndromes like neuropathic pain. Its distinct metabolic pathway, independent of CYP450 enzymes, also offers a safer alternative for patients with concerns about drug-drug interactions. Despite being a "forgotten opioid," levorphanol remains a valuable option in the pain management arsenal for carefully selected patients.

Frequently Asked Questions

While both are potent opioids, levorphanol is generally more potent and has a longer half-life than morphine. A key distinction is that levorphanol's unique mechanism includes NMDA antagonism and inhibition of serotonin/norepinephrine reuptake, making it more effective for neuropathic pain, whereas morphine primarily works on opioid receptors.

Yes, levorphanol is particularly effective for neuropathic pain. Its multimodal action, which includes NMDA receptor antagonism and the inhibition of serotonin and norepinephrine reuptake, addresses the complex mechanisms underlying this type of pain, offering better relief than opioids that only target opioid receptors.

Levorphanol's common side effects are similar to other opioids (e.g., constipation, nausea, sedation). However, its metabolic pathway, which does not involve the CYP450 enzyme system, means it has a lower risk for certain drug-drug interactions compared to opioids like methadone. It is also not associated with the cardiac QTc prolongation risk seen with methadone.

As a Schedule II controlled substance, levorphanol has a high potential for abuse and dependence, similar to other potent opioids. Careful patient assessment, close monitoring, and responsible prescribing practices are necessary to minimize risks associated with its use.

Yes, levorphanol is a viable option for opioid rotation, especially when a patient's current opioid regimen is ineffective or causes unacceptable side effects. Due to incomplete cross-tolerance, a careful conversion process is required.

Levorphanol is often called the "forgotten opioid" because its use has declined over time, largely replaced by more recently developed or familiar opioids like extended-release morphine, oxycodone, and fentanyl. Many prescribers today are less familiar with its unique pharmacological profile and clinical benefits.

Administration for levorphanol must be individualized and carefully managed, particularly due to its long half-life. It is essential to allow adequate time (around 72 hours) to reach a steady-state before making further adjustments to avoid drug accumulation and respiratory depression.