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Levorphanol: An Optimal Choice for Opioid Rotation

The forgotten opioid may be a “new” treatment for chronic pain syndromes that are refractory to other opioids, as well as a favored alternative to methadone, as it has a lower potential for drug-drug interactions, and has no reports of QT interval prolongation.
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Levorphanol, termed “the forgotten opioid,” is a potent opioid analgesic available for the treatment of moderate to severe pain. It was first approved in 1953, and it has a wide range of ascending and descending pain pathway receptor-mediated pharmacological activities, including mu, delta, and kappa (kappa 1 and 3) opioid agonism; N-methyl-D-aspartate (NMDA) antagonism; and reuptake inhibition of both norepinephrine and serotonin.1

Levorphanol’s multimodal profile is unique amongst the class, and may make it an optimal agent both for initial use, as well as for opioid rotation. Levorphanol may address pain that is refractory to other opioid analgesics, such as central and neuropathic pain syndromes, and may also play a role in addressing opioid-induced hyperalgesia (OIH).2 This review will discuss some of the benefits of levorphanol over other opioids and its potential use in difficult-to-treat pain syndromes.

Pharmacokinetics of Levorphanol

Levorphanol (levo-3-hydroxy-N-methylmorphinan) is a dehydroxylated phenanthrene opioid with a chemical structure similar to morphine. In 1983, the pharmacokinetic (PK) profile of levorphanol was studied in 13 chronic pain patients age 20 to 60 years following intravenous (IV), intramuscular (IM), and oral administration.2 Levorphanol was found to be readily absorbed orally, is 40% protein bound, and has a longer half-life (11 to 16 hours) and duration of analgesia (6 to 15 hours) than most opioids. Levorphanol undergoes rapid hepatic conversion to an inactive glucuronide,3 which reaches concentrations 5 to 10 times that of levorphanol, and is eliminated relatively slowly by renal excretion. Data suggest that the glucuronide metabolite is slowly reconverted to free levorphanol, thereby establishing equilibrium between the active drug and the inactive glucuronide metabolite.2,4 The large pool of the slowly excreted glucuronide may serve as a substrate for regenerating free levorphanol, leading to its longer half-life.

Levorphanol is not metabolized by cytochrome P450 (CYP) enzymes or dependent on p-glycoprotein in the gut for absorption, thus eliminating the potential for genetic variations in metabolism, as well as a greater potential for drug-drug and drug-food interactions via those 2 mechanisms. Other opioids that do not require CYP metabolism include hydromorphone, morphine, oxymorphone, and tapentadol—but all of these are metabolized by Phase 2-type reactions, primarily glucuronidation.5 (See Common CYP450 Pharmacokinetic Opioid-Drug Interactions: What Clinicians Need To Know.)

Adverse Events

The prescribing information list adverse events and warnings for levorphanol that are similar to other mu opioid analgesics, and include nausea, vomiting, altered mood and mentation, pruritus, flushing, difficulties in urination, constipation, and biliary spasm.6 No unusual toxicities or effects of levorphanol on the QT interval have been reported in clinical trials. Since levorphanol requires hepatic metabolism to the glucuronated form for elimination, caution should be used when administering levorphanol to patients with severe hepatic dysfunction.

Clinical Utility

Due to its pharmacologic profile, levorphanol has shown to be useful in multitude of pain states, such as chronic pain syndromes—where both nociceptive and neuropathic pathways are involved—and OIH. Glazebrook reported on 200 chronic pain patients treated with levorphanol and successful analgesia was produced in 79.5% of the cases.7

Levorphanol blocks NMDA receptor activity. Because prolonged and repeated activation of the NMDA receptors by glutamate is characteristic of neuropathic pain,8 this would suggest that levorphanol could be an effective treatment for neuropathic pain. In a prospective trial, 81 subjects with neuropathic pain were randomized to either a low-dose (2.7 mg/d) or high-dose (8.9 mg/d) regimen of levorphanol. The results of the study indicated that in the high-dose group, pain was reduced by 36%, and 66% of patients achieved moderate or better pain relief.9 Although the published evidence is very limited on the efficacy of opiates in neuropathic pain, we also use opiates for patients with severe neuropathic pain along with non-neuropathic analgesics.

In addition, activation of NMDA receptors by glutamate has a central role in the development of OIH,10 and NMDA antagonists like ketamine have been used to treat or reduce the development of OIH. Thus, levorphanol is worthy of further investigation for its use in treating OIH and other disease states where both nociceptive and neuropathic pathways are involved.  

Dosage and Administration

The only commercially available preparation is levorphanol tartrate, 2 mg tablets, manufactured by Sentynl Therapeutics in Solana Beach, California.6 The usual recommended starting oral dose is 2 mg repeated in 6-, 8- (most common), or 12-hour intervals, depending on patient age and comorbidities, as needed for pain relief; not exceeding a total daily dose of 6 to 12 mg in 24 hours in non-opioid-tolerant patients.6 (See Figure 1 for conversion ratios recommended by McNulty).3 The dose may be increased to 3 mg (1.5 2 mg tablets) or higher and repeated every 6 to 8 hours, or less frequently, if necessary.

Levorphanol has a half-life of 11 to 16 hours,2 and it accumulates with repeat dosing, reaching steady state in about 3 days (5 half-lives); therefore, adequate timing should be permitted between dose adjustments. Since levorphanol is 4 to 8 times more potent than morphine, when switching to levorphanol, the recommended starting daily dose is 1/15 to 1/12 of the daily morphine dose, which includes a reduction for incomplete cross-tolerance. As with any opioid, the dose should be individualized for the patient, taking into consideration factors such as age and comorbidities.

Recent evidence suggests that the use of dose conversion ratios published in equianalgesic tables may lead to fatal or near-fatal opioid dosing by underestimating the potency of the new opioid.11 Therefore, clinicians should use the most conservative estimates, and then decrease the estimates by 25% to 50% (exceptions: methadone, see below). After this initial dose reduction, a second dose adjustment is made to “best tailor the starting dose to the individual’s presentation, including pain severity, medical factors, and psychosocial characteristics.”12 Once the patient has been successfully started on the new opioid, the dose can be titrated for efficacy.

Last updated on: November 10, 2016
First published on: October 31, 2016
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