Early-Phase Study Rediscovers Potential Alternative to Methadone for Cancer Pain

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Levorphanol was associated with improved pain and symptom control in patients with advanced cancer, according to data from an early phase I trial, reported by Akhila Reddy, MD, at the 2021 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Annual Meeting.1 The pharmacology and clinical findings from this study suggest that levorphanol might be a useful alternative to methadone for this purpose.

Levorphanol is an older opioid, approved in the United States in the 1950s. It is an agonist at the mu, kappa, and delta opioid receptors; a potent NMDA (N-methyl-D-aspartate) receptor antagonist; and a reuptake inhibitor of both serotonin and nor-epinephrine. “All of this sounds very familiar because it’s very similar to methadone,” said Dr. Reddy, who is Associate Professor in the Department of Palliative, Rehabilitation and Integrative Medicine at The University of Texas MD Anderson Cancer Center, Houston. “But, unlike methadone, it does not have any cardiac QTc prolongation effect. It bypasses the cytochrome P450 system, with few drug interactions.”

Unlike methadone, levorphanol does not have any cardiac QTc prolongation effect. It bypasses the cytochrome P450 system, with few drug interactions.
— Akhila Reddy, MD

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The drug has a half-life of about 11 to 16 hours, with a long duration of action (estimated 6 to 15 hours). Peak plasma concentration is achieved at 1 hour, and, like methadone, levorphanol reaches a steady state in approximately 3 days.

“Levorphanol is renally excreted, so it can accumulate in renal failure,” she noted. “We don’t really know how potent it is compared with morphine, but some anecdotal review articles suggest it is perhaps six to eight times more potent.”

Why Was Levorphanol Forgotten?

A previous study demonstrated that higher doses of levorphanol (average, 9 mg/d) are better than lower doses (2.7 mg/d) for treating chronic neuropathic pain.2 Another small study conducted in a palliative care setting showed that patients with chronic nonmalignant pain who did not respond to other opioids (including methadone) did respond to levorphanol.3

“So, why is nobody using it?” asked Dr. Reddy. “First, none of us received any training about levorphanol; we’re not familiar with it.” Additionally, newer and less expensive opioids are available, and limited data exist on the use of levorphanol, especially in patients with cancer.

“At MD Anderson, several of our patients are on clinical trials, and, oftentimes, methadone is contraindicated due to drug interactions,” she explained. “However, we all need something like methadone because that’s our go-to opioid for difficult pain syndromes. So, we investigated levorphanol and thought, why not use it in our patients?”

Study Design

Dr. Reddy and her colleagues designed their study to determine the proportion of successful opioid rotation from other opioids (presented as morphine equivalent daily dose) to levorphanol. They also attempted to identify the median opioid rotation ratio in patients undergoing successful opioid rotations from the morphine equivalent daily dose to levorphanol.

The study included adults with active cancer seen at their supportive care center. Patients had cancer-related pain that was currently being treated with strong, first-line oral opioids (eg, morphine, oxycodone, oxymorphone, hydromorphone, fentanyl, hydrocodone). These patients also had opioid tolerance (baseline morphine equivalent daily dose of 60–300 mg) and a good performance status (Eastern Cooperative Oncology Group ≤ 3).

Exclusion criteria were standard, including no cognitive impairment and no hepatic or renal insufficiency. Patients with primarily neuropathic pain were excluded, as were patients with nonmalignant pain or those receiving methadone (due to its long half-life) or benzodiazepines (due to the risk of excessive sedation).

Experimental Approach

Patients requiring an opioid rotation were identified, approached, and consented in the clinic; levorphanol was prescribed at a ratio of morphine equivalent daily dose/10.

“Someone on a [morphine equivalent daily dose] of 100 would be started on 10 mg of levorphanol, distributed every 8 hours around the clock,” explained Dr. Reddy. “Levorphanol came in only 2-mg tablets in our supply; that’s why we restricted the cutoff [morphine equivalent daily dose] at 300 mg, because we didn’t want patients to take more than 5 tablets of levorphanol at a time.”

Patients were continued on another (either previous or new) immediate-release opioid for breakthrough pain. They received daily calls from the research team, during which opioids were titrated on days 3, 5, and 7, if needed.

On day 5, the breakthrough opioid was changed to levorphanol (5%–20% of the total levorphanol dose) from day 5 until day 10 ± 1 (levorphanol has a quick onset of 30 minutes and can be used for breakthrough pain). Patients continued to have access to the previous immediate-release opioid in case of any uncontrolled pain.

A successful opioid rotation was defined using several criteria: attainment of a personalized pain goal within 3 to 10 days after opioid rotation, a decrease in pain score by 2 points or 30% on the Edmonton Symptom Assessment System (ESAS) on day 10, or resolution of side effects on day 10 if the opioid rotation was performed for side effects.

The opioid rotation ratio was calculated as the net morphine equivalent daily dose/levorphanol dose. In patients who used another immediate-release opioid for breakthrough pain, the net morphine equivalent daily dose was calculated as the morphine equivalent daily dose before opioid rotation minus the morphine equivalent daily dose of the breakthrough opioid used along with levorphanol after the opioid rotation.

“Calculation of the net morphine equivalent daily dose gives us a more accurate opioid rotation ratio,” Dr. Reddy noted.


  • Levorphanol improved pain and other symptoms in patients with advanced cancer.
  • This study suggests that many patients with cancer may be successfully rotated to levorphanol from other opioids.
  • Further well-designed, randomized, controlled trials comparing levorphanol with other opioids are warranted.

Significant Improvements in Pain, Other Symptoms

Of 40 patients enrolled in the study, 33 (82.5%) had a successful opioid rotation. “This is way higher than 65%, which is average for our practice setting based on our previous studies,” reported Dr. Reddy. “There were no significant predictors for a successful opioid rotation, although metastatic cancer came really close, as did the absence of neuropathic pain.”

Most of the study patients (85%) had advanced-stage cancer, and the main reason for opioid rotation (in 35 patients) was uncontrolled pain. After opioid rotation, the investigators observed not only significant improvements in pain, but also in several other symptom scores obtained from the ESAS, including fatigue, nausea, and drowsiness. On day 30, they observed sustained improvement in ESAS scores as compared with baseline.

The median net morphine equivalent daily dose and the levorphanol dose were 95 mg and 10 mg, respectively, and there was a strong association between the morphine equivalent daily dose and the daily dose of levorphanol. The median opioid rotation ratio from morphine equivalent daily dose to levorphanol was 8.56. “It did not change significantly according to the baseline [morphine equivalent daily dose] nor the presence or absence of neuropathic pain. So, this was pretty much the standard median opioid rotation ratio that we obtained from the study,” she said.

Patients experienced few adverse events—mainly grade 1 and 2—which were mostly resolved with supportive care and minor dose adjustments.

According to the investigators, this study provided preliminary data that can be used in future studies: Many patients with cancer may be successfully rotated from morphine equivalent daily dose to levorphanol using an opioid rotation ratio of 8.5. “However, for practical purposes, perhaps a ratio of 10 is better, so that errors of calculation can be avoided,” Dr. Reddy added. 

DISCLOSURE: The study drug levorphanol was supplied free of cost by Sentynl Therapeutics. Dr. Reddy reported no conflicts of interest.


1. Reddy A, Haider A, Arthur J, et al: Levorphanol as a second line opioid in cancer patients presenting to an outpatient supportive care center. 2021 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Annual Meeting. Presented June 24, 2021.

2. Rowbotham MC, Twilling L, Davies PS, et al: Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med 348:1223-1232, 2003.

3. McNulty JP: Can levorphanol be used like methadone for intractable refractory pain? J Palliat Med 10:293-296, 2007.