Opioid Rotation to Levorphanol in Patients With Cancer Is Associated With Improved Pain, Symptom Control

Opioid rotation to levorphanol was feasible for most patients with cancer experiencing opioid side effects or uncontrolled pain.

Authors of an open-label, interventional study published in the Journal of Pain and Symptom Management provided preliminary evidence that opioid rotation to levorphanol is feasible, well tolerated, and improves pain outcomes among patients with cancer.

Patients (N=40) who were taking opioids and were experiencing opioid-related side effects and/or uncontrolled pain were recruited at the supportive care clinic at the University of Texas MD Anderson Cancer Center between 2018 and 2020 (ClinicalTrials.gov Identifier: NCT03927885).  

According to the study authors, “Opioid rotation (OR), substituting 1 opioid with another, is recommended to treat [opioid-induced neurotoxicity] and uncontrolled pain despite opioid up-titration.”

The patients were prescribed levorphanol using a morphine equivalent daily dose (MEDD) to levorphanol ratio of 10:1 divided into 3 daily doses and were given an immediate-release opioid dosed at 5% to 20% of baseline MEDD levels for break-through pain. The primary outcome of the study was successful opioid rotation, defined as the disappearance of side effects, improvement in pain by 30%, or no worsening of pain by days 9 through 11.

Opioid rotation (OR), substituting one opioid with another, is recommended to treat OIN and uncontrolled pain despite opioid up-titration.

The median age of the study participants was 55 years, 55% were women, 60% were White, 87.5% were recruited for the study due to uncontrolled pain, and 62.5% had a baseline MEDD ≥100 mg. The most common opioids at baseline were morphine (37.5%), oxycodone (22.5%), and hydrocodone (15%). Most patients (85%) had metastatic cancer, and the most common cancer diagnoses were lung cancer (25%), gastrointestinal cancer (20%), genitourinary cancer (17.5%), and sarcoma (12.5%).

Rotation to levorphanol was accomplished successfully in 82.5% of patients.  Stratified by rotation success, no characteristics differed at baseline between those with and without successful rotation.

The median opioid rotation ratio (ORR) was 8.56 (interquartile range [IQR], 7.5-10), which was not dependent on MEDD at baseline (P =.2380) or the presence of neuropathic pain (P =.5084).

At day 30, pain (P <.0001), Edmonton Symptom Assessment System (ESAS) score (P <.0001), anxiety (P =.0001), nausea (P =.0045), sleep (P =.0081), confusion (P =.012), drowsiness (P =.019), and depression (P =.049) outcomes were improved compared with baseline.

Adverse events were reported by 8 patients and were mostly of grade 1 severity. These adverse effects were improved with dose adjustments, supportive care, or observation among 6 patients. Two patients withdrew from the study due to somnolence and confusion.

Among patients undergoing unsuccessful rotation, 3 had unrelated hospital admissions, 1 was nonadherent, 1 had increased drowsiness, 1 had uncontrolled pain and developed confusion, and 1 experienced only a 1-point reduction in pain scores by day 10 but had improved Global Perceived Effect (GPE) scores.

Levorphanol was refilled by 27 patients, and 9 patients continued levorphanol for 6 months.

Major limitations of this study include its open-label design, small sample size, and the lack of a comparator cohort.

The data from this pilot study indicate that opioid rotation to levorphanol may be feasible for most patients with cancer experiencing opioid side effects or uncontrolled pain. Additional study of levorphanol and advocacy for making levorphanol more affordable are warranted.

Disclosure: The drug used in this study was supplied by Sentynl Therapeutics, Inc.


Reddy A, Haider A, Arthur J, et al. Levorphanol as a second line opioid in cancer patients presenting to an outpatient supportive care center: an open-label study. J Pain Symptom Manage. Published online January 28, 2023. doi:10.1016/j.jpainsymman.2023.01.013