Hydrocodone bitartrate (Hysingla ER), an extended-release (ER) opioid analgesic, has shown good otological safety in a study recently published in Pain Physician. This medication is prescribed for the management of severe pain that requires around-the-clock chronic opioid treatment. Before this single-agent hydrocodone formulation was approved in November 2014, hydrocodone was available as a fixed-combination product with nonopiate drugs, predominantly acetaminophen. There were reports of the hydrocodone-acetaminophen combination leading to sensorineural hearing loss (SNHL), and acetaminophen alone has been associated with SNHL, but the ototoxic potential of a single-entity hydrocodone product had not been previously assessed.
The investigators analyzed data from 2 phase 3 clinical studies with comprehensive ototoxicity monitoring protocols that were conducted during the clinical development of Hysingla ER. The studies included a randomized placebo-controlled study in patients with chronic low back pain (ClinicalTrials.gov identifier: NCT01452529) and an open-label, long-term safety study in patients with chronic nonmalignant and nonneuropathic pain (ClinicalTrials.gov identifier: NCT01400139). Cumulatively, the studies included 1207 patients.
Both trials assessed ototoxicity at baseline and on completion of the study through comprehensive audiologic assessments by licensed audiologists in audiology clinics around the United States. Assessments included “pure-tone air-conduction audiometry in the conventional [0.25 to 8 kHz] and ultra-high [10-16 kHz] frequencies,” as well as “pure-tone bone-conduction audiometry, tympanometry, speech reception thresholds, and word recognition,” with air-conduction audiometry performed periodically.
A bidirectional variability across all test frequencies was observed, with 82% of patients experiencing no significant threshold changes during the studies, 7% experiencing potential hearing decrement, and 10% experiencing hearing sensitivity improvement; greater fluctuations were generally observed in the higher test frequencies. Mean changes from baseline in air-conduction thresholds remained clinically unremarkable throughout the study, and there were no significant differences in ototoxic potential between patients receiving different doses of Hysingla ER (20 mg, 40 mg, 60 mg, 80 mg, or 120 mg), between Hysingla ER and placebo, and with increasing exposure to Hysingla ER (cumulative doses of ≥0 mg, ≥2100 mg, ≥8000 mg, and ≥22,100 mg).
Although most study patients had previously used medication with ototoxic potential, including acetaminophen, nonsteroidal anti-inflammatory drugs, macrolides, and phosphodiesterase 5 inhibitors, the investigators note that their intake did not alter the conclusions because the use of these agents was balanced between the Hysingla ER and placebo groups. “Additionally, careful monitoring of potential ototoxicity throughout the studies found no evidence of ototoxic synergism between [Hysingla ER] and other potentially ototoxic medications,” the authors wrote.
Summary & Clinical Applicability
The study suggests Hysingla ER might be a safer option than agents with known ototoxicity in patients requiring daily, around-the-clock pain control and who already have SNHL or are at high risk for SNHL, provided they have no contraindications to this treatment.
“It should be noted that while no ototoxicity signal was seen for [Hysingla ER], which is an extended-release, single-entity hydrocodone product, it remains to be determined whether a similar conclusion can be made for short-acting hydrocodone-containing products,” the authors wrote.
Limitations and Disclosures
The investigators reported several study limitations, including a small sample size relative to the size of the general population and the relatively short duration of 12 months of maintenance treatment, both of which could contribute to SNHL being underrepresented in the study. Subsequently, although they suggest use of Hysingla ER does not require routine audiologic assessments, they recommend a full otological examination of any patient developing subjective hearing loss while receiving this medication.
Disclosure: The studies included in the present assessment were funded by Hysingla ER’s manufacturer Purdue Pharma LP, and all authors of the Pain Physician article were paid consultants of the company or full-time employees during the design, planning, and execution of the studies and during the preparation of the manuscript.
- Campbell K, Kutz JW Jr, Shoup A, et al. Evaluation of the ototoxicity potential of once-daily, single-entity hydrocodone in patients with chronic pain: results of two phase-3 clinical studies. Pain Physician. 2017;20:E183-E193.