A long-term, open-label safety study of single-entity hydrocodone bitartrate extended release for the treatment of moderate to severe chronic pain

Abstract

ObjectiveTo evaluate the long-term safety, tolerability, and effectiveness of single-entity extended-release hydrocodone in opioid-experienced subjects with moderate to severe chronic pain not receiving adequate pain relief or experiencing intolerable side effects from their current opioid.MethodsThis multicenter, open-label study started with a conversion/titration phase (≤6 weeks) where subjects (n=638) were converted to individualized doses (range 20–300 mg) of extended-release hydrocodone dosed every 12 hours, followed by a 48-week maintenance phase (n=424). The primary objective (safety and tolerability) and the secondary objective (long-term efficacy as measured by change in average pain score; 0= no pain, 10= worst imaginable pain) were monitored throughout the study.ResultsSubjects were treated for a range of chronic pain etiologies, including osteoarthritis, low back pain, and neuropathic and musculoskeletal conditions. The mean hydrocodone equivalent dose at screening was 68.9±62.2 mg/day and increased to 139.5±81.7 mg/day at the start of the maintenance phase. Unlimited dose adjustments were permitted at the investigator’s discretion during the maintenance phase, reflecting typical clinical practice. No unexpected safety issues were reported. Common adverse events during the conversion/titration and maintenance phases, respectively, were constipation (11.3% and 12.5%), nausea (10.7% and 9.9%), vomiting (4.1% and 9.7%), and somnolence (7.7% and 4.2%). Four deaths occurred during the study; all were considered unrelated to treatment. One subject died 13 months after the study ended. From the start to end of the conversion/titration phase, 84% of subjects had a clinically meaningful improvement in average pain score (≥30% improvement), and the mean average pain scores remained stable through the maintenance phase.ConclusionThis single-entity, extended-release formulation of hydrocodone was generally safe, well tolerated, and effective in reducing chronic pain for 48 weeks. This formulation provides a new option for patients experiencing chronic pain, especially those who are taking immediate-release hydrocodone and have concerns about liver toxicity due to acetaminophen.

Effects of Renal Impairment and Hepatic Impairment on the Pharmacokinetics of Hydrocodone After Administration of a Hydrocodone Extended‐Release Tablet Formulated With Abuse‐Deterrence Technology

“…Despite the higher AUC in subjects with hepatic impairment, the elimination half-life was comparable between subjects with normal hepatic function and those with hepatic impairment. The higher systemic exposure in subjects with hepatic or renal impairment was not associated with an increased incidence of AEs, and AEs were consistent with the known safety profiles of hydrocodone [27][28][29] and naltrexone. 3 This substantially decreases the first-pass metabolism of orally administered drugs, leading to a greater proportion of drug entering systemic circulation and resulting in a significant increase in the extent of absorption.…”

The Clinical Applications of Extended-Release Abuse-Deterrent Opioids

“…Its ER formulation became the first US FDA-approved single-entity ER formulation. In a study evaluating the safety profile of HC-ER compared with other opioid formulations [6], the mean pain score improved (6.4 ± 1.8-3.1 ± 1.1, n = 424) from screening to maintenance and stabilized there (mean 4.0 ± 2.2, n = 391). Likewise, the rate of discontinuation due to adverse events was low (8 %) during the maintenance phase and there was no increase in opioid-related adverse events, suggesting the drug was well tolerated.…”

“…The study by Nalamachu et al [6] on HC-ER (Zohydro Ò ER; from the company Zogenix, Inc., Emeryville, CA, USA) also followed universal precautions of drug screening at day 1, week 12, week 36, and week 48 in addition to blood chemistry, hematology, and urine analysis. There was drug accountability with record keeping of drug administered and drug returned.…”

“…Its clinical application is for the treatment of patients with severe pain needing long-term around-the-clock opioid treatment when other options for pain control have not been adequate. Zohydro ER Ò has been shown in several studies [6,28,29,[30][31][32][33]34] to reliably control chronic pain with daily use. Both Zohydro ER Ò formulations are available to clinicians.…”

“…Despite advances in the treatment of acute pain, significant severe pain still exists after trauma or surgery which requires the use of opioids [2]. Chronic pain affects up to 100 million adults in the United States [3][4][5][6]. A majority of patients with severe pain due to invasive cancer require the use of opioids [7].…”