Twelve-month, open-label assessment of long-term safety and abuse potential of hydrocodone extended-release formulated with abuse-deterrence technology in patients with chronic pain


  • Martin E. Hale, MD
  • Thomas R. Zimmerman, Jr, MD
  • Yuju Ma, MS
  • Richard Malamut, MD



hydrocodone, opioid analgesics, chronic pain, narcotic abuse


Objective: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA® Abuse-Deterrence Technology platform.

Design: Phase 3, open-label study.

Setting: Sixty-one US study centers.

Patients: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study.

Intervention: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received 52 weeks of open-label treatment.

Main outcome measures: Safety: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control.

Results: Of 329 patients who received 1 hydrocodone ER dose, 284 (86 percent) reported 1 AE and 27 (8 percent) experienced 1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug-related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low.

Conclusions: Hydrocodone ER demonstrated acceptable safety when administered for 12 months in patients with chronic pain. Low occurrence of aberrant drug-related behavior may support the abuse-deterrence properties of hydrocodone ER.

Author Biographies

Martin E. Hale, MD

Assistant Clinical Professor, Nova Southeastern Medical College, Fort Lauderdale, Florida; Medical Director, Gold Coast Research, LLC, Plantation, Florida

Thomas R. Zimmerman, Jr, MD

Medical Monitor, Teva Pharmaceuticals, Frazer, Pennsylvania

Yuju Ma, MS

Associate Director, Statistics, Teva Pharmaceuticals, Frazer, Pennsylvania

Richard Malamut, MD

Vice President, Global Clinical Development, Pain Therapeutic Area Head, Teva Pharmaceuticals, Frazer, Pennsylvania.


Institute of Medicine Committee on Advancing Pain Research, Care, and Education: Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Available at Accessed July 10, 2013.

Moore RA, Derry S, Taylor RS, et al.: The costs and consequences of adequately managed chronic non-cancer pain and chronic neuropathic pain. Pain Pract. 2014; 14(1): 79-94.

Chaparro LE, Furlan AD, Deshpande A, et al.: Opioids compared with placebo or other treatments for chronic low back pain: An update of the Cochrane Review. Spine (Phila Pa 1976). 2014; 39(7): 556-563.

Passik SD: Issues in long-term opioid therapy: Unmet needs, risks, and solutions. Mayo Clin Proc. 2009; 84(7): 593-601.

Brennan MJ, Stanos S: Strategies to optimize pain management with opioids while minimizing risk of abuse. PM R. 2010; 2(6): 544-558.

Spitz A, Moore AA, Papaleontiou M, et al.: Primary care providers’ perspective on prescribing opioids to older adults with chronic non-cancer pain: A qualitative study. BMC Geriatr. 2011; 11: 35.

Mahowald ML, Singh JA, Majeski P: Opioid use by patients in an orthopedics spine clinic. Arthritis Rheum. 2005; 52(1): 312-321.

Vicodin® (hydrocodone bitartrate and acetaminophen tablets, USP) 5 mg/500 mg [package insert]. North Chicago, IL: AbbVie Inc., 2014.

US Food and Drug Administration: Drug products containing hydrocodone; enforcement action dates. Fed Regist. 2007; 72(72): 55780-55784.

IMS Health Incorporated: Top 20 U.S. pharmaceutical products by dispensed prescriptions. Available at Accessed December 21, 2011.

Vicoprofen [package insert]. North Chicago, IL: AbbVie Inc., 2014.

Barkin RL: Acetaminophen, aspirin, or ibuprofen in combination analgesic products. Am J Ther. 2001; 8(6): 433-442.

CIMA LABS, Inc.: OraGuard™: Tamper-deterrent, alcohol-resistant extended release technology. 2012. Available at Accessed January 12, 2015.

Rothman M, Vallow S, Damaraju CV, et al.: Using the Patient Global Assessment of the method of pain control to assess new analgesic modalities in clinical trials. Curr Med Res Opin. 2009; 25(6): 1433-1443.

Butler SF, Fernandez K, Benoit C, et al.: Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R). J Pain. 2008; 9(4): 360-372.

Wu SM, Compton P, Bolus R, et al.: The Addiction Behaviors Checklist: Validation of a new clinician-based measure of inappropriate opioid use in chronic pain. J Pain Symptom Manage. 2006; 32(4): 342-351.

Butler SF, Budman SH, Fernandez KC, et al.: Development and validation of the current opioid misuse measure. Pain. 2007; 130(1-2): 144-156.

Hale ME, Ahdieh H, Ma T, et al.: Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: A 12-week, randomized, double-blind, placebo-controlled study. J Pain. 2007; 8(2): 175-184.

Katz N, Rauck R, Ahdieh H, et al.: A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain. Curr Med Res Opin. 2007; 23(1): 117-128.

Martell BA, O’Connor PG, Kerns RD, et al.: Systematic review: opioid treatment for chronic back pain: Prevalence, efficacy, and association with addiction. Ann Intern Med. 2007; 146(2): 116-127.

McNaughton EC, Coplan PM, Black RA, et al.: Monitoring of Internet forums to evaluate reactions to the introduction of reformulated OxyContin to deter abuse. J Med Internet Res. 2014; 16(5): e119.

Ho T, Vrabec JT, Burton AW: Hydrocodone use and sensorineural hearing loss. Pain Physician. 2007; 10(3): 467-472.

Friedman RA, House JW, Luxford WM, et al.: Profound hearing loss associated with hydrocodone/acetaminophen abuse. Am J Otol. 2000; 21(2): 188-191.

Chau JK, Cho JJ, Fritz DK: Evidence-based practice: management of adult sensorineural hearing loss. Otolaryngol Clin North Am. 2012; 45(5): 941-958.

Rawool VW, Harrington BT: Middle ear admittance and hearing abnormalities in individuals with osteoarthritis. Audiol Neurootol. 2007; 12(2): 127-136.

Stolzberg D, Salvi RJ, Allman BL: Salicylate toxicity model of tinnitus. Front Syst Neurosci. 2012; 6: 28.

Yorgason JG, Kalinec GM, Luxford WM, et al.: Acetaminophen ototoxicity after acetaminophen/hydrocodone abuse: Evidence from two parallel in vitro mouse models. Otolaryngol Head Neck Surg. 2010; 142(6): 814-819.



How to Cite

Hale, MD, M. E., T. R. Zimmerman, Jr, MD, Y. Ma, MS, and R. Malamut, MD. “Twelve-Month, Open-Label Assessment of Long-Term Safety and Abuse Potential of Hydrocodone Extended-Release Formulated With Abuse-Deterrence Technology in Patients With Chronic Pain”. Journal of Opioid Management, vol. 11, no. 5, Sept. 2015, pp. 425-34, doi:10.5055/jom.2015.0292.