Relationship between change in pain intensity and functional outcomes in patients with chronic pain receiving twice daily extended-release hydrocodone bitartrate


  • Charles Argoff, MD
  • Paul Arnstein, RN, PhD, FAAN
  • Steven Stanos, DO
  • Cynthia Y. Robinson, PhD
  • Bradley S. Galer, MD
  • Errol Gould, PhD
  • Arnold Gammaitoni, PharmD



chronic pain, long-term, hydrocodone-extended release, functional improvement


Objective: Evaluate levels of pain relief achieved in patients with chronic pain treated with hydrocodone-extended release (HC-ER) up to 48 weeks and show that these levels were associated with secondary functional and global outcomes.

Design: Post hoc analyses were based on a previously reported study that started with an open-label conversion/titration phase for 6 weeks followed by an open-label 48-week treatment phase.

Setting: Private practice and institutional pain centers.

Participants: Three hundred ninety-one opioid-experienced subjects with moderate to severe pain for 3 months.

Interventions: Individualized doses (20-300 mg) of extended-release hydrocodone every 12 hours.

Main outcome: Almost 60 percent (232/391) of subjects achieved moderate or substantial levels of pain relief (30 percent reduction in pain score) during the study.

Results: Subjects who achieved moderate or substantial pain relief demonstrated significant (p < 0.001) improvements in Oswestry Disability Inventory (ODI), all pain interference outcomes, and Subject Global Assessment of Medication. Subjects with substantial pain relief had decreases in ODI, Hospital Anxiety and Depression Scale (HADS) anxiety, and HADS depression scores of 13.4 ± 14.92, 1.9 ±  3.37, and 1.7 ± 3.26, respectively. The five most commonly reported treatment-emergent adverse events were constipation (12.5 percent), back pain (11.1 percent), nausea (9.9 percent), vomiting (9.7 percent), and arthralgia (7.8 percent) and are consistent with opioid therapy.

Conclusions: Moderate or substantial levels of pain relief were associated with the greatest functional improvements in patients treated with HC-ER. These results may help define success of opioid therapy and determine if it should be continued or an alternative treatment should be tried.

Author Biographies

Charles Argoff, MD

Department of Neurology, Albany Medical College, Albany, New York

Paul Arnstein, RN, PhD, FAAN

Nurse Practitioner Program, Massachusetts General Hospital, Boston, Massachusetts

Steven Stanos, DO

Medical Director, Swedish Pain Center, Seattle, Washington

Cynthia Y. Robinson, PhD

Development Department, Zogenix, Inc., Emeryville, California

Bradley S. Galer, MD

Medical Affairs, Zogenix, Inc., Emeryville, California.


Errol Gould, PhD

Director, Medical Affairs, Zogenix, Inc., Emeryville, California

Arnold Gammaitoni, PharmD

Medical and Scientific Affairs, Zogenix, Inc., Emeryville, California


Skevington SM: Investigating the relationship between pain and discomfort and quality of life, using the WHOQOL. Pain. 1998; 76(3): 395-406.

Stewart WF, Ricci JA, Chee E, et al.: Lost productive time and cost due to common pain conditions in the US workforce. JAMA. 2003; 290(18): 2443-2454.

Husain MM, Rush AJ, Trivedi MH, et al.: Pain in depression: STAR*D study findings. J Psychosom Res. 2007; 63(2): 113-122.

Moore A, Derry S, Eccleston C, et al.: Expect analgesic failure; pursue analgesic success. BMJ. 2013; 346: f2690.

Moore RA, Straube S, Paine J, et al.: Fibromyalgia: Moderate and substantial pain intensity reduction predicts improvement in other outcomes and substantial quality of life gain. Pain. 2010; 149(2): 360-364.

Chou R, Turner JA, Devine EB, et al.: The effectiveness and risks of long-term opioid therapy for chronic pain: A systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015; 162(4): 276-286.

Noble M, Treadwell JR, Tregear SJ, et al.: Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010; (1): CD006605.

Zogenix: Zohydro® ER (hydrocodone bitartrate) extended-release capsules, for oral use, CII [prescribing information]. San Diego, CA: Zogenix, Inc., January 2015.

Nalamachu S, Rauck RL, Hale ME, et al.: A long-term, open-label safety study of single-entity hydrocodone bitartrate extended release for the treatment of moderate to severe chronic pain. J Pain Res. 2014; 7: 669-678.

Rauck RL, Nalamachu S, Wild JE, et al.: Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: A randomized double-blind, placebo-controlled study. Pain Med. 2014; 15(6): 975-985.

Farrar JT, Young JP Jr, LaMoreaux L, et al.: Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001; 94(2): 149-158.

Daut RL, Cleeland CS, Flanery RC: Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain. 1983; 17(2): 197-210.

Bjelland I, Dahl AA, Haug TT, et al.: The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res. 2002; 52(2): 69-77.

Fairbank JCT, Pynsent PB: The Oswestry Disability Index. Spine. 2000; 25(22): 2940-2952.

Dworkin RH, Turk DC, Wyrwich KW, et al.: Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008; 9(2): 105-121.

Moore RA, Moore OA, Derry S, et al.: Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: Bridging a gap between clinical trials and clinical practice. Ann Rheum Dis. 2010; 69(2): 374-379.

Allan L, Richarz U, Simpson K, et al.: Transdermal fentanyl versus sustained release oral morphine in strong-opioid naïve patients with chronic low back pain. Spine. 2005; 30(22): 2484-2490.

Roth SH, Fleischmann RM, Burch FX, et al.: Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain. Arch Intern Med. 2000; 160(6): 853-860.

Milligan K, Lanteri-Minet M, Borchert K, et al.: Evaluation of long-term efficacy and safety of transdermal fentanyl in the treatment of chronic noncancer pain. J Pain. 2001; 2(4): 197-204.

Mystakidou K, Parpa E, Tsilika E, et al.: Long-term management of noncancer pain with transdermal therapeutic systemfentanyl. J Pain. 2003; 4(6): 298-306.

Argoff C, Arnstein P, Stanos S, et al.: Extended-release hydrocodone bitartrate in chronic pain: Association of reduction in pain intensity with functional improvement. Paper presented at PAINWeek 2014, Las Vegas, NV, September 2-6, 2014.

Yarlas A, Miller K, Wen W, et al.: A randomized, placebo-controlled study of the impact of the 7-day buprenorphine transdermal system on health-related quality of life in opioid-naïve patients with moderate-to-severe chronic low back pain. J Pain. 2013; 14(1): 14-23.

Miller K, Yarlas A, Wen W, et al.: Buprenorphine transdermal system and quality of life in opioid-experienced patients with chronic low back pain. Expert Opin Pharmacother. 2013; 14(3): 269-277.

Wallace M, Thipphawong J: Open-label study on the long-term efficacy, safety, and impact on quality of life of OROS hydromorphone ER in patients with chronic low back pain. Pain Med. 2010; 11(10): 1477-1488.

Manchikanti L, Vallejo R, Manchikanti KN, et al.: Effectiveness of long-term opioid therapy for chronic non-cancer pain. Pain Physician. 2011; 14(2): E133-E156.

Kidner CL, Mayer TG, Gatchel RJ: Higher opioid doses predict poorer functional outcome in patients with chronic disabling occupational musculoskeletal disorders. J Bone Joint Surg Am. 2009; 91(4): 919-927.

Peloso PM, Gammaitoni A, Smugar SS, et al.: Longitudinal numbers-needed-to-treat (NNT) for achieving various levels of analgesic response and improvement with etoricoxib, naproxen, and placebo in ankylosing spondylitis. BMC Musculoskelet Disord. 2011; 12: 165.



How to Cite

Argoff, MD, C., P. Arnstein, RN, PhD, FAAN, S. Stanos, DO, C. Y. Robinson, PhD, B. S. Galer, MD, E. Gould, PhD, and A. Gammaitoni, PharmD. “Relationship Between Change in Pain Intensity and Functional Outcomes in Patients With Chronic Pain Receiving Twice Daily Extended-Release Hydrocodone Bitartrate”. Journal of Opioid Management, vol. 11, no. 5, Sept. 2015, pp. 417-24, doi:10.5055/jom.2015.0291.