Efficacy and tolerability of a hydrocodone extended-release tablet for the treatment of chronic pain in patients with osteoarthritis or low back pain

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SCIENCE
Efficacy and tolerability of a hydrocodone extended-release tablet for the treatment of chronic pain in patients with osteoarthritis or low back pain
Key Take-Away: 
  • This study did not meet the primary end point, although results support the effectiveness of hydrocodone extended release (ER) formulation in managing chronic low back or osteoarthritis pain.
  • The adverse events (AEs) observed were consistent with those observed with other opioid products, and there was a low occurrence of inappropriate opioid use and aberrant drug-use behaviors.

Chronic pain affects an estimated 100 million adults in the US and the conditions most frequently associated with chronic pain include low back pain and osteoarthritis. Clinical guidelines support the use of opioids as part of a comprehensive pain management program for patients with chronic, moderate-to-severe pain. Short-acting opioids (e.g., immediate-release [IR] hydromorphone, IR hydrocodone, IR oxycodone) typically provide 4–6 hours of pain relief and have relatively short plasma half-lives that require frequent dosing, potentially reducing medication compliance. 

ABSTRACT: 
Background: 

Chronic pain affects an estimated 100 million adults in the US and the conditions most frequently associated with chronic pain include low back pain and osteoarthritis. Clinical guidelines support the use of opioids as part of a comprehensive pain management program for patients with chronic, moderate-to-severe pain.

Short-acting opioids (e.g., immediate-release [IR] hydromorphone, IR hydrocodone, IR oxycodone) typically provide 4–6 hours of pain relief and have relatively short plasma half-lives that require frequent dosing, potentially reducing medication compliance. In such case, extended release formulations may offer advantage, but to avoid its misuse, development of abuse deterrent opioid formulation should be emphasized. A new, single-agent (i.e. acetaminophen and ibuprofen free) ER formulation of hydrocodone bitartrate that employs Abuse-Deterrence Technology (ADT) platform was developed to provide sustained pain relief with twice-daily dosing. In Phase I studies, this formulation of hydrocodone ER was well tolerated and shown to have a dose-proportional pharmacokinetic profile that was qualitatively similar after single- and multiple-dose administration.

Rationale behind research

  1. Short-acting opioids typically provide 4–6 hours of pain relief and have relatively short plasma half-lives that require frequent dosing, potentially reducing medication compliance
  2. Thus, there is an unmet need for extended-release (ER) opioid formulations which may offer a longer duration of effect and less frequent dosing however, they require an increase in total medication load, which introduces a need to protect against the potential for abuse i.e. development of abuse-deterrent opioid formulations
  • Objective

To evaluate the efficacy and safety of hydrocodone ER tablets at doses of 15–90 mg administered every 12 hours compared with placebo in alleviating moderate-to-severe chronic pain in patients with osteoarthritis or low back pain.

Methods: 

 

NOTE: The study consisted of a screening period, an open-label titration period, and a double blind treatment period 

Study outcomes

  • Primary outcomes:
    • Change from baseline (final visit of the open label titration period) to week 12 in the mean weekly API.
  • Secondary outcomes:
    • Change from the baseline in the weekly average of daily API scores at weeks 1,2,4 and 8
    • The percentage of patients with >33% and >50% increases from baseline in weekly API at weeks 1,2,4,8 and 12
    • Change from baseline in weekly average of daily WPI scores at weeks 1,2,4,8 and 12
    • Use of supplemental opioids during double blind treatment period
    • Functional improvement and change in patient overall status, evaluated through the use of several questionnaires like patient assessment function (PAF), clinical assessment of patient function (CAPF), clinical global impression of severity of illness (CGI-S), brief pain inventory short form (BPI-SF) and 36-item short form (SF-36)

Time Points

  • Primary outcomes: Baseline and up to week 12
  • Secondary outcomes: Baseline and up to  week 12

Side effects

  • Adverse events: Baseline and up to week 12
Results: 

Outcomes

  • Baseline: At baseline, disease characteristics were generally similar between treatment groups
  • Primary Outcomes:
  • From baseline to week 12, the adjusted least squares mean (LSM) of weekly API decreased for patients in hydrocodone ER group (-0.22), while the value increased for patients in placebo group (0.14). However, the change from baseline to week 12 in mean weekly API score was not statistically significant between placebo and hydrocodone ER (P=0.134).
  • Secondary Outcomes:
  • Significant differences between hydrocodone ER and placebo were observed at week 2 {LSM: -0.17 vs. 0.14 (P=0.049)}and week 8 {LSM: -0.61 vs. 0.02 (P=0.002)}
  • A significantly higher proportion of patients had >33% increases from baseline in mean weekly API with placebo vs. hydrocodone ER starting at week 2 (22% vs. 11% [P=0.016]) and persisting through week 12 (24% vs. 11% [P=0.017]. Also, a significantly higher incidence of >50% increases from baseline were observed with placebo vs. hydrocodone ER at week 8 (18% vs. 6% [P=0.005]) and week 12 (15% vs. 6% [P=0.041])
  • The change from the baseline in the mean weekly WPI score was significantly different with placebo vs. hydrocodone ER at week 2 {0.27 vs. -0.15 (p=0.025), week 8 {0.00 vs. -0.68 (P=0.004)}, and week 12 {-0.03 vs. -0.60 (P=0.025)}
  • A larger percentage of patients in the placebo group required supplemental opioid medication to control pain during the double-blind treatment period compared with patients in the hydrocodone ER group (86% vs. 79%).
  • No significant differences observed between placebo and hydrocodone ER on PAF, CAPF, CGI-S or most subscales of BPI-SF or SF-36
  • Adverse events: Incidence of aberrant drug-use behaviors was low and adverse events were similar between groups. The most frequent AEs were nausea and constipation
Conclusion: 

This study shows that hydrocodone ER tablets, at doses of 15-90 mg administered every 12 hours, were generally safe and well tolerated. Although this study did not meet its primary endpoint, hydrocodone ER was associated with a statistically significant improvement in patient’s pain vs. placebo as measured by change from baseline to week 12 in mean weekly pain intensity score (secondary end point).

These results combined with the established efficacy of hydrocodone as an analgesic generally supports the effectiveness of this hydrocodone ER formulation for treating chronic pain.

Journal of pain research. 2015 Sep15;8:623-636
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