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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.
Rauck R L, et al.
Journal: Pain Med. 2014; 15:975-985. 24 references.
Reprint: Richard L. Rauck, MD, Carolinas Pain Institute, 145 Kimel Park Drive, Ste 330, Winston-Salem, NC 27103, USA.
Faculty Disclosure: Abstracted by N Walea, who has nothing to disclose.
Extended release hydrocodone achieved much notoriety in the face of the opioid abuse crisis and actually was banned in Massachusetts. However in a study, flawed in part by its manufacturer sponsorship, the investigators have taken care to show it works.
Class: Pharmacology: Zohydro
Hydrocodone (HC), until recently, was only available in an immediate-release (IR) formulation in combination with non-opioid analgesics such as acetaminophen N-acetyl-para-aminophenol (APAP). The short duration of action of these IR opioids results in increased dosing frequency in chronic pain that is associated with greater incidence of adverse events (AEs), dosing errors, lack of adherence to treatment and possibly (with APAP) a predictable hepatotoxin that can lead to liver damage and acute failure.In this trial, an enriched enrollment randomized withdrawal (EERW) design composed of an open-label conversion/titration (C/T) phase followed by a placebo-controlled, randomized, double-blind treatment phase was used. During the C/T phase, subjects were converted from their current opioid to hydrocodone extended-release (HC-ER) and titrated in an open-label fashion to the optimum dose of HC-ER. Study drugs were supplied in blister packs containing either HC-ER as 10-, 20-, 30-, 40-, and 50-mg capsules or matching placebo. To decrease withdrawal from opioid effects in placebo users, HC-ER doses were tapered during the first 14 days of the treatment phase. A maximum of two tablets of HC 5mg/APAP 500mg per day was allowed for both treatment groups during the 85 day treatment period as rescue medication.The change in average pain intensity (PI) score from randomization to day 85 (end of treatment) on the 11-point NRS (0 = no pain, 10 = worst pain imaginable), recorded daily, was the primary efficacy end point. Treatment response was based on the proportion of subjects with a >30% average PI score improvement over the 85 days. The Subject Global Assessment of Medication (SGAM) was used to assess subject satisfaction with their pain medication with a higher mean score indicating greater satisfaction with the treatment.The 302 subjects were randomized into two groups (n = 151 in each). The subjects in the placebo group experienced a significantly greater increase or worsening in daily PI score from base line to day 85 than the HC-ER group. In the responder analysis 102 (68%) subjects were classified as responders in the HC-ER group compared to 47 (31%) of subjects in the placebo group. The mean change from screening to day 85 in SGAM was 0.8 + 1.3 for the HC-ER group compared with 0.0 +1.4 for the placebo group, which indicates a significantly greater degree of satisfaction with HC-ER than the placebo. In the HC-ER group, significantly more subjects (60%) experienced at least one treatment-emergent AE (TEAE) than in the placebo group (44%). The most frequently reported TEAE was constipation in 12 patients (8%) in the HC-
ER group vs no subjects in the placebo group. In the HC-ER group other frequently reported AEsincluded nausea (7%), urinary tract infection (5%), vomiting (5%), and back pain (4%). In the placebo group, frequently reported TEAEs included withdrawal symptoms (6%), diarrhea (5%), and insomnia (5%). In the placebo group, there was a significantly greater proportion of subjects experiencing withdrawal syndrome (6%) than in the HC-ER group (1%).
These results are the first placebo-controlled trial to show the efficacy of single-entity extended-release HC. The EERW study demonstrated that HC-ER is more effective than placebo in relieving pain in this subject population by showing significant improvements in pain relief measured by mean change in PI score.