Effects of naltrexone exposure observed in two phase three studies with ALO-02, an extended-release oxycodone surrounding sequestered naltrexone.

OBJECTIVE:To evaluate the clinical effects of naltrexone following ALO-02 administration. DESIGN:Two phase three studies: an open-label, single-arm safety study, and a double-blind, placebo-controlled, randomized withdrawal, efficacy study (ClinicalTrials.gov identifiers: NCT01428583, NCT01571362). SETTING:Seventy US research centers. PATIENTS:Eight hundred and five patients with moderate-to-severe chronic noncancer pain (n = 395) or moderate-to-severe chronic low back pain (n = 410). INTERVENTIONS:Oral ALO-02 capsules (daily dose 20-160 mg oxycodone): openlabel titration followed by double-blind fixed dose ALO-02 or placebo (12 weeks) for the efficacy study; and open-label administration (≤12 months) for the safety study. MAIN OUTCOME MEASURES:Brief Pain Inventory-Short Form (BPI-sf), withdrawal-related adverse events, Clinical Opiate Withdrawal Scale (COWS), and naltrexone plasma concentrations. RESULTS:ALO-02 was received for = 30 days by 592 patients (73.5 percent), = 90 days by 348 patients (43.2 percent), and ≤361 days by 105 patients (13.0 percent). Maximum COWS scores were below the cutoff for mild withdrawal for the majority of patients: 86.6 percent of patients in the safety study, and for the efficacy study, 96.8 percent during titration and 95.0 percent during double-blind treatment. The frequency of quantifiable naltrexone plasma concentrations was similar between studies (18-23 percent of samples), and the levels were low, generally not exceeding 200 pg/mL. There was no apparent relationship between naltrexone plasma concentrations and COWS scores (total or change from baseline), or change from baseline in BPI-sf scores in the efficacy (R2 = 0.0184, 0.0224, and 0.0173, respectively) or safety studies (R2 = 0.0010, 0.0000, and 0.0122, respectively). CONCLUSIONS:Naltrexone plasma concentrations were low, not correlated with COWS or BPI-sf scores, and considered clinically insignificant.