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

Joseph S. Gimbel, MD, Richard L. Rauck, MD, Almasa Bass, PharmD, Jacquelyn Wilson, PharmD, Glenn Pixton, MS, Bimal Malhotra, PhD, Gary Wilson PhD, Gernot Wolfram, MD

Abstract


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 (R 2 = 0.0184, 0.0224, and 0.0173, respectively) or safety studies (R 2 = 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.


Keywords


opioids, oxycodone, substance withdrawal syndrome, opioid overdose, naltrexone

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References


Dart RC, Surratt HL, Cicero TJ, et al.: Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015; 372 (3): 241-248.

Centers for Disease Control and Prevention, Public Health Service, US Department Health and Human Services: Opioid overdoses in the United States. J Pain Palliat Care Pharmacother. 2012; 26 (1): 44-47.

US Food and Drug Administration: Guidance for industry: Abuse-deterrent opioids—Evaluation and labeling. Available at https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm440121.htm. Accessed May 22, 2017.

Arora S, Setnik B, Michael D, et al.: A multicenter, 12-month, open-label, single-arm safety study of oxycodone-hydrochloride/naltrexone-hydrochloride extended-release capsules (ALO-02) in patients with moderate-to-severe chronic noncancer pain. J Opioid Manag. 2014; 10 (6): 423-436.

Rauck RL, Hale ME, Bass A, et al.: A randomized double-blind, placebo-controlled efficacy and safety study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) for moderate-to-severe chronic low back pain treatment. Pain. 2015; 156 (9): 1660-1669.

Targiniq® Prescribing Information [package insert]. Stamford, CT: Purdue Pharma L.P., July 2014. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205777lbl.pdf. Accessed June 14, 2018.

Donroe JH, Tetrault JM: Substance use, intoxication, and withdrawal in the critical care setting. Crit Care Clin. 2017; 33 (3): 543-558.

Meyer MC, Straughn AB, Lo MW, et al.: Bioequivalence, dose-proportionality, and pharmacokinetics of naltrexone after oral administration. J Clin Psychiatry. 1984; 45 (9 Pt 2): 15-19.

Setnik B, Roland CL, Goli V, et al.: A clinical trial to determine if corelease of morphine and naltrexone from crushed extended-release capsules induces withdrawal in opioid-dependent patients: A descriptive analysis of six patients. J Opioid Manag. 2013; 9 (2): 139-150.

Riley J, Eisenberg E, Müller-Schwefe G, et al.: Oxycodone: A review of its use in the management of pain. Curr Med Res Opin. 2008; 24 (1): 175-192.

Lenz H, Sandvik L, Qvigstad E, et al.: A comparison of intravenous oxycodone and intravenous morphine in patient-controlled postoperative analgesia after laparoscopic hysterectomy. Anesth Analg. 2009; 109 (4): 1279-1283.

Chindalore VL, Craven RA, Yu KP, et al.: Adding ultra-low-dose naltrexone to oxycodone enhances and prolongs analgesia: A randomized, controlled trial of Oxytrex. J Pain. 2005; 6(6): 392-399.




DOI: https://doi.org/10.5055/jom.2019.0530

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