A double-blind, placebo-controlled study of dual-opioid treatment with the combination of morphine plus oxycodone in patients with acute postoperative pain

Lynn Webster, MD; Patricia Richards, MD, PhD; Warren Stern, PhD; Robin Kelen, RN, BA, CNN

doi:10.5055/jom.2010.0030

Authors

Lynn Webster, MD
Patricia Richards, MD, PhD
Warren Stern, PhD
Robin Kelen, RN, BA, CNN

DOI:

https://doi.org/10.5055/jom.2010.0030

Keywords:

opioid, morphine, oxycodone, bunionectomy, postoperative pain, acute pain

Abstract

Objective: Animal and human studies suggest that coadministration of two opioids with different receptor binding properties may result in enhanced analgesia and fewer opioid-related adverse events (AEs). Q8003 (MoxDuo®), an oral dual-opioid formulation with a fixed ratio (3:2) of morphine and oxycodone, was evaluated for analgesic effects and safety in the management of acute moderate to severe pain.
Design: Randomized, double-blind, placebo-controlled, ascending-dose cohort, dose-response study with flexible dosing.
Setting: Private clinic.
Patients: Adults undergoing unilateral bunionectomy surgery. Following surgery, patients were required to have moderate or severe intensity pain on a 4-point Likert scale and ≥4 on an 11-point Numerical Pain Rating Scale to continue in the study.
Interventions: Q8003 was administered in four ascending-dose cohorts of 3/2, 6/4, 12/8, and 18/12 mg during the 48-hour period following surgery.
Main Outcome Measures: Sum of the pain intensity differences from baseline over 48 hours (SPID48), percentage of responders, and use of ibuprofen.
Results: Of 263 patients, 256 were randomly assigned to treatment. In patients treated with Q8003, 12 to 18 percent withdrew before study completion versus 30 percent on placebo. The mean dose of morphine/oxycodone per 6-hour period and the mean interdose interval (hours) was 6/4 mg (2.9), 9.8/6.5 mg (4.1), 11/7.5 mg (6.8), and 15/10 mg (6.6) for the 3/2-, 6/4-, 12/8-, and 18/12-mg groups, respectively. The mean SPID48 was significantly greater with each Q8003 dose when compared with placebo (p ≤ 0.0017 for all doses versus placebo). The 12/8-mg group (11/7.5 mg/6 h) had the greatest percentage of patient responders (76 percent; p < 0.001 versus placebo) and required the fewest daily doses of ibuprofen. AEs were typical of those associated with opioid use, with the highest occurrence for nausea (38-65 percent) and low rates of somnolence (2-8 percent). Minimal or no changes in respiration and blood oxygenation were observed and euphoria was not reported.
Conclusions: The 12/8 mg dose of Q8003, an immediate-release formulation, provided the optimal combination of analgesic efficacy and tolerability, with the 3/2 and the 6/4 mg doses being an effective alternative for treatment.

Author Biographies

Lynn Webster, MD

Medical Director, Lifetree Clinical Research, Salt Lake City, Utah.

Patricia Richards, MD, PhD

Department of Clinical Research, QRxPharma, Bedminster, New Jersey.

Warren Stern, PhD

Division of Drug Development, QRxPharma, Bedminster, New Jersey.

Robin Kelen, RN, BA, CNN

Department of Clinical Research, QRxPharma, Bedminster, New Jersey.

References

Schug SA, Chong C: Pain management after ambulatory surgery. Curr Opin Anaesthesiol. 2009; 22: 738-743.

Kehlet H, Jensen TS, Woolf CJ: Persistent postsurgical pain: Risk factors and prevention. Lancet. 2006; 367: 1618-1625.

Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000; 93: 1123-1133.

Macrae WA: Chronic pain after surgery. Br J Anaesth. 2001; 87: 88-98.

Krenzischek DA, Dunwoody CJ, Polomano RC, et al.: Pharmacotherapy for acute pain: Implications for practice. J Perianesth Nurs. 2008; 23: S28-S42.

Purdue Pharma L.P.: MS Contin [package insert]. Stamford, CT: Purdue Frederick Company, 2003.

Purdue Pharma L.P.: Oxycontin [package insert]. Stamford, CT: Purdue Pharma L.P., 2003.

Wheeler M, Oderda GM, Ashburn MA, et al.: Adverse events associated with postoperative opioid analgesia: A systematic review. J Pain. 2002; 3: 159-180.

Shaw IR, Lavigne G, Mayer P, et al.: Acute intravenous administration of morphine perturbs sleep architecture in healthy pain-free young adults: A preliminary study. Sleep. 2005; 28: 677-682.

Ross FB, Wallis SC, Smith MT: Co-administration of sub-antinociceptive doses of oxycodone and morphine produces marked antinociceptive synergy with reduced CNS side-effects in rats. Pain. 2000; 84: 421-428.

Nielsen CK, Ross FB, Smith MT: Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat. J Pharmacol Exp Ther. 2000; 295: 91-99.

Dosaka-Akita K, Tortella FC, Holaday JW, et al.: The kappa opioid agonist U-50,488H antagonizes respiratory effects of mu opioid receptor agonists in conscious rats. J Pharmacol Exp Ther. 1993; 264: 631-637.

Nielsen CK, Ross FB, Lotfipour S, et al.: Oxycodone and morphine have distinctly different pharmacological profiles: Radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain. 2007; 132: 289-300.

Holaday JW, Tortella FC, Maneckjee R, et al.: In vivo interactions among opiate receptor agonists and antagonists. In Brown RM, Clouet DH, Friedman DP (eds.): Opiate Receptor Subtypes and Brain Function. Rockville, MD: National Institute on Drug Abuse, US Department of Health and Human Services, 1986: 173-188.

Bolan EA, Tallarida RJ, Pasternak GW: Synergy between mu opioid ligands: Evidence for functional interactions among mu opioid receptor subtypes. J Pharmacol Exp Ther. 2002; 303: 557-562.

Pasternak GW: Opioid pharmacotherapy: From receptor to bedside. In Inturrisi CE, Nicholson B, Pasternak GW (eds.): Dual Opioid™ Therapy. Proceedings of an Expert Panel Meeting of the Royal Society of Medicine, UK. London: Royal Society of Medicine Press, 2009: 1-10.

Grach M, Massalha W, Pud D, et al.: Can coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study. Br J Clin Pharmacol. 2004; 58: 235-242.

Ladd LA, Kam PC, Williams DB, et al.: Ventilatory responses of healthy subjects to intravenous combinations of morphine and oxycodone under imposed hypercapnic and hypoxaemic conditions. Br J Clin Pharmacol. 2005; 59: 524-535.

Blumenthal S, Min K, Marquardt M, et al.: Postoperative intravenous morphine consumption, pain scores, and side effects with perioperative oral controlled-release oxycodone after lumbar discectomy. Anesth Analg. 2007; 105: 233-237.

Jamison RN, Raymond SA, Slawsby EA, et al.: Opioid therapy for chronic noncancer back pain: A randomized prospective study. Spine. 1998; 23: 2591-2600.

Lauretti GR, Oliveira GM, Pereira NL: Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer. 2003; 89: 2027-2030.

Gimbel J, Ahdieh H: The efficacy and safety of oral immediate-release oxymorphone for postsurgical pain. Anesth Analg. 2004; 99: 1472-1477.

Daniels S, Casson E, Stegmann JU, et al.: A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009; 25: 1551-1561.

Daniels SE, Upmalis D, Okamoto A, et al.: A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009; 25: 765-776.