Preclinical Studies of the Combination of Morphine Plus Oxycodone

Pharmacology

Different opioids appear to interact differently with various opioid receptor subtypes (mu, delta, kappa), and some opioids have mixed agonist/antagonist effects. Recent studies have shown that there are at least 10 mu receptor subtypes in humans, and that individual patients differ in the extent to which a drug such as morphine binds to a subset of these mu receptors. Based on results of molecular pharmacology studies, a research team headed by Maree Smith (Univ. Queensland, AUS) and others have demonstrated morphine binds to multiple mu receptors with varying potencies, whereas oxycodone binds to kappa-2 receptors, as well as a subset of mu-receptors (Nielsen et al, Pain, 2007, 132: 289-300).

This work supports the concept of opioid potentiation (see Fig 1). Isobologram analysis (Fig 2) in rodent pain models demonstrated that the concurrent administration of morphine and oxycodone in ratios of 3:1, 1:1 or 1:3, produced marked analgesic synergy in response to painful stimuli (Ross et al, Pain, 2000, 84: 421-428). Interestingly, Smith’s group observed no potentiation of side effects.

Specifically, sedation and respiratory depression were not enhanced by Dual Opioid®s. Other studies in rodents suggest that a kappa agonist (eg, oxycodone) and a mu agonist (morphine) are antagonistic in respect to respiratory depression (Dosaka-Akita, J. Pharm. Exptl. Ther., 1993, 264: 631-637). Subsequently, Pasternak’s group in U.S. similarly demonstrated in rodents that combinations of other opioid agonists commonly produced analgesic synergy compared to the doses needed of either opioid given alone (Bolan et al, J. Pharmacol. Exptl. Ther., 2002, 303: 557-562).

Pharmacokinetics

Pharmacokinetic (PK) studies in rodents and humans show that concurrent dosing of morphine sulfate and oxycodone HCl in a ratio of 3:2 had no effect on the kinetics of either opioid. The half lives of each opioid in humans are similar, thus supporting the co-administration of each at the same dosing interval.

Toxicology

Because morphine and oxycodone each have decades of history of clinical use as marketed products, the U.S. FDA has agreed that the animal safety testing conducted by QRx for NDA purposes had been completed. The studies conducted by QRx include single dose CNS, GI, CV (dog study) and respiratory safety pharmacology studies in rodents and a 2 week and 13 week repeat dose GLP toxicology in rodents. Each of these studies contained high dose controls of morphine alone and oxycodone alone. Results showed the toxicity profile of the morphine plus oxycodone combination to be highly similar to that of the indiviDual Opioid control groups.

Chemistry

QRx has established near commercial scale production of the following dosage strengths of MoxDuo® IR—capsules containing 3 mg/2 mg, 6mg/4 mg and 12 mg/8 mg of morphine/oxycodone.