Archive for 13/02/2010


In vitro experiments suggest that circulating metabolites of oxycodoneare opioid receptor agonists.
Clinical and animal studies to date have failed to demonstrate a significant contribution of the O-demethylated
metabolite oxymorphone toward the clinical effects of the parent drug, but the role of other putative circulating
active metabolites in oxycodone pharmacodynamics remains to be examined.
Methods: Pharmacokinetics and pharmacodynamics of oxycodone were investigated in healthy human volunteers;
measurements included the time course of plasma concentrations and urinary excretion of metabolites derived
from N-demethylation, O-demethylation, and 6-keto-reduction, along with the time course of miosis and subjective
opioid side effects. The contribution of circulating metabolites to oxycodone pharmacodynamics was
analyzed by pharmacokinetic-pharmacodynamic modeling. The human study was complemented by in vitro
measurements of opioid receptor binding and activation studies, as well as in vivo studies of the brain distribution
of oxycodone and its metabolites in rats.
Results: Urinary metabolites derived from cytochrome P450 (CYP) 3A–mediatedN-demethylation of oxycodone
(noroxycodone, noroxymorphone, and - and -noroxycodol) accounted for 45%  21% of the dose, whereas
CYP2D6-mediated O-demethylation (oxymorphone and - and -oxymorphol) and 6-keto-reduction (- and
-oxycodol) accounted for 11%6% and 8%6% of the dose, respectively. Noroxycodone and noroxymorphone
were the major metabolites in circulation with elimination half-lives longer than that of oxycodone, but their
uptake into the rat brain was significantly lower compared with that of the parent drug. Pharmacokineticpharmacodynamic
modeling indicated that the time course of pupil constriction is fully explained by the plasma
concentration of the parent drug, oxycodone, alone. The metabolites do not contribute to the central effects,
either because of their low potency or low abundance in circulation or as a result of their poor uptake into the


Abstract Oxycodone has become
one of the most popular opioids in
the United States. It is superior to
morphine in oral absorption and bioavailability,
and similar in terms of
protein binding and lipophilicity.
Gender more than age influences
oxycodone elimination. Unlike morphine,
oxycodone is metabolized by
the cytochrome isoenzyme CYP2D6,
which is severely impaired by liver
dysfunction. Controlled-release (CR)
oxycodone has become one of the
most frequently utilized sustainedrelease
opioids in the United States.
Both its analgesic benefits and its
side effects are similar to those of
CR morphine. CR oxycodone is similar
to morphine and other opioids in
its abuse potential. Deaths attributable
to oxycodone are usually associated
with polysubstance abuse in
which oxycodone is combined with
psychostimulants, other opioids,
benzodiazepines or alcohol. Oxycodone’s
kappa receptor binding has
little role in abuse or addiction. The
cost of CR oxycodone is prohibitive
for most American hospices.


Pain Therapeutics, Inc. (Nasdaq: PTIE) today announced the initiation of a Phase III study with Oxytrex, an investigational drug. Oxytrex is a unique oral painkiller for patients who suffer from persistent severe chronic pain. The Company believes Oxytrex offers less physical dependence/withdrawal than oxycodone, an 80-year-old prescription painkiller still widely used today to treat persistent severe chronic pain.

„We remain encouraged by the strong science around Oxytrex published in several top journals, including a recent article in Journal of Neurobiology that further elucidates the unique attributes of ultra-low-dose opioid antagonists,“ said Remi Barbier, president and chief executive officer.

This study is being referred to as the „Extreme Study“ in deference to patients who depend on extremely high daily doses of oxycodone (greater than or equal to 120 mg per day) to treat severe chronic pain. The Company believes this sub-population of patients is prone to physical dependence/withdrawal.

In the second half of 2007, Pain Therapeutics plans to initiate a large study with Oxytrex in a broad patient population.

„Extreme Study“ Design

This clinical study is randomized, double-blinded, multi-center and placebo-controlled. The study will enroll approximately 120 patients who have each been taking greater than or equal to 120 mg of oxycodone per patient per day for over a year. Patients who meet this and all other eligibility requirements are randomized to receive twice-daily doses of 100 nanograms (i.e., 0.0001 mg) ultra-low-dose naltrexone or matching placebo for two weeks. At the conclusion of the treatment period, patients check into a clinic and receive an injection of a high-dose opioid antagonist to precipitate withdrawal. During the withdrawal phase of the study, patients are closely monitored and measured for signs and symptoms of physical dependence/withdrawal using the Subjective Opiate Withdrawal Scale. The study’s primary endpoint is prospectively defined as physical dependence/withdrawal scores in the treated arm compared to placebo. For ethical and other reasons, the study protocol allows an interim analysis.

About Oxytrex

Pain Therapeutics owns commercial rights to Oxytrex, a unique oral painkiller that preferentially inhibits an excitatory effect of opioid receptors. This excitatory effect is believed to counteract analgesia (pain relief) and cause tolerance. Its inhibition enhances pain relief and minimizes opioid tolerance. The FDA has not yet evaluated the merits, safety or efficacy of Oxytrex.

Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

PMID: 17685875 [PubMed – indexed for MEDLINE]