PAIN MEDICINE
Volume 10 • Number S1 • 2009
INTRODUCTION
Oxymorphone Status
T his is the second in a hoped-for series of Pain
Medicine supplements that will deal with
medications of interest to the pain medicine
clinician. The first of these was in references to
duloxetine [1]. The editors of Pain Medicine
have decided to launch these supplements because
research information about specific medications is
often scattered among various journals and some
early information may only be in poster form pre-
sented at various meetings. As such, it is difficult
for the busy clinician to get an overall impression
of the status of this research. Therefore, the
purpose of these supplements is to provide this
information to the pain clinician in one volume,
which could be used as a reference. In addition, the
articles within the supplement are designed, if pos-
sible, to compare the medication in question with
similar medications and/or to review a topic of
relevance to the medication in question. The topic
of this supplement is oxymorphone and the clini-
cal research issues related to this medication.
Oxymorphone is a semi-synthetic agonist of the
m- and d-opioid receptors first approved by the
United States Food and Drug Administration
(FDA) in 1959. The proposed advantage of the
d-opioid receptor activity is to possibly potentiate
or enhance m-opioid receptor analgesic effects [2].
Oxymorphone has greater analgesic potency than
morphine and until recently was only available in
parenteral injection or suppository form. Oxymor-
phone differs from morphine by having a ketone-
group substitution at the C-6 position of morphine,
which makes the molecule more lipid soluble
and structurally more closely related to hydro-
morphone [3]. Recently, oxymorphone became
available in immediate-release (IR) and extended-
release (ER) formulations. Subsequently, oxymor-
phone obtained FDA approval for the treatment of
moderate to severe acute pain (IR) and for relief of
moderate to severe pain in patients requiring con-
tinuous around-the-clock opioid therapy for an
extended time period (ER).
Drug release from the ER form is based on a
controlled-release technology that involves the rate
of penetration of water entering a hydrophilic
matrix with resultant expansion of the gel coa-
© American Academy of Pain Medicine 1526-2375/09/$15.00/S1 S1–S2
ting (TIMERx, Penwest Pharmaceuticals Co.,
Danbury, CT) [4]. This technology has been re-
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ported to confer the following to the ER prepara-
tion: proportionality; linear pharmacokinetics; an
extended release profile lasting more than 4 hours
with a half-life of 9–12 hours; a reduced fluctuation
in oxymorphone concentration during the dosing
interval, which keeps blood levels more centered
within the theoretical “therapeutic window”; and
no dose dumping [2,4–6]. The effect of ingestion of
oxymorphone ER with a high-fat meal has been
evaluated in two studies. In both, the mean peak
drug concentration (Cmax) was increased by 50% in
fed vs fasted subjects [6]. Thus, the ER formulation
should be dosed on an empty stomach (at least 1
hour before or at least 2 hours after eating). Inges-
tion of 40% alcohol can increase the Cmax of oxy-
morphone ER by a mean of 70% [6]. This appears
to be unrelated to the direct effect of alcohol on ER
tablets [6,7] as alcohol has no effect on the ER
preparation in vitro studies [8]. On the basis of
these data, the manufacturer cautions against coad-
ministration of both formulations with alcohol.
Finally, the ER preparation is subject to the same
abuse potential as other available opioids, as the
TIMERx technology offers no protection against
methods of abuse such as crushing the tablet [9].
Oxymorphone is extensively metabolized,
undergoing oxidation and reduction with sub-
sequent conjugation of parent compound and
metabolites to glucuronic acid [2,6]. Cytochrome
P450 enzymes do not catalyze the conversion of
oxymorphone to 6-hydroxy-oxymorphone (the
actual metabolite) [6]. As such, it is not metabo-
lized by CYP2D6 [2,9] and does not have any
clinically significant interactions with CYP3A4
and CYP2C9 [2,6,9,10]. In addition, it does not
inhibit or induce enzymes within the P450 system
[9]. Most patients with chronic pain are on mul-
tiple medications that are metabolized by P450
enzymes, or inhibit or induced P450 enzymes.
Thus, in these patients there is significant poten-
tial for drug interactions with the addition of a
drug that impacts on the P450 system. As such,
drugs such as oxymorphone, which do not have a
significant effect on the P450 system, are useful in
doi:10.1111/j.1526-4637.2009.00593.x
S2
populations taking multiple drugs because no
dosage adjustments would perhaps be necessary to
prevent drug interactions [9].
The efficacy and safety of oxymorphone ER for
chronic pain have been evaluated in six published
randomized controlled trials covering a variety of
indications and three published open-label studies,
two of which lasted up to 1 year [11,12]. The
durability of response to oxymorphone ER in
opioid-experienced and opioid-naïve patients was
demonstrated in two 12-week trials [8,9]. Interest-
ingly, in the two 52-week open-label studies
[11,12], there was little or no dose escalation with
attainment of meaningful pain relief for patients
remaining in the studies (there were a significant
number of patients who dropped out). In the
6-month nonrandomized open-label study [13],
oxymorphone ER was demonstrated to improve
quality of life (QOL) as measured by seven QOL
indicators.
Adverse events reported to the FDA from
placebo-controlled clinical trials (a greater than
placebo) for oxymorphone ER in order of decreas-
ing frequency were as follows: nausea, constipa-
tion, dizziness, somnolence, vomiting, pruritus,
headache, increased sweating, dry mouth, seda-
tion, diarrhea, insomnia, fatigue, decreased appe-
tite, and abdominal pain [6]. It has also been
reported that rotation from oxycodone to oxymor-
phone ER did not lead to a greater incidence of
adverse events [14].
The articles/reviews in this supplement will
expand on some of the research data summarized
above. In the first article, Dr. Smith reviews
the clinical pharmacology of oxymorphone. The
second article, by Dr. Brennan, reviews the short-
term and long-term efficacy studies for oxymor-
phone. In the third article, Dr. Holmquist, reviews
the P450 enzyme system and the effects of oxy-
morphone on the P450 enzyme system in com-
parison to other opioids. The fourth article, by Dr.
Smith, reviews all the current enteral controlled-
release opioid delivery systems. In the final article,
Dr. Pergolizzi reviews the evidence for the
concept of opioid rotation from oxymorphone
studies and from other opioids.
Disclosures
Consultant, Advisory Board, and Speaker’s Bureau: Eli
Lilly.
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David A. Fishbain, MD
Distinguished FAPA, Professor of Psychiatry and
Adjunct Professor of Neurological Surgery and
Anesthesiology, Miller School of Medicine,
University of Miami, Miami, Florida