Oxymorphone Hydrochloride, a Potent Opioid

TOXICOLOGICAL SCIENCES 96(1), 162–173 (2007)
doi:10.1093/toxsci/kfl178
Advance Access publication November 30, 2006
Oxymorphone Hydrochloride, a Potent Opioid Analgesic, Is Not
Carcinogenic in Rats or Mice
Dana L. Shuey,*,1 Cindy Woodland,† Claudine Tremblay,† Richard Gregson,† and Ronald J. Gerson*
*Endo Pharmaceuticals Inc., Chadds Ford, Pennsylvania 19350; and †Charles River Laboratories,
Preclinical Services, Senneville, Quebec, Canada H9X 3R3
Received July 20, 2006; accepted November 21, 2006
Despite their long history of chronic use, little information is
available regarding the carcinogenicity of opioid analgesics. Oxymorphone is a potent morphinan-type mu-opioid analgesic used for
treatment of moderate-to-severe pain. Oxymorphone was tested for
carcinogenicity in Crl:CD IGS BR rats and CD-1 mice. Oxymorphone hydrochloride was administered orally once daily for 2
years to rats at doses of 2.5, 5 and 10 mg/kg/day (males) and 5, 10
and 25 mg/kg/day (females), and mice at 10, 25, 75 and 150 mg/kg/
day (65 animals per sex per group; 100 animals per sex in controls).
In rats, survival was generally higher than controls in oxymorphone-treated groups, attributable to lower body weight gain. In
mice, survival was generally higher than controls in females at all
doses and males given 25 mg/kg/day but lower in males given 75 mg/kg/day due to a high incidence of obstructive uropathy.
Opioid-related clinical signs and reduced body weight gain occurred in both species throughout the study. Nonneoplastic findings
associated with oxymorphone pharmacology included ocular and
pulmonary changes in rats considered secondary to inhibition of
blinking and mydriasis, and antitussive activity, respectively, and
urinary tract and renal findings in mice considered secondary to
urinary retention. There was no target organ toxicity, and no
increase in any neoplastic lesions attributed to oxymorphone.
Plasma oxymorphone levels achieved in these studies exceeded
those in patients taking high therapeutic doses of oxymorphone
(Area under the curve [AUC0–24 h] values up to 5.6-fold and 64-fold
in rats and mice, respectively). Oxymorphone is not considered to be
carcinogenic in rats or mice under the conditions of these studies.
Key Words: opioids; carcinogenicity; analgesics.
Potent mu-opioid agonists are widely used for short- and
long-term treatment of pain. Many of these drugs (e.g., oxycodone, hydromorphone, hydrocodone) are structurally related
to morphine (i.e., morphinans), whereas fentanyl and related
compounds are structurally distinct phenyl-propranamides.
Despite their common long-term use, there is no information
1
To whom correspondence should be addressed at Endo Pharmaceuticals
Inc., 100 Endo Blvd., Chadds Ford, PA 19350. Fax: (484) 840-4291. E-mail:
[email protected]
on the carcinogenic potential of potent opioid analgesics.
Codeine, a weak morphinan-type opioid, with potency about
1/10 that of morphine, was not carcinogenic in 2-year feeding
studies in F344 rats and B6C3F1 mice (National Toxicology
Program, 1996). L-alpha-Acetylmethadol (LAAM) and DLmethadone, structurally distinct diphenyl-heptane mu-opioid
agonists commonly used in opioid replacement therapy for
drug addiction, have also been tested in 2-year feeding studies.
Methadone exhibited no carcinogenic potential in either rats or
mice (Rosenkrantz and Fleischman, 1988a). LAAM was not
carcinogenic in mice but increased incidences of liver neoplastic nodules and possibly liver carcinoma occurred in F344
rats in the presence of hepatomegaly, hepatocellular hypertrophy, and nuclear enlargement (Rosenkrantz and Fleischman,
1988b).
Genotoxicity data for mu-opioid agonists are also limited.
No information was found in the literature or product information for hydrocodone, hydromorphone, or mepiridine.
None of the opioid agonists that have been tested are mutagenic
in the Ames bacterial mutation test. However, mixed results
have been found in in vitro cytogenetics assays and in vivo
micronucleus studies. Morphine induces chromosome damage
in peripheral lymphocytes and bone marrow cells of treated
mice (Das and Swain, 1982; Sawant and Couch, 1995; Swain
et al., 1980). These effects can be partially blocked by
administration of the opioid antagonist, naloxone (Sawant
and Couch, 1995). Morphine does not induce chromosome
aberrations in cultured human lymphocytes (Falek et al., 1972)
or mouse splenocytes in vitro (Sawant and Couch, 1995).
Oxycodone produced chromosome aberrations in human
peripheral blood lymphocytes in vitro and was positive in the
mouse lymphoma assay but did not increase micronuclei in the
bone marrow of treated mice (OxyContin Package Insert).
Fentanyl has shown no evidence of mutagenic activity, either in
in vitro chromosome aberrations or in an in vivo micronucleus
assay (DURAGESIC Package Insert). Collectively, these
results suggest that potent mu-opioid agonists, particularly
those of the morphinan class, produce chromosomal alterations, through either primary or secondary mechanisms, and
may thus raise a concern for potential carcinogenicity.
The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
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CARCINOGENICITY STUDIES OF OXYMORPHONE
163
Oxymorphone is a potent morphinan mu-opioid agonist used
for the treatment of acute and chronic moderate-to-severe pain.
When administered parenterally, oxymorphone is generally about
10- to 20-fold more potent than morphine in acute antinociception models in rats (Peckham and Traynor, 2006) and mice (Endo
Pharmaceuticals Inc., unpublished results). Oxymorphone is not
mutagenic in the Ames bacterial mutation test and does not
produce chromosome aberrations in Chinese hamster ovary
cells in vitro, either in the absence or presence of metabolic
activation (OPANA Package Insert). A single oral dose of
oxymorphone resulted in increased micronuclei in the bone
marrow of Sprague-Dawley rats at doses of 20 mg/kg and higher,
and in CD-1 mice at doses of 250 mg/kg and higher (OPANA
Package Insert). Further investigation indicated that these findings may be secondary to body temperature changes associated
with oxymorphone administration (Shuey et al., 2006).
The studies reported herein were conducted to evaluate the
carcinogenic potential of oxymorphone when administered
orally for 2 years to Crl:CD IGS BR (Sprague-Dawley) rats and
CD-1 mice. The study designs and dose selection were
reviewed and approved by the Food and Drug Administration
(FDA) Executive Carcinogenicity Assessment Committee
prior to study initiation. To our knowledge, these studies
represent the first available carcinogenicity data for a potent
mu-opioid analgesic.
mice). Additional animals were assigned to groups 2–4 (rats, 12 animals per sex
per group) and groups 2–5 (mice, 23 animals per sex per group) for
determination of plasma oxymorphone levels after 6 months of dosing; these
animals were discarded after sample collection. Doses in rats were 0, 2.5, 5, and
10 mg/kg/day in males and 0, 5, 10, and 25 mg/kg/day in females. Doses in
mice were 0, 10, 25, 75, and 150 mg/kg/day for both males and females.
Doses were selected based on results of previous 13-week toxicity studies in
these species (Endo Pharmaceuticals Inc., unpublished data); the selected high
doses were considered to be the maximum tolerated dose based on mortality,
body weight deficits, and behavioral changes observed at higher doses. The
doses selected for the mouse carcinogenicity study would not be tolerated in
naı̈ve animals. Therefore, doses were gradually escalated over the first 4 weeks
of the study in mice.
The studies were conducted in accordance with U.S. FDA Good Laboratory
Practices (21 CFR 58). The testing facility is accredited by the Association for
Assessment and Accreditation of Laboratory Animal Care. The protocol and
amendments were reviewed and approved by the facility Institutional Animal
Care and Use Committee. The care and use of animals during the study was
conducted in accordance with the U.S. National Research Council (1996), and
the Canadian Council on Animal Care.
MATERIALS AND METHODS
Toxicokinetics. During week 26 of the treatment period, blood samples
(~0.5 ml) were collected into heparinized tubes 0- (predose), 0.5-, 1-, 2-, 4-, 8-,
12-, and 24-h postdose in rats, and at 1-, 2-, 4-, 8-, 16-, and 24-h postdose in
mice. Samples were collected from three animals at each time point. Up to three
samples were collected from each rat; one sample was collected from each
mouse. Samples were collected from the jugular vein in unanesthetized rats, or
from the abdominal aorta under isoflurane anesthesia in mice. Plasma was
isolated and stored at approximately 20C. After sample collection, toxicokinetic animals were humanely euthanized and the carcasses were discarded
without further examination. Plasma oxymorphone levels were determined
using a fully validated liquid chromatography/mass spectrometry/mass spectrometry method. Noncompartmental toxicokinetic analysis was performed.
Animals and husbandry. All animals were received from Charles River
Canada, St-Constant, Quebec Canada. Rats (Crl:CD IGS BR) were 6–8 weeks
of age and weighed 206–286 g (males) or 6–10 weeks of age and weighed
162–226 g (females) at initiation of dosing. Mice (Crl:CD-1[ICR]BR) were 6–8
weeks of age and weighed 24.8–34.0 g (males) or 19.2–27.3 g (females) at
initiation of dosing. Each animal was uniquely identified using the AIMS
Tattoo Identification System (AIMS, Hornell, NY) system. Animals were
housed individually in stainless steel wire mesh-bottomed cages. Cage racks
were rotated every 2 weeks. Rooms were environmentally controlled with
targeted temperature and humidity of 22 ± 3C and 50 ± 20%, respectively, and
a 12-h light/dark cycle. Animals had free access to purified water and feed (PMI
Certified Rodent 5002: PMI Nutrition International, Inc.). Certified Nylabones
were provided as necessary to prevent self-chewing.
Test article and treatment. Oxymorphone hydrochloride was obtained
from Mallinckrodt Inc (St Louis, MO). Oxymorphone was administered as
aqueous solutions (in water) by oral gavage (5 ml/kg) once daily, 7 days per
week for 104 weeks. Formulations were adjusted for purity (98.3–99.3%), and
salt and water content such that doses represent free base equivalents. Dose
formulations were prepared weekly and stored at room temperature; stability
under these conditions has been established for at least 21 days. Dose
formulations were analyzed every 13 weeks and found to be within 10% of
nominal concentrations.
Oxymorphone is a Schedule II controlled substance. Appropriate handling
precautions were taken. All unused materials were disposed of in accordance
with DEA regulations.
Study design. Animals were randomized into four (rats) or five (mice)
treatment groups based on a body weight stratification. Males and females were
randomized separately. Main study groups consisted of 100 animals per sex
(group 1; vehicle control) or 65 animals per sex (groups 2–4 rats; groups 2–5
In-life parameters evaluated. All animals were observed twice daily for
mortality and moribundity. Cage side observations for drug-related adverse
clinical signs were performed daily at approximately 1-hour postdose. Detailed
examinations were performed weekly. From week 26 onwards, all animals were
examined for the presence of palpable masses (minimal dimensions 1 3 1 3 1
mm) during the detailed examination. Animals were weighed and food
consumption determined weekly. Ophthalmoscopic evaluations were performed during pretest and at approximately 1 year. Atropine sulfate (0.5%)
was used as a mydriatic agent for these examinations. Total and differential
white blood cell (WBC) counts (including blood cell morphology) were
performed at approximately 1 year and at the end of the dosing period.
Gross pathology. All main study animals were subjected to necropsy.
Animals were fasted overnight before scheduled necropsy. Animals were
euthanized by exsanguination under isoflurane anesthesia. The following
tissues were preserved: abnormalities, adrenals, animal identification, aorta
(thoracic), bone and marrow (sternum), brain (cerebrum, cerebellum, midbrain,
medulla oblongata), cecum, colon, duodenum, epididymides, esophagus, eyes,
gallbladder (mice), Harderian glands, heart (including section of aorta), ileum,
jejunum, kidneys, lacrimal glands, liver (2 lobes), lungs, lymph nodes
(mandibular and mesenteric), mammary gland (inguinal; females only), optic
nerves, ovaries, pancreas, pituitary, prostate, rectum, salivary gland, sciatic
nerve, seminal vesicles, skeletal muscle, skin (inguinal), spinal cord (cervical),
spleen, stomach, testes, thymus, thyroid lobes (and parathyroids), tongue,
trachea, urinary bladder, uterus (cervix, horns) vagina. Neutral buffered 10%
formalin was used for fixation and preservation for all tissues except for
epididymides, eyes, optic nerves, and testes, which were fixed in Zenker’s fluid.
Bone was decalcified prior to sectioning. Each clinically observed mass,
together with the nearest identifiable drainage lymph node, was preserved.
All collected tissues and all gross lesions were examined histopathologically
from all animals (except animals designated for toxicokinetics). Tissues were
prepared for histopathological examination by embedding in paraffin wax,
164
SHUEY ET AL.
sectioning, and staining with hematoxylin and eosin and examined. Suspected
tumors were diagnosed and incidences of benign and malignant tumors were
tabulated.
Statistical analyses—in-life data. All statistical analyses were conducted
using release 8.1 of the SAS/STAT module (SAS Institute Inc., Cary, NC).
Group means and standard deviations were calculated for all numerical data
collected during the studies. Group variances were compared using Levene’s
test at the 0.05 significance level. When group variances were not significantly
different, a parametric one-way analysis of variance (ANOVA) was performed.
If significant differences among the means were indicated by the ANOVA ( p 0.05), then pairwise comparisons of each group mean to the control were
performed using Dunnett’s ‘‘t’’-test. If Levene’s test indicated heterogeneous
group variances ( p 0.05), the nonparametric Kruskal-Wallis test was used to
compare all considered groups. If the Kruskal-Wallis test was significant ( p 0.05), pairwise comparisons of each group mean to the control were performed
using Dunn’s test (Dunn, 1964).
Statistical analyses—mortality and tumor data. All statistical analyses
were conducted using release 8.1 of the SAS/STAT module (SAS Institute Inc.,
Cary, NC). For mortality data, an initial analysis was conducted in order to
compare the survival curves of all groups. Significance of group effects on
mortality rates was assessed by applying the logrank test to all groups. If the
homogeneity comparison (logrank test) revealed significant differences among
the groups, then the significance of a dose-related trend in mortality was
evaluated using the method of Tarone, 1975). Tarone’s test was implemented as
a Peto two-sided test using the arithmetic dose level scores with all uncensored
deaths coded as 2 and all censored deaths coded as 0. In addition, each treated
group was compared against the control group. These pairwise comparisons
were implemented with Peto’s trend test, which was done in the direction
indicated by the sign of the statistic of the previous overall trend test. Each
statistical test was conducted at the 5% significance level.
Statistical evaluation of tumor data was limited to tissues and groups for
which all animals were examined histopathologically. For statistical analysis of
tumors of the skin and subcutaneous tissue, the incidence of these tumors was
also based on the total number of animals in each group, even though
histopathologic examination was only performed on abnormalities, because it
was assumed that all neoplasias were detected during necropsy at these sites.
Lymphosarcomas (malignant lymphomas), leukemias granulocytic and mast
cell tumors, and histiocytic sarcomas were collectively tabulated under
hemolymphoreticular tissue and were evaluated using the total number of
animals in each group. For the purpose of the statistical analysis, hemangiosarcomas were combined across all sites.
Statistical evaluation was performed using the Multtest procedure of the
SAS/STAT module, where each tumor was classified as fatal (i.e., the cause of
death) or incidental. All tumors detected in animals that survived until the
scheduled necropsy were classified as incidental. The analysis of incidental
tumors was conducted by creating a single separate interval for the time period
following the experimental period and by dividing the experimental period into
the following fixed intervals: 1–52 weeks, 53–78 weeks, 79–92 weeks, and > 92
weeks (U.S. FDA, 2001). Fatal tumors were analyzed using the death rate
method and incidental tumors were analyzed using the prevalence method. The
results from the analyses of fatal and incidental tumors were combined to
provide an overall survival-adjusted trend test (Peto et al., 2000).
For each tumor type/site, the significance of a linear dose-related increase in
tumor occurrence rates was evaluated using Peto’s survival-adjusted trend test
using the arithmetic dose level scores. Furthermore, Peto’s one-tailed trend test
was used to test whether or not the tumor rate in each treated group was
significantly higher than in the control group.
For each statistical test performed on a data set containing 10 or less tumor
occurrences, the discrete permutation distribution was used to calculate the
corresponding p value (U.S. FDA, 1997). The overall trend test and pairwise
comparisons were conducted at the 5% significance level but were evaluated
according to the recommendations of Lin and Rahman (1998). Specifically, the
nominal level of significance for a trend test was p < 0.005 for common tumors
(> 1% historical background incidence) and p < 0.025 for rare tumors, and the
nominal level of significance for pairwise comparisons was p < 0.01 for
common tumors and p < 0.05 for rare tumors (U.S. FDA, 2001).
RESULTS
Survival, Clinical Signs, Body Weight and Food Consumption
Rats. The survival rate of both male and female rats given
oxymorphone tended to be higher than the control group at all
doses (Fig. 1a, 1b). There was a statistically significant negative
dose-related trend in mortality in females, and the mortality
rate in group 4 was significantly lower than in the controls (p <
0.05). The lower mortality rate in males did not reach statistical
significance. The higher survival rate in rats given oxymorphone may be attributed to decreased numbers of fatal chronic
progressive nephropathy (males) and pituitary tumors (males
and females) observed preterminally in these groups (Table 1),
which was likely related to decreased body weight gain (see
below).
The most prominent treatment-related clinical signs in both
males and females were excessive licking, self-biting/selfmutilation (which was the likely cause of observed increases in
skin lesions and scabs). Increased activity was also observed in
oxymorphone-treated groups. These behavioral changes are
typical of rodents administered opioid agonists and therefore
considered to be related to the pharmacologic activity of
oxymorphone.
Body weight gain was significantly reduced in both males
and females at all doses of oxymorphone (Fig. 1c, 1d). This
effect was both time and dose dependent.
There were no treatment-related effects on food consumption in males given 2.5 or 5 mg/kg/day oxymorphone. Food
consumption was slightly (< 15%) but statistically significantly
reduced over the first 8 weeks of dosing in males given 10 mg/
kg/day and females at all doses. Thereafter, food consumption
was generally similar to controls.
Mice. The survival rate of males given 10 or 25 mg/kg/day
and females at all doses tended to be higher than the survival
rate in the control groups (Fig. 2a, 2b). The higher survival in
males in these groups may be associated with a lower incidence
of amyloidosis observed preterminally (Table 2).
A treatment-related decrease in survival occurred in males
given 75 or 150 mg/kg/day (Fig. 2a). The major treatmentrelated effect contributing to early death of males at these doses
was a pronounced increase in the incidence of obstructive
uropathy and, to a lesser extent, renal inflammatory changes
(Table 2). No obvious urinary tract blockages were evident.
Treatment-related increases in mydriasis and behavioral
changes including circling, self-biting, excess grooming,
licking, and/or scratching occurred in both males and females,
generally at all doses, which were considered to be the result of
the pharmacological action of oxymorphone. Other treatmentrelated clinical signs in both males and females included firm
165
CARCINOGENICITY STUDIES OF OXYMORPHONE
B
120
120
100
100
80
80
% Survival
% Survival
A
60
40
40
20
20
0
60
0
8
16
24
32
40
48
56
64
72
80
88
0
96 104
0
8
16
24
32
40
weeks
D
900
Mean body weight (grams)
Mean body weight (grams)
C
750
600
450
300
150
0
0
8
16
24
32
40
48
56
48
56
64
72
80
88
96 104
64
72
80
88
96 104
weeks
64
72
80
88
600
500
400
300
200
100
0
96 104
0
8
16
24
32
40
48
56
weeks
weeks
FIG. 1. Survival and body weights of rats administered oxymorphone for 2 years. (A and B) Survival (%) of male and female rats, respectively. (C and D)
Mean body weight of male and female rats, respectively. ¤ ¼ controls; n ¼ 2.5 mg/kg/day; : ¼ 5 mg/kg/day; * ¼ 10 mg/kg/day; ) ¼ 25 mg/kg/day.
internal structure (abdominal), oily fur, and yellow fur staining.
An increased incidence of protruding penis, and other urogenital findings (skin lesions, swelling, redness of penis, prepuce,
and/or scrotum) were observed in treated males. Other clinical
signs (thin fur cover, severed tail, various skin lesions/scabs)
were considered secondary to behavioral changes noted above.
Mean body weights were statistically significantly lower
than controls generally throughout the treatment period in both
males and females administered oxymorphone at all doses
(Fig. 2c, 2d). These effects were more pronounced in females
than in males.
Variable, dose-related effects on food consumption were
noted in males and females at all doses.
Ophthalmology. Treatment-related ophthalmoscopic findings after 1 year of dosing in rats included an increased
incidence of corneal opacities (superficial punctuate keratopathy) in females at 25 mg/kg/day (11/65 animals vs. 0/100
controls), and a slight increase in the incidence of diffuse
retinal degeneration in females at 10 and 25 mg/kg/day (3/65
and 5/65 animals, respectively vs. 1/100 controls). These
findings are consistent with histopathologic findings of
TABLE 1
Mortality and Most Common Causes of Preterminal Death in Rats
Sex
Dose (mg/kg/day)
Number of animals
Number (%) of preterminal deaths
Cause of death undetermined
Pituitary tumors
Mammary tumors
Subcutaneous tumors
Chronic progressive nephropathy
Female
Male
0
100
64 (64)
13
20
—
5
10
2.5
65
38 (58)
13
5
—
3
3
5
65
35 (54)
12
9
—
4
0
10
65
27 (42)
6
6
—
3
0
0
100
71 (71)
13
35
9
1
0
5
65
43 (66)
6
25
4
1
1
10
65
40 (62)
9
20
4
0
0
25
65
28 (43)
5
12
7
1
0
166
B
120
120
100
100
80
80
% Survival
% Survival
A
SHUEY ET AL.
60
40
20
0
60
40
20
0
8
16
24
32
40
48
56
64
72
80
88
0
96 104
0
8
16
24
32
40
weeks
D
45
Mean body weight (grams)
Mean body weight (grams)
C
40
35
30
25
20
15
0
8
16
24
32
40
48
48
56
64
72
80
88
96 104
64
72
80
88
96 104
weeks
56
64
72
80
88
96 104
weeks
45
40
35
30
25
20
15
0
8
16
24
32
40
48
56
weeks
FIG. 2. Survival and body weights of mice administered oxymorphone for 2 years. (A and B) Survival (%) of male and female mice, respectively. (C and D)
Mean body weight of male and female mice, respectively. ¤ ¼ controls; n ¼ 10 mg/kg/day; : ¼ 25 mg/kg/day; * ¼ 75 mg/kg/day; ) ¼ 150 mg/kg/day.
increased acute to chronic corneal inflammation and retinal
atrophy observed at the end of the study (Table 2). These
findings are likely secondary to pharmacologically induced
inhibition of the blink reflex and mydriasis. There were no
treatment-related ophthalmoscopic findings in mice.
Hematology. After 1 year of dosing, mean total WBC
counts were statistically significantly lower than controls in male
and female rats (up to 28 and 22%, respectively) and male mice
(up to 47%) at all doses of oxymorphone, although there was not
a clear dose-response in female rats and male mice. In the
differential counts there were statistically significant increases in
mean percent neutrophils and decreases in mean percent
lymphocytes and monocytes. At study termination, these
changes were no longer apparent in male rats. In high-dose
female rats, the mean percent lymphocytes remained significantly lower than controls and mean percent neutrophils
remained significantly higher than controls, while the total
WBC counts were similar to controls. In male mice, total WBC
counts and associated changes in neutrophils, lymphocytes, and
monocytes were still present at the end of dosing. While there
appeared to be a treatment-related effect, all values remained
within historical control values for rats and mice of this age, and
there were no histopathologic findings at termination which
correlated with these findings. Thus, the hematologic changes
were not considered to be of toxicological significance.
Necropsy Findings and Histopathology
Rats. Treatment-related nonneoplastic changes were found
in the eyes and lungs of both males and females (Table 3). In the
eye, dose-related increases in minimal to moderate retinal
atrophy, characterized by a partial to total loss of the outer
nuclear layer of the retina, and acute to chronic corneal
inflammation were observed. In the lung there were doserelated increases in histiocytosis and granuloma/subacute inflammation (Table 3). Pulmonary granuloma and/or subacute
inflammation were often associated with the presence of foreign
material (plant material) in the bronchi, bronchioles, and/or
alveoli. These results are consistent with aspiration of food.
There was no evidence of treatment-related neoplasia in
either male or female rats. In the trend tests for uterine
endometrial polyp (females), malignant lymphoma (males),
and renal tubular adenoma (males), p values were 0.0266,
0.0264, and 0.0414, respectively. However, these trends were
not considered statistically significant, because the nominal
level of significance was not met (p < 0.005 for common
tumors [uterine endometrial polyp and malignant lymphoma]
and p < 0.025 for rare tumors [renal tubular adenoma]) (U.S.
FDA, 2001). In pairwise comparisons for adrenal benign
pheochromocytoma and mammary gland adenoma and adenocarcinoma in female rats given 10 mg/kg/day versus control,
167
CARCINOGENICITY STUDIES OF OXYMORPHONE
TABLE 2
Mortality and Common Causes of Preterminal Death in Mice
Sex
Dose (mg/kg/day)
Number of animals
Number (%) of
preterminal deaths
Cause of death
undetermined
Lymphoma/histiocytic
sarcoma
Pulmonary tumors
Liver tumors
Amyloidosis
Obstructive uropathy
Pyelitis/pyelonephritis
Females
Male
0
100
50 (50)
10
65
25
65
75
65
150
65
26 (40)
24 (37)
39 (60)
0
100
42 (65)
62 (62)
10
65
25
65
75
65
30 (46)
33 (51)
30 (46)
150
65
36 (55)
5
3
5
10
7
6
3
4
1
9
8
4
5
5
1
19
11
9
10
12
7
3
13
6
0
3
2
4
7
1
0
2
3
7
2
0
1
4
12
2
0
0
2
26
4
3
0
2
0
0
3
0
3
0
0
0
0
5
0
1
3
0
3
0
1
0
0
1
3
3
p values were 0.0449, 0.0231, and 0.0466, respectively.
However, as common tumors, the nominal level of statistical
significance (p < 0.01) was not met. Therefore, based on the
lack of statistical significance and absence of similar findings at
25 mg/kg/day, these findings were not considered to be
treatment related.
A number of nonneoplastic and neoplastic findings showed
apparent dose-related decreases including hepatocellular vacuolation and hepatic cystic degeneration in males and females,
adrenal cystic degeneration and parathyroid hyperplasia in
males, bile duct hyperplasia in females (Table 3), and pituitary
adenoma in males (Table 4), which were likely attributable to
dose-related decreases in body weight gain in these animals.
Mice. Treatment-related nonneoplastic findings in mice
were limited to the urogenital tract (Table 5). An increased
incidence and severity of findings consistent with obstructive
uropathy was observed in males and females given 75 or 150
mg/kg/day. These changes were more frequently observed in
males than in females, and often associated with preterminal
TABLE 3
Nonneoplastic Findings in Rats Administered Oxymorphone for 2 Years
Sex
Dose (mg/kg/day)
Number of animals
Female
Male
0
100
2.5
65
5
65
Finding
Adrenal
Cystic degeneration
Eye
Lens degeneration
Retinal atrophy
Corneal inflammation
Liver
Hepatocellular vacuolation
Cystic degeneration
Bile duct hyperplasia
Lung
Histiocytosis
Granuloma/subacute
inflammation
Parathyroid
Hyperplasia
10
65
0
100
5
65
10
65
25
65
Number with finding (%)
17 (17)
5 (8)
1 (2)
1 (2)
37 (37)
27 (42)
27 (42)
34 (52)
2 (2)
10 (10)
4 (4)
2 (3)
7 (11)
3 (5)
2 (3)
13 (20)
1 (2)
1 (2)
24 (37)
9 (14)
1 (1)
14 (14)
6 (6)
1 (2)
32 (49)
6 (9)
1 (2)
31 (48)
5 (8)
5 (8)
43 (66)
15 (23)
40 (40)
30 (30)
40 (40)
20 (31)
13 (20)
29 (45)
11 (17)
8 (12)
24 (37)
4 (6)
2 (3)
28 (43)
41 (41)
4 (4)
33 (33)
2 (3)
4 (6)
11 (17)
2 (3)
2 (3)
7 (11)
0 (0)
0 (0)
3 (5)
22 (22)
7 (7)
19 (29)
5 (8)
21 (32)
11 (17)
40 (62)
35 (54)
19 (19)
11 (11)
23 (35)
5 (8)
40 (62)
10 (15)
56 (86)
37 (57)
11 (13)
3 (7)
0 (0)
0 (0)
3 (4)
1 (2)
0 (0)
0 (0)
Note. Only findings with an apparent dose-relationship (increase or decrease) in one or both sexes are presented. All other findings showed no apparent
relationship to treatment or dose in either species.
168
SHUEY ET AL.
TABLE 4
Neoplastic Findings in Rats Administered Oxymorphone for 2 Years
Sex
Dose (mg/kg/day)
Number of animals
Female
Male
0
100
2.5
65
5
65
Finding
Adrenal
Adenoma: cortical
Benign pheochromocytoma
Hemolymphoreticular tissue
Histiocytic sarcoma
Malignant lymphoma
Kidney
Adenoma: tubular cell
Carcinoma: tubular cell
Liver
Carcinoma: hepatocellular
Adenoma: hepatocellular
Mammary gland
Fibroadenoma
Adenoma
Adenocarcinoma
Pituitary
Adenoma: pars distalis
Carcinoma: pars distalis
Uterus
Polyp:
endometrial
stromal
Sarcoma: endometrial
stromal
Adenoma: endometrial
10
65
0
100
5
65
10
65
25
65
Number with finding (%)
4 (4)
17 (17)
2 (3)
9 (14)
2 (3)
13 (20)
2 (3)
15 (23)
10 (15)
1 (1)
2 (3)
1 (2)
2 (3)
5 (8)*
1 (2)
4 (6)
2 (2)
1 (1)
2 (3)
0 (0)
1 (2)
0 (0)
4 (6)
4 (6)#
1 (1)
2 (2)
0 (0)
1 (2)
0 (0)
1 (2)
0 (0)
2 (3)
0 (0)
1 (1)
0 (0)
0 (0)
0 (0)
0 (0)
2 (3)#
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1)
1 (2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
4 (4)
1 (2)
0 (0)
1 (2)
6 (6)
0 (0)
3 (5)
2 (3)
0a
1a
0a
1
0
1
2
0
0
0
0
1
44 (44)
6 (6)
24 (24)
28 (44)
1 (2)
23 (36)
21 (34)
9 (15)*
25 (41)*
21 (33)
2 (3)
17 (27)
78 (78)
5 (5)
45 (69)
7 (11)
49 (75)
3 (5)
46 (71)
0 (0)
64 (64)
1 (1)
30 (46)
0 (0)
33 (51)
1 (2)
23 (35)
0 (0)
—
—
—
—
5 (5)
1 (2)
5 (8)
9 (14)#
—
—
—
—
1 (1)
3 (5)
2 (3)
0 (0)
—
—
—
—
1 (1)
0 (0)
0 (0)
0 (0)
Note. Neoplastic findings with an apparent dose-relationship (increase or decrease) in one or both sexes, selected other findings in these same tissues or target
tissues (tissues with treatment-related nonneoplastic findings), and selected findings for comparison to the mouse are presented. All other findings showed no
apparent relationship to treatment or dose in either species.
*p < 0.05 (pairwise comparison),
#
p < 0.05 (positive dose-related trend).
a
Percent of animals was not calculated because mammary glands were only examined in males when there were grossly observed lesions.
morbidity as previously described. Findings consisted of
dilatation of the renal pelvis, ureters, and urinary bladder with
or without thickening of the urinary bladder wall observed at
necropsy. Protrusion of the penis, commonly associated with
obstructive uropathy, was also observed in males at these doses.
Histopathologic evaluation showed renal pelvic dilatation,
renal tubular dilatation, pyelitis/pyelonephritis, dilatation of
the ureters with or without inflammation, and dilatation of the
urinary bladder with or without inflammation. In males
a marginal increase was noted in transitional cell hyperplasia
of the urinary bladder, although this may have been secondary
to dilatation, inflammation, and presumptive urinary retention.
In females an increase was noted in subepithelial edema and/or
connective tissue thickening in the urinary bladder which, may
also have been secondary to primary urinary retention. In
a small number of animals, bacterial colonization was present,
particularly in marked cases of pyelonephritis. Increased
incidences of prostate and seminal vesicular inflammation
were also noted in males given 75 or 150 mg/kg/day.
There was no evidence of treatment-related neoplasia in
male or female mice at any dose (Table 6).
A number of gross lesions appeared to be diminished in
frequency in treated animals when compared to controls. These
included masses/nodules of the liver, lung, ovary, and uterus, and
enlargement of lymphoid tissues. A dose-related reduction in
a number of normally age-related changes in many organs was
noted in both males and females including lipofuscin deposits
and cortical hyperplasia in the adrenal in males and females at all
169
CARCINOGENICITY STUDIES OF OXYMORPHONE
TABLE 5
Nonneoplastic Findings in Mice Administered Oxymorphone for 2 Years
Sex
Dose (mg/kg/day)
Number of animals
Females
Male
0
100
10
65
25
65
75
65
150
65
Finding
Adrenal
Lipofuscin deposits
Cortical hyperplasia
Kidney
Glomerulonephritis/glomerulopathy
Amyloidosis/hyaline droplet deposition
Pyelitis/pyelonephritis
Pelvic dilatation
Prostate
Inflammation
Seminal vesicle
Inflammation
Ureter
Dilatationa
Inflammationa
Urinary bladder
Dilatation
Transitional cell hyperplasia
Mononuclear cell infiltration
Inflammation
Congestion
Edema or subepithelial thickening
0
100
10
65
25
65
75
65
150
65
49 (49)
7 (7)
20 (31)
0 (0)
12 (18)
2 (3)
13 (20)
2 (3)
(22)
(22)
(25)
(57)
18
23
3
4
7
10
0
10
Number with finding (%)
17 (17)
17 (17)
26
21
3
16
(26)
(21)
(3)
(16)
6 (9)
4 (6)
6
6
4
17
(9)
(9)
(6)
(26)
5 (8)
1 (2)
8
8
5
21
(12)
(12)
(8)
(32)
1 (2)
2 (3)
6
6
13
31
(9)
(9)
(20)
(48)
1 (2)
2 (3)
14
14
16
37
(18)
(23)
(3)
(4)
(11)
(15)
(0)
(15)
7
8
1
4
(11)
(12)
(2)
(6)
8
8
2
16
(12)
(12)
(3)
(25)
8 (12)
0 (0)
8
6
5
18
(12)
(9)
(8)
(28)
9 (9)
9 (14)
5 (8)
16 (25)
26 (40)
—
—
—
—
—
5 (5)
4 (6)
2 (3)
12 (18)
11 (17)
—
—
—
—
—
12/16
0/16
18/22
2/22
18/24
1/24
28/36
3/36
28/37
1/37
12/14
2/14
14/19
3/19
19
7
15
2
1
1
14
6
26
3
4
4
18
5
25
1
2
3
36
12
20
7
5
5
49
10
33
6
6
1
10
2
40
1
0
17
19
3
30
3
1
13
(19)
(7)
(15)
(2)
(1)
(1)
(22)
(9)
(40)
(5)
(6)
(6)
(28)
(8)
(38)
(2)
(3)
(5)
(56)
(18)
(31)
(11)
(8)
(8)
(75)
(15)
(51)
(9)
(9)
(2)
1/1
0/1
4
1
29
3
0
1
8/9
0/9
(4)
(1)
(29)
(3)
(0)
(1)
1
2
24
1
0
3
(2)
(3)
(37)
(2)
(0)
(5)
4/4
0/4
1
1
34
1
0
2
(2)
(2)
(52)
(2)
(0)
(3)
(15)
(3)
(62)
(2)
(0)
(26)
(29)
(5)
(46)
(5)
(2)
(20)
Note. Only findings with an apparent dose-relationship (increase or decrease) in one or both sexes are presented. All other findings showed no apparent
relationship to treatment or dose.
a
Number with finding/number examined. Percent of animals was not calculated because ureters were only examined in animals with grossly observed lesions.
doses, glomerulonephritis and renal amyloidosis in males at 10
and 25 mg/kg/day (Table 5). The incidence of hepatocellular
adenoma and carcinoma appeared to be decreased in males at all
doses, and the incidence of pituitary adenoma was decreased in
females. These changes were likely attributable to higher
preterminal mortality in males at 75 and 150 mg/kg/day and/or
treatment-related reductions in body weight.
Toxicokinetics. Toxicokinetic parameters are summarized
in Table 7. The rate of gastrointestinal absorption of the
oxymorphone was rapid in both species, with peak plasma
concentrations observed within 1–2 h after dosing.
In rats, systemic exposure generally increased slightly more
than proportionally with dose. Similar elimination half-lives
(t1/2) were seen in both sexes, ranging from 3.6–6.3 h. Plasma
levels were comparable in males and females given the same
dose (5.0 or 10 mg/kg/day).
In mice, maximal plasma concentration (Cmax) and area
under the plasma concentration vs. time curve (AUC0–24 h)
increased approximately proportionally with increasing dose
from 10 to 75 mg/kg/day, and more than proportionally with
increasing dose from 75 to 150 mg/kg/day in both males and
females. Shorter elimination half-lives (t1/2) were observed in
females (1.4–3 h) than in males (3–5.3 h).
DISCUSSION
There is little information in the published literature on the
chronic toxicity of opioid analgesics, despite their long history
of use in the treatment of chronic pain. To our knowledge, this
is the first report of carcinogenicity testing of a potent
morphinan opioid analgesic.
Oxymorphone hydrochloride was administered daily, by oral
gavage, for 2 years to rats and mice. Plasma concentrations
determined after 6 months of dosing showed rapid absorption
and increasing systemic exposure with dose. Cmax and AUC
values were similar to those found in 3-month toxicity studies
in rats and mice at comparable doses (unpublished data),
indicating that accumulation did not occur over long-term
exposure. One exception was in the high-dose mice (150 mg/
kg/day), where plasma concentrations increased greater than
proportionally with dose between 75 and 150 mg/kg/day, and
plasma concentrations at 150 mg/kg/day were higher than
expected based on 3-month toxicity studies. Plasma concentrations achieved in these studies are comparable to, or exceed
those in patients administered high therapeutic doses of
oxymorphone. Healthy subjects administered 40 mg of
extended-release oxymorphone every 12 h had a steady-state
170
SHUEY ET AL.
TABLE 6
Neoplastic Findings in Mice Administered Oxymorphone for 2 Years
Sex
Females
Male
Dose (mg/kg/day)
Number of animals
0
100
10
65
25
65
75
65
150
65
Finding
0
100
10
65
25
65
75
65
150
65
Number with finding (%)
Adrenal
Adenoma: cortical
Benign pheochromocytoma
Hemolymphoreticular tissue
Histiocytic sarcoma
Malignant lymphoma
Kidney
Adenoma: tubular cell
Carcinoma: tubular cell
Liver
Adenoma: hepatocellular
Carcinoma: hepatocellular
Lung
Adenoma: alveolar/bronchiolar
Carcinoma: alveolar/bronchiolar
Pituitary
Adenoma: pars distalis
Urinary bladder
Submucosal mesenchymal tumor
1 (1)
1 (1)
1 (2)
0 (0)
1 (2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1)
0 (0)
1 (1)
0 (0)
0 (0)
1 (1)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1)
9 (9)
2 (3)
3 (5)
0 (0)
7 (11)
1 (2)
5 (8)
0 (0)
1 (2)
12 (12)
13 (13)
7 (11)
8 (12)
2 (3)
11 (17)
0 (0)
10 (15)
2 (3)
12 (18)
0 (0)
1 (1)
0 (0)
0 (0)
0 (0)
0 (0)
1 (2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
18 (18)
13 (13)
3 (5)
4 (6)
6 (9)
2 (3)
4 (6)
1 (2)
5 (8)
1 (2)
1 (1)
1 (1)
1 (2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (2)
0 (0)
14 (14)
12 (12)
9 (14)
6 (9)
10 (15)
2 (3)
11 (17)
2 (3)
4 (6)
1 (2)
7 (7)
6 (6)
6 (9)
7 (11)
6 (9)
3 (5)
9 (14)
3 (5)
3 (5)
1 (2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
10 (10)
2 (3)
3 (5)
1 (2)
0 (0)
0 (0)
1 (2)
2 (3)
1 (2)
1 (2)
0 (0)
0 (0)
1 (2)
4 (6)
1 (2)
Note. For nonneoplastic findings, only findings with an apparent dose-relationship (increase or decrease) in one or both sexes are presented. Neoplastic findings
with an apparent dose-relationship (increase or decrease) in one or both sexes, selected findings in these same tissues, target tissues (tissues with treatment-related
nonneoplastic findings), and selected findings for comparison to the rat are presented. All other findings showed no apparent relationship to treatment or dose in
either species.
AUC0–12 h of 37 ng h/ml (Adams and Ahdieh, 2004). The AUC
achieved at the high doses in the carcinogenicity studies were
1.3- and 5.6-fold in male and female rats, respectively, and 54and 64-fold in male and female mice, respectively, this human
exposure (based on 24 h).
TABLE 7
Oxymorphone Toxicokinetic Parameters
Cmax (ng/ml)
Dose
(mg/kg/day)
Rats
2.5
5.0
10
25
Mice
10
25
75
150
M
F
3.83
6.98
24.0
—
—
6.44
26.8
103
37.1
142
325
919
31.7
248
432
1249
Tmax (h)
M
F
1.0 —
0.5 1.0
1.0 1.0
— 1.0
1.0
1.0
1.0
1.0
AUC0–24
M
13.6
37.5
92.7
—
h
(ng h/ml)
F
Fold humana (M/F)
—
27.2
120
415
0.18/—
0.51/0.37
1.3/1.6
—/5.6
2.0
98.5 116
1.0 371
523
1.0 1040 1758
2.0 4002 4767
1.3/1.6
5.0/7.1
14/24
54/64
a
Healthy subjects administered 40 mg of extended-release oxymorphone
every 12 h had a steady-state AUC0–12 h of 37 ng h/ml. This value was doubled
for AUC0–24 h comparison.
Administration of oxymorphone produced deficits in body
weight gain in rats and mice at all doses. The reductions in
body weight gain exceeded standard definitions of maximum
tolerated doses (> 10% reduction in body weight gain)
(International Conference on Harmonization, 1995). These
reductions, particularly in rats, were not anticipated based on
results of previous 13-week toxicity studies (unpublished
results). Interestingly, the effects on body weight gain in rats
were both dose and time dependent, and became apparent only
after prolonged exposure at the low- and mid-doses (~10–12
weeks in female rats and > 40 weeks in mid-dose male rats).
Moreover, the effects on body weight gain occurred in the
absence of consistent reductions in food consumption, which
was only minimally and variably affected during the first few
weeks of the study. Therefore, the basis for the deficit in body
weight gain is unclear. In recent studies we found that
oxymorphone produces rapid hyperthermia in rats and mice
(Shuey et al., 2006). However, these studies were conducted at
doses higher than those used in the carcinogenicity studies.
Further, it is unknown if this effect is sustained with repeated
dosing, although studies with morphine suggest the development of tolerance to this effect (Mucha et al., 1987).
Hyperactivity was observed in both rats and mice throughout
the dosing period in the carcinogenicity studies. Thus, it is
CARCINOGENICITY STUDIES OF OXYMORPHONE
possible that the effects of oxymorphone on body weight may
be secondary to other physiologic changes, though additional
studies would be required to further characterize these effects.
The reductions in body weight gain were likely the basis for
increased survival in oxymorphone-treated rats and mice
relative to the in-study controls. The association of reduced
body weight gain resulting from caloric restriction, with
increased survival is well established in rats (Keenan et al.,
1999; National Toxicology Program, 1997) and mice (National
Toxicology Program, 1997). These effects are related to
decreased occurrence, progression, and/or delayed onset of
common endocrine tumors and other degenerative diseases
associated with obesity and aging in these animals. The results
of the rat carcinogenicity study are consistent with these
conclusions. The decreased mortality in oxymorphone-treated
rats appeared to be associated with a decreased incidence of
pituitary tumors in males and females and chronic progressive
nephropathy in males observed preterminally. Although the
overall incidence of pituitary adenoma in treated females was
similar to controls, the lower incidence of this finding observed
preterminally suggests a delayed onset for this tumor. The basis
for increased survival in mice given oxymorphone was less
clear. In males there was clear reduction in fatal amyloidosis
observed preterminally but there was no obvious reduction in
any findings leading to preterminal death of females. However,
there were dose-related reductions in a number of common
age-related pathologic findings in both male and female mice.
Tolerance to the analgesic effects of opioids in rodents is
well described, where antinociceptive activity is diminished
in animals with prolonged dosing such that increasing doses
are required to sustain analgesic activity. The mechanism for
development of tolerance is not fully understood but appears
to involve complex interactions of opioid receptors with other
neurotransmitter and second messenger systems (reviewed in
Reisine and Pasternak, 1996). Development of tolerance is
variable among species, sex, and strains (Craft et al., 1999;
Kest et al., 2000; Mas et al., 2000; Roerig and Fujimoto,
1988). Further, different behavioral and physiologic effects of
opioids show differential development of tolerance (Ling
et al., 1989; Solomon et al., 1987). In the carcinogenicity
studies reported here, gradual dose escalation improved
tolerability to oxymorphone in mice allowing for testing of
doses that would not be tolerated in naı̈ve animals, consistent
with development of tolerance. However, clinical signs
typical of high-dose opioid administration in rodents (hyperactivity and/or hypoactivity, excessive grooming/biting) continued to be observed throughout the dosing period in both
rats and mice, and effects on body weight gain developed only
after prolonged dosing at the lower doses. These results
indicate incomplete tolerance to the effects of oxymorphone
over the course of the study.
There was no evidence of target organ toxicity in mice or rats
given oxymorphone. All findings were attributable to the
pharmacologic action of oxymorphone (i.e., mu-opioid ago-
171
nist), including ocular and pulmonary findings in rats, and
urogenital changes in mice. The retinal change observed in rats
was consistent with light-induced retinal degeneration (i.e.,
phototoxicity) (Yoshitomi and Boorman, 1990) and was
probably secondary to both decreased palpebral closure (inhibition of the blink reflex) and mydriasis. Morphine is known
to produce mydriasis in rats (Kamenetsky et al., 1997),
although miosis is observed with opioid treatment in humans
(Reisine and Pasternak, 1996). Similarly, the increased incidence of corneal inflammation was most likely the result of
a pharmacologically induced decrease in palpebral closure and
subsequent reduction in corneal lubrication (i.e., chronic dry
eye). The increased incidence in pulmonary histiocytosis and
inflammatory lesions, and presence of the associated plant
material (presumably food), was likely the result of food
aspiration. Opioids produce relaxation of the gastroesophageal
sphincter (Hall et al., 1987), prolong gastric emptying (reviewed in Gutstein and Akil, 2001), and have antitussive
activity (reviewed in Kamei, 1996), which could promote
gastroesophageal reflux and aspiration. The observed urogenital findings in mice are consistent with chronic urinary
retention. Urinary retention is a known effect of morphinerelated mu-opioid agonists, resulting from pharmacologic
effects on muscle tone in the urinary bladder, ureter, and
external sphincter (reviewed in Gutstein and Akil, 2001). The
urogenital findings in this study are thus considered secondary
to the pharmacologic effects of oxymorphone and not indicative of a direct toxicologic effect on the urinary tract.
There are a number of reports in the literature, both in
animals and humans that suggest potent opioids may affect
immune function (Bryant et al., 1987; LeVier et al., 1994; West
et al., 1997). In the oxymorphone carcinogenicity studies
reported here, total WBC counts and the mean percent
lymphocyte counts were slightly decreased in male and female
rats and male mice after 1 year of dosing when compared to
concurrent control groups, although values remained within
historical control ranges. These effects persisted until the end
of the study in male mice and in high-dose female rats.
However, there were no nonneoplastic or neoplastic lesions in
tissues of the immune system in oxymorphone-treated animals
indicative of chronic immunosuppression.
In genotoxicity studies, oxymorphone increased bone marrow micronucleated polychromatic erythrocytes (MPCEs) in
both rats and mice, which appear to be secondary to
pharmacologically mediated increases in body temperature
(Shuey et al., 2006). This in vivo genotoxic effect of oxymorphone did not translate into a carcinogenic effect. Investigational studies have indicated a threshold for body
temperature changes leading to increased MPCEs (Asanami
and Shimono, 1997b; Shuey et al., 2006). Studies with
morphine showed that increased MPCEs were observed after
a single dose but diminished after repeated administration,
indicating the development of tolerance (Swain et al., 1980).
Repeat-dose micronucleus studies of oxymorphone have not
172
SHUEY ET AL.
been conducted. Either the existence of a threshold and/or
development of tolerance for genotoxicity could explain the
lack of a carcinogenic response with oxymorphone. These
results underscore the importance of understanding genotoxic
mechanisms and associated carcinogenic risk, particularly if
secondary or indirect mechanisms are indicated.
In conclusion, oxymorphone is not carcinogenic in rats and
mice. Doses used in these studies produced deficits in body
weight gain that exceeded standard definition of a maximum
tolerated dose. Increased survival in rats and female mice likely
resulted from the decrease in body weight gain and associated
decreases in age-related diseases. There was no evidence of
target organ toxicity; all findings were related to the pharmacologic action of oxymorphone.
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