Note: Descriptions are shown in the official language in which they were submitted.
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ANALGESIC REGIMEN
FIELD OF THE INVENTION
This invention relates to a dosing regimen for the
administration of the analgesic tramadol. The dosing
regimen achieves the desired analgesic effect while
reducing or delaying the on-set of the side effects
generally associated with the administration of tramadol.
BACKGROUND OF THE INVENTION
Tramadol, the chemical name for which is
2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol,
is a synthetic, centrally-acting analgesic that is
effective for the treatment of moderate to moderately-
severe chronic pain. It has been marketed under the trade
name TramalT"" since 1977 in the dosage forms of capsules,
injections, suppositories and drops. The compound can be
employed as the free base or its pharmaceutically
acceptable salts, stereo isomers and solvates. It is
generally supplied in the form of its hydrochloride salt
and over 400 million doses of tramadol have been
administered since its introduction in Germany.
Patients experiencing chronic pain require an
analgesic therapeutic regimen that is both effective and
well tolerated. The two traditional categories of
analgesics, i.e. opioids and nonsteroidal anti-
inflammatory drugs (NSAIDs), are both effective but are
associated with potentially serious side effects.
Concerns regarding tolerance and dependence minimize the
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chronic use of narcotics such as morphine and codeine for
the treatment of chronic pain. Patients on chronic NSAID
therapy risk severe gastrointestinal symptoms, including
ulceration and bleeding which have been estimated to
result in up to 20,000 deaths each year. An alternative to
this dilemma is tramadol, a non-narcotic, non-NSAID
analgesic which is indicated for the management of
moderate to moderately-severe pain.
After oral administration, tramadol is rapidly and
almost completely absorbed and is extensively metabolized.
The major metabolic pathways appear to be N- and O-
demethylation and glucuronidation or sulfation in the
liver. Only one metabolite, i.e. mono-O-
desmethyltramadol, has been found to be pharmacologically
active.
After a single 100 mg oral dose in healthy subjects,
peak plasma concentrations of tramadol hydrochloride
occurring two hours after administration are 308~78 ng/ml
mean~standard deviation). Peak plasma concentrations of
mono-O-desmethyl tramadol, the active metabolite of
tramadol, are 55~20 ng/ml, occurring approximately three
hours after administration. The terminal plasma
elimination half-lives of tramadol hydrochloride and its
active metabolite are 6.3~11.4 hours and 7.4~1.4 hours
respectively. Tramadol is poorly bound to plasma proteins
(20.2°x) thus decreasing the potential for drug
interactions with highly protein-bound agents.
The mode of action of tramadol is not completely
understood, but in animal models at least two
complementary mechanisms appear to be involved and they
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are 1) weak binding to the ~t opioid receptors and 2) weak
inhibition of the reuptake of norepinephrine and
serotonin. Tramadol is not chemically related to opiates,
but its actions are similar to those of opioid (narcotic)
analgesics. The opioid activity of tramadol results from
the low-affinity binding of tramadol hydrochloride and the
higher affinity binding of the metabolite to ~ receptors;
however, its induced antinociception is only partially
antagonized by the opiate antagonist naloxone in several
animal tests. The inhibition of norepinephrine and
serotonin reuptake, which has been demonstrated in vitro,
is postulated to contribute independently to the overall
analgesic profile of tramadol hydrochloride.
Tramadol is well tolerated, however, nuisance adverse
events such as drowsiness, vomiting and dizziness can
occur during the initiation of treatment which may lead to
early discontinuation of the treatment. The most
frequently reported adverse events observed in clinical
trials of tramadol hydrochloride are constipation, nausea,
dizziness/vertigo, headache, somnolence, and vomiting.
Taken together, the efficacy, safety, and pharmacokinetic
profile of tramadol hydrochloride indicate that the drug
may be useful in treating chronic pain.
An object of the present invention is to demonstrate
that the frequency of nausea and vomiting, two of the most
frequently reported adverse events and the events most
commonly associated with discontinuation of treatment, as
well other adverse events, can be reduced using a lower
dosage titration scheme without diminishing the efficacy
of the compound.
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The present invention relates to a dosage regimen
which consists of slowing the titration rate for tramadol
which results in a reduction of the incidence of
discontinuation due to side effects such as nausea and
S vomiting.
SUMMARY OF THE INVENTION
The present invention relates to a dosage regimen for
tramadol which involves a slower titration rate than that
currently prescribed. The slower rate of titration of
tramadol therapy results in improved tolerability of the
drug. The novel regimen results in a significant
reduction in discontinuations due to a lower incidence or
severity of side effects. As used hereinafter, the word
tramadol is intended to include its pharmaceutically
acceptable salts, stereo isomers and solvates thereof.
DETAILED DESCRIPTION OF THE INVENTION
Tramadol is indicated for the treatment of moderate
to moderately-severe pain and its typical dosing regimen
is 50-100 mg every 4 to 6 hours. About 200 mg/day is
considered to be a normal initial dose. Clinical studies
have shown tramadol to be an effective treatment for
chronic joint pain. Tramadol is well tolerated, however,
nuisance adverse events cari occur during initiation of
treatment with tramadol. These side effects may lead to
early discontinuation of tramadol therapy.
Slow titration of a therapeutic agent is often used
by practicing clinicians to minimize adverse events
associated with centrally-acting agents such as
antidepressants, analgesics and anticonvulsants. Although
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slow titration may minimize the adverse side effects
associated with a particular agent, it may also delay the
onset of the effect of the agent as well. It has now been
discovered that initiating tramadol therapy using slow
titration rates according to the regimen of this invention
minimizes discontinuations due to adverse side effects
associated with tramadol while maintaining its therapeutic
effectiveness which results in a greater tolerance of the
drug during therapy.
The regimen which is the basis of the present
invention is a 1-28 day regimen. In practice, tramadol is
administered over a ten-28 day period starting on day one
in a pharmaceutical composition containing from about 10 -
50 mg of tramadol and the amount of drug is increased
incrementally over the next 9-28 days until the target
dose of about 200-400 mg/day is reached. Many patients
find effective pain relief at 200 mg/day, however, some
patients may require doses of up to 400 mg/day in order to
achieve the desired relief. Generally, on days 1-3 of the
regimen tramadol, in the form of the free base or its
pharmaceutically acceptable salt, is administered at a
dose of about 10-50 mg. On days 4-6 of the regimen
tramadol is administered at a dose in the range of about
20-100 mg. On days 7-9 tramadol is administered at a dose
in the range of about 30-150 mg and on days 10-28 and
thereafter at a dose of about 40-400 mg. At the end of the
period the therapy is continued at the target dose which
may be anywhere from 200 to about 400 mg of tramadol.
In a preferred embodiment of the invention
tramadol is administered in a regimen which comprises
administering tramadol at the rate of about 25 mg of
tramadol on days 1-3; 50 mg of tramadol on days 4-6; 75 mg
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of tramadol on days 7-9; 100 mg of tramadol on days 10-12;
150 mg of tramadol on days 13-15; and 200 mg of tramadol
on days 16-28 and thereafter.
In another preferred embodiment of the invention
tramadol is administered in a regimen which comprises
administering tramadol at the rate of 50 mg of tramadol on
days 1-3; 100 mg of tramadol on days 4-6; 150 mg of
tramadol on days 7-9; and 200 mg of tramadol on day 10 and
thereafter.
The drug is generally administered in the form of its
pharmaceutically salt. Suitable pharmaceutically
acceptable salts include salts of inorganic acids such as
hydrochloric and hydrobromic acid. The preferred salt is
the hydrochloride salt.
The slower initial titration rate of tramadol is
effective in reducing discontinuations due to adverse
effects while maintaining the analgesic properties of the
compound. This~is particularly true in the case of
patients who previously had difficulty tolerating an
analgesic because of side effects such as nausea and/or
vomiting. This result is based on the cumulative
proportion of patients who discontinued use of the agent
due to adverse side effects.
The following examples describe the invention in
greater detail and are intended to illustrate the
invention but not to limit it.
EXAMPLE 1
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Tramadol, in the form of its hydrochloride salt, was
studied in a multicenter, outpatient, randomized, double-
blind parallel study that compared the effect of different
titration rates of tramadol versus placebo on the
incidence of discontinuations resulting from adverse
events in patients with chronic joint pain.
A total of 465 patients with chronic joint pain were
enrolled in the study and randomized into one of four
treatment groups for 14 days. Patients continued on their
prestudy dose of NSAIDs while concurrently receiving
tramadol or placebo. Tramadol groups were titrated at
three different rates to achieve the study target dose of
200 mg/day. Each group was examined to determine if a
slower titration resulted in a statistically significant
(p<0.05) trend towards fewer discontinuations due to
nausea and/or vomiting and dizziness and/or vertigo.
Discontinuation due to any adverse event was similarly
analyzed. If the trend was statistically significant,
pairwise comparisons were performed to determine the
statistical significance between titration rates.
The study protocol was approved by an
Institutional Review Board at each study site and informed
consent regarding the risks and benefits of participation
was obtained for all patients. Patients who were (1) 45
years of age or older; (2) had a diagnosis of symptomatic
chronic joint pain, as confirmed by x-ray; (3) were in
otherwise good general health; (4) were on a stable dose
of NSAID for at least 30 days; and (5) required additional
pain relief were eligible to enroll in the study.
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Patients with chronic joint pain who had been
receiving a maintenance dose (~ 25~) of NSAID for at least
30 days, and who required additional pain relief, were
randomized into three titration groups and a placebo group
using a 2:2:2:1 randomization schedule. Double-blind
therapy began on Day 1, with patients receiving either
placebo or one of three titration regimens, ultimately
reaching the study target dose of 200 mg/day of tramadol
in either 1 day, 4 days (increasing by 50 mg increments
each day; Figures la, lb and lc), or 10 days (increasing
by 50 mg increments every 3 days) Patients continued to
take their stable dose of NSAID throughout the double-
blind phase, in addition to the study drug or placebo. On
Day 14, all patients underwent a physical examination with
clinical laboratory tests, as well as adverse event
assessment Patients could be discontinued from the study
as the result of adverse events, treatment failure,
significant protocol violation, development of an
intercurrent illness or at their own request.
Patients were randomly assigned according to a
central computer-generated schedule to receive placebo or
one of three tramadol dosage regimens that involved either
a 1-, 4- or 10-day titration schedule to attain the study
target dose of 200 mg/day. Study medication or placebo
was administered four times a day using a double-dummy
technique to ensure blinding throughout the full titration
schedule. Medication distribution was blinded and
controlled through the use of blister packs which
contained medication with the appropriate number of active
tablets and placebos for the 14-day study period, plus 2
additional days of therapy. Three hundred and fifty-two
(352) patients completed the study. Reasons leading to
discontinuation included adverse events, lack of drug
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effectiveness, intercurrent illness, protocol violation
and patient choice.
The results of the study showed that a slower initial
titration of tramadol is effective in reducing
discontinuations due to all adverse effects and, in
particular, dizziness and nausea.
Among the three tramadol titration groups, patients
in the 10-day titration group experienced the fewest
discontinuations due to dizziness and/or vertigo, nausea
and/or vomiting, and any other adverse event. The 10-day
titration rate was statistically significantly different
(<0.05} from both the 1-day rate and the 4-day rate for
discontinuations due to dizziness and/or vertigo and any
other adverse event. The study demonstrated that a slower
rate of initiation of tramadol therapy (i.e. 50 mg
increments every 3 days) will result in improved
tolerability because of significantly fewer
discontinuations due the occurrence of adverse events.
EXAMPLE 2
Tramadol, in the form of its hydrochloride salt,
was studied in a multicenter, outpatient, randomized,
double-blind parallel study comprised of two phases: a
screening/open-label run-in study and a double-blind
phase. Subjects with chronic pain (e. g. musculoskeletal,
neuropathic, joint etc.} for at least three months prior
to the study, who had been receiving a daily NSAID dose
for at least 30 days prior to the study, who required
additional relief of their chronic pain, and who completed
the screening evaluations were enrolled in the open-label
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phase on Day 0 and began open-label study medication on
Day 1. Tramadol hydrochloride was titrated in 50 mg/day
increments to 200 mg/day over four days. Subjects
continued on the 200 mg/day dosage for up to an additional
10 days.
Subjects who experienced nausea and/or vomiting
within the 14-day open-label period severe enough for the
subjects to discontinue tramadol hydrochloride treatment
had the opportunity to enter the double-blind phase.
Approximately 150 adult male and female subjects who
discontinued the open-label phase due to nausea and/or
vomiting were randomized in the double-blind phase to one
of three tramadol hydrochloride treatment regimens.
Subjects who entered the double-blind phase were assigned
in an even-distribution, randomized, double-blind fashion
to one of three treatment regimens 10 days after
discontinuing open-label tramadol hydrochloride. Subjects
were randomized on Day 0 and began double-blind therapy on
Day 1 with one of three dosage regimens of tramadol
hydrochloride that employed either a 10-, 16- or 13-day
titration schedule in order to achieve a maximum dose of
either 200 mg/day for the 10- and 16-day regimen or 150
mg/day for the 13-day regimen. On Days 1-28, the subjects
took double-blind study medication consisting of either 25
mg of tramadol hydrochloride or matching placebo (two
capsules q.i.d.). The three tramadol hydrochloride dosage
regimens were designed to achieve a maximum dose (200
mg/day or 150 mg/day) at different rates of titration (10-
, 16- or 13-day) .
Subjects assigned to the 10-day titration group
received tramadol hydrochloride at 50 mg q.d. on Days 1-3,
50 mg b.i.d. on Days 4-6, 50 mg t.i.d. on Days 7-9 and 50
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mg q.i.d. on Days 10-28; subjects assigned to the 16-day
titration group received tramadol hydrochloride at 25 mg
q.d. on Days 1-3, 25 mg b.i.d. on Days 4-6, 25 mg t.i.d.
on Days 7-9, 25 mg q.i.d. on Days 10-12, 50 mg t.i.d. on
Days 13-15 and 50 mg q.i.d. on Days 16-28; and subjects
assigned to the 13-day titration group received tramadol
hydrochloride at 25 mg q.d. on Days 1-3, 25 mg b.i.d. on
Days 4-6, 25 mg t.i.d. on Days 7-9, 25 mg q.i.d. on Days
10-12, and 50 mg t.i.d. on Days 13-28. Subjects who did
not experience nausea and/or vomiting severe enough to
discontinue tramadol hydrochloride treatment by the end of
the open-label run-in phase were discontinued from the
study. Subjects continued taking their daily dose of
NSAID throughout both the open-label/run-in and double-
blind phases of the study. At the completion of the
double-blind phase or at the time of premature
discontinuation, subjects returned to the invesitgational
site for follow-up efficacy and safety evaluations.
Efficacy evaluations were performed at all visits.
These evaluations included a subject assessment of pain
using a 10 cm pain visual analogue (PVA) scale and overall
assessments of the study medication made by the subject
and the investigator. Safety evaluations were performed
at screening, at the end of the open-label/run-in phase
and at the end of the double-blind phase and included
assessments of the occurrence of adverse events, vital
signs and body weight measurements and physical
examinations.
Analyses and summaries were performed for all
subjects who discontinued the screening/open-label/run-in
phase due to nausea and/or vomiting, who were then
randomized to one of the three double-blind titration
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groups, who took at least one dose of the study
medication, and who provided post baseline information.
Subjects who participated in the open-label/run-in phase
but who either did not qualify for or chose not to
participate in the double-blind group
are included only in the overall accounting of subjects
entering the open-label/run-in phase.
A total of 931 subjects were enrolled in the study at
29 centers for the open-label/run-in phase. There were no
apparent differences between the non-randomized and
randomized population in terms of the demographic
attributes of race, age, chronic painful condition, or
time since diagnosis; however, a slightly higher
percentage of women were randomized into the double-blind
phase of the study. Osteoarthritis and chronic low-back
syndrome were the most common chronic painful conditions
reported for the overall population (29.3% and 28.8% of
subjects, respectively}.
The primary analysis group included 167 subjects,
including 54, 59 and 54 subjects in the tramadol
hydrochloride treatment groups that employed 10-, 16- and
13-day titration periods, respectively. Chronic low-back
syndrome and osteoarthritis were the most common chronic
painful conditions reported for the overall population
(each represented 28.1% of subjects). The relative
proportions of other chronic painful conditions varied
somewhat across treatment groups.
The mean reduction from baseline PVA scores for
subjects in the open-label/run-in phase was 2.1 cm. In
the double-blind phase, the mean reduction from baseline
PVA scores was highest in the 13-day tramadol
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hydrochloride titration group (1.6 cm), followed by the
16-day titration group (1.5 cm); and the 10-day titration
group ( 1 . 4 cm) .
The pairwise log-rank test revealed statistically
significant differences (p=0.006) between the Kaplan-Meier
survival curve of the 10-day titration group and the
survival curves of both the 16-day (p=0.007) and the 13-
day titration group (p=0.006) with respect to
discontinuations from nausea and/or dizziness. The
survival curve plots the relationship between the
cumulative probability of discontinuation and the length
of exposure. Examination of the curves (Figure 2) shows
the cumulative probability of discontinuation due to
nausea and/or vomiting in the three titration groups to be
similar through the first five days of titration. After
day 5, the cumulative probability of discontinuation due
to nausea and/or vomiting in the 10-day titration group
continues to increase at essentially the same rate as seen
in the first five days while the survival curves of the
two slower titration groups plateau. The pairwise
comparison between the survival curves of the 16-day and
13-day titration groups was not statistically significant
(P=0.94).
The median time to discontinuation due to nausea
and/or vomiting was shorter for the 16-day tramadol
hydrochloride titration group (4.0 days; (Figure 2)
followed by the 13-day group (5.5 days) and the 10-day
group (9:0 days).
The pairwise log-rank test revealed statistically
significant differences between the Kaplan-Meier survival
curve of the 10-day titration group and the survival
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curves of both the 16-day titration group (p=0.030) and
the 13-day titration group (p=0.010) with respect to
discontinuations because of any adverse effect. The
survival curve plots the relationship between the
cumulative probability of discontinuation and length of
exposure. Examination of the curves (Figure 3) shows the
cumulative probability of discontinuation due to any
adverse event in the three titration groups to be similar
through the first five days of titration. After day 5,
the cumulative probability of discontinuation due to any
adverse event in the 10-day and 16-day titration groups
continue to increase while the survival curves of the 13-
day titration group begins to fall below them. After 10
days of titration, the survival curves of the 16-day and
13 day titration groups begin to plateau while the
cumulative probability of discontinuation in the 10-day
titration group continues to increase. The pairwise
comparison between the survival curves of the 13-day and
the 16-day groups was not statistically significant
(p=0.620).
The median time to discontinuation due to any adverse
event was shorter for the 16-day tramadol hydrochloride
titration group (6.0 days; Figure 5) followed by the 13-
day group (6.5 days) and the 10-day group (9.0 days).
The studies demonstrated that a slower initial
titration rate of tramadol hydrochloride reduced the
incidence of discontinuation due to nausea and/or vomiting
in subjects with chronic pain who previously had
difficulty tolerating tramadol hydrochloride because of
nausea and/or vomiting. This is based on the cumulative
proportion of subjects who discontinued due to nausea
and/or vomiting, with the group that titrates to 200
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mg/day over 10 days showing a 20 percentage advantage over
the groups that titrate to 200 mg/day over 16 days.
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