Beruflich Dokumente
Kultur Dokumente
94 Volume 37 Number 1
M.J. Sánchez del Águila et al.
these treatments were not effective or were only some- predictable and reliable pharmacokinetic profile for
what effective.3 clinical use.20,21 By combining MOR agonism and
The challenges associated with achieving adequate NRI in a single molecule, tapentadol may offer
pain management for patients with severe chronic improvements in efficacy and tolerability compared
pain are manifold. Patients with severe chronic pain with classic opioid analgesics.17 In preclinical studies,
may require treatment with an opioid analgesic, which tapentadol was found to have a lower affinity for the
may provide effective analgesia for severe chronic pain MOR than was morphine.16,22 Despite this lower
but may be associated with adverse effects (eg, nausea, affinity for the MOR, clinical trials have reported
vomiting, constipation, and somnolence) that could that tapentadol provides at least comparable pain
lead to the use of inadequate doses or to the dis- relief to other classic strong opioids (eg, oxyco-
ruption or discontinuation of therapy.4–7 Some done)23–30 because of the synergistic contribution of
opioid-induced adverse effects, such as constipation, NRI to its analgesic activity.31 The lower affinity of
may be refractory to standard treatments and may not tapentadol for the MOR compared with classic opioid
resolve with continued opioid treatment.8,9 Patients analgesics may contribute to the reduction in opioid-
may also develop tolerance to opioid analgesics over related adverse effects observed with tapentadol com-
time and may require higher doses to achieve adequate pared with oxycodone.23–30
analgesia,10 which may exacerbate tolerability issues. For patients with chronic pain who require long-
Furthermore, the use of a single analgesic (eg, an term analgesic treatment, prolonged-release (PR) an-
opioid) may be insufficient to address mixed or neuro- algesics allow for less frequent dosing and more
pathic chronic pain because nociceptive and neuro- consistent pain management.32 The PR formulation
pathic types of chronic pain arise from different pain of tapentadol, which is taken twice daily, is approved
mechanisms.11 The development of chronic pain in in Europe for the management of severe chronic pain
general, and neuropathic pain in particular, seems to be in adults, which can be adequately managed only with
related to alterations in descending noradrenergic opioid analgesics,33 and in the United States
modulation mechanisms11; thus, addressing mixed or (tapentadol extended release) for the management of
neuropathic pain may require the use of combination moderate to severe chronic pain in adults when a
therapy that addresses the ascending and descending continuous, around-the-clock opioid analgesic is
pain pathways.12,13 The use of combination therapy needed for an extended period.34 In the United
with an opioid analgesic and a coanalgesic may be States, the extended-release formulation is also indi-
associated with an increased risk of adverse effects or cated for pain associated with diabetic peripheral
treatment discontinuation in relation to monother- neuropathy (DPN).34 Tapentadol PR, a World
apy.14,15 In addition, determining the correct balance Health Organization (WHO) step III analgesic, is a
of doses of the opioid analgesic and coanalgesic to scheduled substance in the United States and
optimize efficacy and tolerability may pose a substan- Europe.33,35 Since 2010, PR formulations of tapenta-
tial challenge, and patients may be less willing to dol have been launched in a variety of major Euro-
comply with treatment with multiple medications. pean countries, the United States, Canada, and
The use of a single analgesic that could address multi- Australia.
ple pain mechanisms while providing tolerable and Tapentadol PR has been evaluated in patients with
effective pain control for long-term treatment may severe or moderate to severe chronic low back
alleviate many of the problems associated with manag- pain,24,29,36,37 osteoarthritis knee pain,23,29,38 pain
ing severe chronic pain. associated with DPN,39–41 and cancer-related pain,42–44
Tapentadol represents a proposed new class of and has been found to provide strong and reliable
centrally acting analgesics with 2 mechanisms of analgesia across a broad range of indications. Tapen-
action, μ-opioid receptor (MOR) agonism and nora- tadol PR has also been associated with improvements
drenaline reuptake inhibition (NRI),16,17 that contrib- in neuropathic pain symptoms and quality of life in
ute synergistically to its analgesic activity.18,19 Both patients with neuropathic pain,37,45 which are not con-
mechanisms of action reside in the parent compound; sistently observed with classic opioid treatments.46–51
thus, the analgesic activity of tapentadol is not reliant The broad effectiveness of tapentadol PR for nocicep-
on metabolic activation, and tapentadol has a tive, neuropathic, and mixed types of chronic pain,
January 2015 95
Clinical Therapeutics
which is likely due to its combination of MOR by rapid increases in doses.53 Opioid-naive patients
agonism and NRI activities,18,19 may simplify chronic are particularly at risk for early adverse effects (eg,
pain treatment by eliminating the need to isolate and nausea and vomiting) and are more vulnerable to the
treat the individual types of chronic pain with a rare, but serious, tolerability issue of respiratory
combination of different analgesics and coanalgesics. depression.7,54 With a slow titration schedule, how-
Tapentadol PR may also facilitate chronic pain man- ever, patients may experience delays in achieving
agement because tapentadol is associated with a low adequate analgesia. Furthermore, patients may be
risk of pharmacokinetic interactions,20,21 making it a unable to use sufficient doses of opioid analgesics to
viable option for poly-medicated patients, including achieve adequate pain control owing to the occurrence
elderly patients. In addition, the favorable tolerability of intolerable adverse effects.4–7
profile of tapentadol PR23,24,29 relative to classical Tapentadol PR has been associated with improved
opioid analgesics may be associated with improved tolerability (specifically, lower incidences of nausea,
patient compliance, which, along with the low risk of vomiting, dizziness, and constipation) relative to the
tolerance development observed over 1 year of treat- classic opioid analgesics oxycodone controlled release
ment,30 may allow for stable long-term dosing and (CR)23,24,29,30 and morphine CR.42 In a randomized
consistent analgesia. Furthermore, the relatively low placebo- and active-controlled study of tapentadol PR
risk of adverse effects associated with tapentadol PR for the management of moderate to severe chronic low
may allow for rapid up-titration, allowing patients to back pain, the odds of experiencing constipation or
achieve pain control more quickly. Thus, the integra- the composite of nausea and vomiting was signifi-
tion of tapentadol PR as a first option for patients cantly lower with tapentadol PR than with oxycodone
needing an opioid analgesic to control their pain, or as CR (P o 0.001 for both comparisons).24 In that same
an alternative for patients with inadequately managed study, the incidence of the central nervous system
pain or intolerable adverse effects when taking an- (CNS)–related adverse event of dizziness was
other opioid, may simplify chronic pain management significantly lower with tapentadol PR than with
and improve patient outcomes. This article summa- oxycodone CR (P o 0.05).55 The rate of discontinua-
rizes various aspects of the practical handling of tions due to any CNS-related adverse event was also
tapentadol PR in a clinical setting, including the numerically lower with tapentadol PR (6.2%) than
established titration regimen for tapentadol PR, the with oxycodone CR (14.0%).24 Although patients
convenient conversion from other strong opioid an- often develop tolerance to these adverse effects with
algesics to tapentadol PR, the efficacy of the available continuing opioid treatment, the occurrence of nausea
dose range for severe pain, the low potential of and vomiting early in the course of therapy may
withdrawal after discontinuation of tapentadol PR, reduce patient adherence to treatment4,5,7 or may
the use of tapentadol PR with concomitant medica- delay increases in analgesic doses, resulting in inad-
tions, and the low potential for tapentadol PR abuse. equate analgesia. Furthermore, tapentadol PR has also
been associated with a reduction in the occurrence of
INITIATION, TITRATION, AND DOSING OF adverse effects that typically do not resolve with
TAPENTADOL PR TREATMENT continued opioid treatment (eg, constipation) relative
Initiation, Titration, and Dosing of Tapentadol to other opioids,23,24,29 which may improve quality of
PR in the General Population With Chronic Pain life for patients undergoing long-term therapy. The
Achieving adequate pain control rapidly while improved tolerability profile, particularly the im-
minimizing intolerable adverse effects is a goal for proved gastrointestinal tolerability profile, of tapenta-
many patients with chronic pain initiating a new dol PR may allow for relatively rapid up-titration of
analgesic regimen. For patients with severe chronic doses and the use of higher doses (up to 500 mg/d),
pain who are treated with an opioid analgesic, low which may allow patients to achieve effective pain
starting doses and slow upward titration are recom- control more rapidly.
mended to minimize the risk of opioid-related adverse In opioid-naive patients, the recommended starting
events.52,53 This cautious approach is warranted be- dose of tapentadol PR is 50 mg BID (approximately
cause opioid analgesics may be associated with po- every 12 hours), and that dose should be individually
tential severe adverse effects that may be exacerbated titrated to the dose within the range of 50 to 250 mg
96 Volume 37 Number 1
M.J. Sánchez del Águila et al.
BID that provides an optimal balance of analgesic analgesics were permitted in the Phase III studies other
efficacy and tolerability (Figure 1).33 For patients who than paracetamol/acetaminophen, which was used as
are currently taking opioid analgesics, the recommended a rescue drug.23,24,30,40 At these doses, tapentadol PR
starting dose of tapentadol PR depends on the type and was associated with effective and tolerable relief of
daily dose of the previous opioid. A titration regimen in chronic pain.23,24,30,37,38,40
which twice-daily doses of tapentadol PR are increased Efficacy data were pooled from 3 similarly de-
by 50 mg BID every 3 days is appropriate for most signed, randomized, double-blind, Phase III studies
patients to achieve adequate pain control.33 A more comparing tapentadol PR (100–250 mg bid) with
rapid titration schedule may be considered for patients placebo and oxycodone hydrochloride CR (20–50
with uncontrolled pain.37,38,45,56 The recommended mg bid) in patients with moderate to severe, chronic
dose range of tapentadol PR is 50 to 250 mg BID; daily low back pain (1 study24) and chronic osteoarthritis
doses of 4500 mg of tapentadol PR are not recom- pain (2 studies23). Mean changes from baseline in pain
mended.33 Tapentadol PR is available in 50-, 100-, 150-, intensity (last observation carried forward [LOCF])
200-, and 250-mg dose strengths.33 A 25-mg tapentadol over time from that pooled analysis are shown in
PR tablet formulation, currently available in Spain, may Figure 2.29 Based on the change in mean pain intensity
offer a future option for finer dose adjustments up to (11-point numerical rating scale [NRS]) from baseline
250 mg BID in patients with a potential higher sensi- for the overall 12-week maintenance period (LOCF),
tivity to the analgesic effects of tapentadol PR (eg, tapentadol PR met the primary end point of showing
elderly patients, patients with hepatic impairment). noninferior efficacy, and even superior efficacy based
The easy and reliable titration schedule and the use on the outcome of a preplanned additional analysis, to
of doses within the recommended dose range are that of oxycodone CR (least-squares mean difference
supported by the results of 4 key Phase III studies of for tapentadol PR vs oxycodone CR ¼ 0.2; 95% CI,
tapentadol PR in patients with moderate to severe 0.01–0.40; P ¼ 0.037 for superiority). Sensitivity
chronic low back pain,24,30 osteoarthritis pain,23,30 or analyses using different methods of imputation (base-
pain related to DPN,40,57 and the results of 2 recent line observation carried forward [BOCF], worst ob-
Phase IIIb studies of tapentadol PR in patients with servation carried forward (WOCF), and modified
severe chronic osteoarthritis knee pain38 or low back BOCF) also indicated that tapentadol PR provided
pain with or without a neuropathic component.37 The superior analgesic efficacy to oxycodone CR
mean (SD) doses of tapentadol PR taken after the (Figure 3). Tapentadol PR also showed significantly
initial titration periods in each study are shown in greater improvements from baseline than oxycodone
Table I; mean total daily doses (TDDs) in the Phase CR for measures of health-related quality of life,
IIIb studies37,38 were lower than those observed in the including the 36-item Short Form Health Survey
Phase III studies.23,24,30,40 This difference was possibly physical and mental component summary scores
due to the permitted use of concomitant WHO step I (P o 0.001 for both comparisons) and all subscale
analgesics or coanalgesics during study treatment scores (P r 0.048 for all comparisons) except general
(which is more representative of clinical practice) in health (P ¼ 0.061; Figure 4). Similar results were
the Phase IIIb studies,37,38 whereas no concomitant observed when efficacy data were pooled from the
January 2015 97
Clinical Therapeutics
Table I. Total daily doses (TDDs) of tapentadol PR in clinical studies. Data are given as mean (SD)
milligrams.
Study TDD
2 studies in patients with moderate to severe chronic the overall 12-week maintenance period (LOCF),
osteoarthritis pain23 only. Based on the change in tapentadol PR showed superior analgesic efficacy to
mean pain intensity (11-point NRS) from baseline for that of oxycodone CR (least-squares mean difference
Study Week
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0
–0.5
Mean (SE) Change in Pain
Intensity From Baseline
–1.0
–1.5
–2.0
–2.5
–3.0
–3.5
Placebo Tapentadol PR Oxycodone CR
Figure 2. Mean change from baseline in mean pain intensity over time using the last observation carried
forward (intention-to-treat population).29 CR ¼ controlled release; PR ¼ prolonged release; SE ¼
standard error. Reproduced with permission from Lange et al.97 Copyright & 2010 Springer.
98 Volume 37 Number 1
M.J. Sánchez del Águila et al.
WOCF <0.001
January 2015 99
Clinical Therapeutics
yf
yf
ar
ar
m
m
m
m
Su
Su
ng b
nt
ng c
nt
ne
ni
ne
lc
e
th c
io
po
ni
po
lth
na
c
ct
io
om
in d
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ica
om
tio
ea
al
un
ct
e
un
lH
lC
o
ys
lF
lH
Pa
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yc
Em
Ph
lF
ica
ica
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ly
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cia
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le-
ne
di
ys
en
en
ys
ta
Ro
Ro
Bo
Ge
Ph
Ph
So
M
Vi
0
–1
LSMD for Tapentadol PR
–2 –1.8 j
–3 –2.4g
–3.1i
–4 h
–3.8
–5 –4.4h –4.3h
–6
–5.8h
–7
Figure 4. Least-squares mean difference (LSMD) for tapentadol PR versus oxycodone CR for the change from
baseline in 36-item Short Form Health Survey subscale and summary scores (last observation
carried forward). CR ¼ controlled release; PR ¼ prolonged release. aBased on pooled data from 3
randomized, double-blind, placebo- and active-controlled, 15-week, Phase III studies of similar
design. bTapentadol PR, n ¼ 976; oxycodone CR, n ¼ 996. cTapentadol PR, n ¼ 978; oxycodone
CR, n ¼ 997. dTapentadol PR, n ¼ 977; oxycodone CR, n ¼ 997. eTapentadol PR, n ¼ 978;
oxycodone CR, n ¼ 995. fTapentadol PR, n ¼ 978; oxycodone CR, n ¼ 998. gP ¼ 0.008. hP o
0.001. iP ¼ 0.048. jP ¼ 0.010.
program for tapentadol is ongoing at the time of this other potential benefits (eg, improved pharmacoki-
publication. netic profile, improved ease of administration).61
In summary, the favorable tolerability profile for Opioid switching between opioid analgesics with
tapentadol PR relative to other classic opioid analge- similar mechanisms of action may not yield long-
sics allows for a simple titration schedule with term improvements in tolerability or efficacy.62–64
relatively rapid up-titration so that patients do not Given its improved tolerability profile relative to the
need to remain at a low dose for an extended period. classic opioid analgesics oxycodone CR23,24,29,30,40
The recommended dosing regimen and rapid titration and morphine CR42 and its proposed lower cross-
schedule for tapentadol PR (Figure 1) have been tolerance for analgesia due to a unique mechanism
successfully used in clinical studies23,24,30,40 and in a of action, tapentadol PR may offer a better option
noninterventional trial.58,60 This titration schedule than classic opioid analgesics when converting pa-
may facilitate earlier establishment of pain control tients from a previous strong opioid to a new
for patients with chronic pain, and the recommended analgesic.
dose range (up to 500 mg/d) has been sufficient to When switching from a previous strong opioid
control severe to very severe pain. analgesic to tapentadol, the type and dose of the
previous opioid analgesic should be considered in
CONVERSION/SWITCHING FROM CLASSIC selecting a starting dose of tapentadol PR, which
STRONG OPIOIDS may be higher than that required for opioid-naive
Patients may need to switch opioid analgesics if their patients.33 Recommended starting doses of tapentadol
pain does not respond to increasing doses of their PR based on previous opioid doses are summarized in
current opioid, if increasing doses of their current Tables II and III. A dose reduction is typically
opioid are associated with unmanageable adverse recommended when switching from one opioid to
effects, or if opioid switching may be associated with another.65,66 When switching opioids, it may be
difficult to find the ideal dose of the new opioid Table II. Dosage conversions for the start of
therapy to achieve an equianalgesic
analgesic in terms of balancing the potential for provid-
dose when switching from strong
ing too high of a dose, which may exacerbate potential
opioids: dosing conversions used in
opioid-related adverse effects, and underdosing, which Phase IIIb conversion studies. Repro-
may increase the risk of pain peaks or withdrawal duced with permission.56
symptoms. For tapentadol PR, which exerts less opioid
receptor activation than conventional opioids owing to Starting Dose of
*
its MOR and NRI mechanisms of action, it may be Mean MED (mg/d) Tapentadol PR per Day
considered to not reduce the dose by 430% of the
r100 50 mg BID†
calculated equianalgesic dose of the previous opioid (if
101–160 100 mg BID†
that dose is within the therapeutic dose range of
4160 150 mg BID†
tapentadol PR) because this may minimize the risk of
withdrawal symptoms related to discontinuation of the
previous opioid. Generally, titration after conversion MED ¼ morphine-equivalent dose; PR ¼ prolonged
release.
from previous strong opioid analgesics should follow *
Includes all formulations of all strong opioids taken.
the same schedule described in Section 2. Because of †
Approximately every 12 hours.
tapentadol’s favorable tolerability profile, it may be
Table III. Dosage conversions for the start of therapy to achieve an equianalgesic dose when switching from
strong opioids: European dosing recommendations.
pain symptoms (P o 0.05 for all comparisons). Equi- in a study of patients with chronic nonmalignant pain
analgesic ratios of tapentadol PR and WHO step III who were switched from one strong opioid to another.68
opioids in the Phase IIIb study in patients with severe In that study,68 the rate of withdrawal was 32% for
chronic low back pain are summarized in Table IV.45 patients switching from one PR opioid to another and
Although the number of patients used to determine 44% for patients switching from an immediate-release
each of these equianalgesic ratios was relatively small, (IR) opioid to a PR opioid.68 Withdrawal symptoms
the equianalgesic ratio determined for tapentadol PR occurring on opioid switching may be addressed by
to oxycodone CR in this Phase IIIb study45 was in line coadministration of another opioid analgesic, preferably
with that observed in a pooled analysis of data from the IR formulation of the previous opioid.63 For con-
randomized, double-blind, placebo- and active- comitant use of IR opioids with tapentadol PR for
controlled, Phase III studies comparing tapentadol breakthrough pain, please refer to the “Concomitant
PR and oxycodone CR,29 and was confirmed in a Analgesics and Coanalgesics” subsection later herein.
second Phase IIIb study of similar design.56 In both Findings from the previously described noninter-
studies,45,67 the prevalence of TEAEs that were re- ventional trial58 provided further evidence for the
ported as the reason for switching from previous successful rotation of patients directly from a
WHO step III therapy (most commonly constipation previous strong opioid analgesic to tapentadol PR.
and nausea) decreased with tapentadol treatment At the time of this trial, a refined conversion table,
(Figure 6). Approximately 6% of patients in the osteo- based on the results of Phase IIIb studies and early
arthritis study45 and 20% of patients in the low back practical postlaunch experience, was used. In this non-
pain study4 experienced drug withdrawal syndrome, interventional trial,58 1331 patients had previously
largely on switching from their previous strong opioid received a WHO step III analgesic; the most common
to tapentadol PR. Withdrawal symptoms on opioid reasons that patients switched to tapentadol PR from
switching are relatively common, and the rates of their previous strong opioid analgesic were a lack of
withdrawal observed on switching from a previous efficacy, poor quality of life, and poor tolerability. The
WHO step III opioid to tapentadol PR in these mean (SD) dose of tapentadol PR used by this subset
2 studies45,67 are notably lower than those observed of patients at the end of the study was 227.8 (108.8) mg.
Patients (%)
25
PR PR and IR 20 18.3
20.0
40
35 31.7
Patients (%)
IR ¼ immediate release; PR ¼ prolonged release; 30
24.1
WHO ¼ World Health Organization. 25
* 20 17.5
Based on data from a Phase III study in which patients 15
with severe chronic low back pain with or without a 10 7.4
5.6 4.0
neuropathic component switched directly from previous 5 2.2
strong (WHO step III) opioid therapy to tapentadol PR 0
Constipation Nausea Dry Mouth Dizziness
use.45
† Previous Strong Opioid (n = 63) Tapentadol PR (n = 54)
Buprenorphine was administered transdermally or as an
IR formulation (sublingually); fentanyl was administered Figure 6. Reduction in the prevalence of gastro-
transdermally; all other WHO step III opioids were
intestinal and nervous system adverse
administered orally.
‡
Equianalgesic dose ratios calculated for tapentadol PR
events reported as the reason for
to PR formulations of WHO step III opioids. switching from strong opioid therapy
§
Equianalgesic dose ratios calculated for tapentadol PR to tapentadol PR therapy in patients
plus tapentadol IR to PR plus IR formulations of WHO with (A) severe chronic low back pain
step III opioids. with or without a neuropathic compo-
||
PR formulations, n ¼ 21. nent45 and (B) severe chronic osteo-
¶
PR formulations, n ¼ 34. arthritis knee pain.67 The prevalence of
these adverse effects for previous
strong opioids was summarized during
the week before starting tapentadol PR
Most patients (480%) continued tapentadol PR treatment, when patients were still on
treatment after the end of the 3-month observation their previous opioid regimen, and the
period, and 88% of patients achieved their treat- prevalence of these adverse effects for
ment goal with tapentadol PR. Based on the results of tapentadol PR was summarized during
this trial58 and further refined practice-related experi- the last week of a 12-week treatment
period with tapentadol PR. PR ¼
ence, a further refined conversion table was developed
prolonged release.
in Europe (Table III).
In summary, the efficacy and tolerability profile of
tapentadol PR make it a favorable option for patients
who need to be switched from a previous strong opioid STOPPING TAPENTADOL PR TREATMENT
analgesic owing to poor tolerability or a lack of efficacy Patients taking opioid analgesics for chronic non-
at the current doses. Evidence from Phase IIIb stud- cancer pain may experience withdrawal as a symptom
ies45,67 and a noninterventional trial support the ease of of physical dependence after cessation of therapy.69,70
successfully switching patients directly from a previous Withdrawal symptoms may represent a significant
strong opioid analgesic to tapentadol PR, even for problem for patients who need to discontinue their
those who had achieved adequate analgesia (but opioid treatment. As an analgesic with MOR agonist
experienced poor tolerability) on their previous opioid. activity, tapentadol PR may be associated with the
potential for withdrawal symptoms after abrupt dis- PR versus oxycodone CR30 and the 1-year, open-label
continuation.33 extension study support the well-tolerated and effec-
To determine the extent of any possible opioid tive use of tapentadol PR for up to 2 years. Among
withdrawal after cessation of tapentadol PR treat- patients who received tapentadol PR during the 1-year
ment, the occurrence of withdrawal after abrupt tolerability study30 and continued treatment in the
discontinuation of tapentadol PR has been evaluated 1-year extension study,76 mean pain intensity (11-point
in a 1-year, open-label, Phase III tolerability study30; NRS; LOCF) decreased from a baseline score of 7.6 to
in a 1-year, open-label extension study including 3.4 within 4 weeks of treatment and then remained
patients who had previously taken tapentadol PR for relatively constant during the remaining up to 2 years
1 year during the tolerability study71; and in a pooled of treatment (Figure 7). After the initial titration
analysis of 9 randomized, multiple-dose Phase II or III period, mean TDDs of tapentadol PR remained
studies in patients with chronic osteoarthritis pain, relatively stable, as did mean pain intensity scores,
low back pain, or pain related to DPN of up to for up to 2 years of treatment, indicating that
1 year.72 The Clinical Opiate Withdrawal Scale in the tapentadol PR treatment was not associated with
1-year tolerability study30 and open-label extension acquired tolerance.30,76 During the initial 1-year
study71 found that most patients (Z88%) who were tolerability study,30 mean TDDs of oxycodone CR
treated with tapentadol PR for r2 years experienced remained relatively stable after the titration period, as
no opioid withdrawal after abrupt discontinuation of did mean pain intensity scores. For the overall popu-
treatment and that all occurrences of withdrawal were lation in the initial tolerability study,30 tapentadol PR
of mild to moderate intensity. Clinical Opiate treatment was associated with clinically meaningful
Withdrawal Scale results from the pooled analysis72 improvements77,78 in measures of health-related qual-
found that most patients (85% [972 of 1145]) ity of life during 1 year of treatment; these improve-
experienced no opioid withdrawal and that all ments were maintained during the second year of
occurrences of opioid withdrawal were of mild to treatment for patients who continued tapentadol PR
moderate intensity after discontinuation of tapentadol treatment in the extension study.76 Tapentadol PR
PR (mean TDD, 260 mg). was well tolerated, with a particularly favorable
In summary, these results indicate that withdrawal gastrointestinal tolerability profile, during up to
after discontinuation of tapentadol PR treatment is 2 years of treatment.30,76 During the initial 1-year
minimal on abrupt cessation. Nevertheless, to mini- tolerability study,30 22.1% of patients in the tapentadol
mize the possibility that respective symptoms will extended-release group and 36.8% of patients in the
occur, tapentadol PR doses may be tapered gradually oxycodone CR group experienced TEAEs leading to
rather than being stopped abruptly.33 study discontinuation. The overall incidence of gastro-
intestinal TEAEs leading to discontinuation was lower
LONG-TERM TREATMENT WITH in the tapentadol PR group (8.6%) than in the oxy-
TAPENTADOL PR codone CR group (21.5%), as were the incidences of
Patients with chronic pain often require long-term the individual gastrointestinal TEAEs of nausea (3.4%
analgesic treatment.73 The use of opioid analgesics to vs 12.1%), constipation (1.6% vs 7.2%), and vomiting
manage chronic noncancer pain is increasing74; (2.6% vs 6.7%).30 For the overall population in the
however, evidence supporting the long-term efficacy initial tolerability study,30 the incidences of the
and tolerability of these agents is frequently lacking.73 following gastrointestinal adverse events were lower
In addition to the generally favorable efficacy and with tapentadol PR than with the active comparator,
tolerability profile reported for tapentadol PR in oxycodone CR: nausea (18% vs 33%), vomiting (7%
patients with chronic pain for approximately 3 to vs 14%), and constipation (23% vs 39%). The
4 months,23,24,29,36–44 tapentadol PR has been found incidences of the most common TEAEs (incidence
to be effective and well tolerated for up to 2 years in Z5%) reported by patients who received up to
patients with chronic osteoarthritis knee pain or low 2 years of tapentadol PR treatment are summarized
back pain.30,71,75 in Table V.
Findings from the previously mentioned 1-year, In summary, these results indicate that tapentadol
open-label, Phase III tolerability study of tapentadol PR is well tolerated and effective during up to 2 years
Figure 7. Mean (SE) pain intensity scores over time for patients in the open-label extension study who
received previous tapentadol prolonged release treatment in the 1-year tolerability study. *The
baseline (BL) value for the open-label extension study and the end point value for the 1-year
tolerability study. SE ¼ standard error.
of treatment in patients with chronic pain,30,76 with patients ( 55% to 89%) did not require additional
no development of acquired tolerance to the analgesic analgesia with tapentadol IR, and the mean daily
effects of tapentadol over time (based on evaluations doses of tapentadol IR used were relatively low (6.7–
of mean pain intensity and mean TDDs over time). 24.6 mg).37,38,45,56 In all 4 studies,37,38,45,56 tapenta-
dol treatment, which included a combination of
USE OF TAPENTADOL IR IN ADDITION TO tapentadol PR and IR, was well tolerated and effec-
TAPENTADOL PR FOR ACUTE PAIN EPISODES tive. The data collected on the use of tapentadol IR for
Tapentadol IR is indicated for the relief of moderate the treatment or prevention of withdrawal symptoms
to severe acute pain in adults, which can be ad- after discontinuation of previous opioids in these
equately managed only with opioid analgesics.79 trials37,38,45,56 were not sufficient to allow for a
Tapentadol IR has been used on top of tapentadol detailed analysis.
PR treatment for acute pain episodes or for the relief In summary, these results suggest that the use of
of withdrawal symptoms after direct conversion from tapentadol IR on top of tapentadol PR could be a
previous strong opioid analgesics in several Phase IIIb feasible option for addressing particularly acute pain
studies.37,38,45,56 The results of these studies suggest episodes.37,38,45,56 Both the IR and PR formulations of
the effectiveness and tolerability of tapentadol IR on tapentadol may not be available in all countries. In
top of tapentadol PR in patients with low back pain those cases, it may be possible to use other IR opioids
with or without a neuropathic pain component37,45 (eg, morphine, oxycodone) for the management of
and in those with osteoarthritis knee pain.38,56 acute pain episodes or withdrawal symptoms based on
In 4 open-label, Phase IIIb studies in patients with the positive results observed with tapentadol IR on
severe low back pain or osteoarthritis knee top of tapentadol PR.
pain,37,38,38,45 tapentadol IR (50 mg, twice daily or
less; Z4 hours apart) was permitted for acute pain USE OF CONCOMITANT MEDICATIONS
episodes or for the relief of withdrawal symptoms WITH TAPENTADOL PR
occurring after the discontinuation of previous opioid Pharmacokinetic Interactions
analgesics; the total tapentadol doses (including PR and Patients with severe chronic pain may have comor-
IR formulations) could not exceed 500 mg/d.37,38,45,56 bid conditions that necessitate the use of concomitant
After the tapentadol PR doses had stabilized, most medications. Tapentadol is largely metabolized by
variety of studies.36–38,42,45,56 The concomitant use of suggest that combination therapy with tapentadol
WHO step I analgesics and coanalgesics was permit- PR and pregabalin was well tolerated and effective
ted in the 4 previously described open-label, Phase IIIb and that tapentadol may be a more favorable and
studies of tapentadol PR in patients with low back complementary combination partner than pure strong
pain with or without a neuropathic pain compo- opioid agonists.36
nent37,45 or with osteoarthritis knee pain.38,56 Across Findings from the previously described prospective
all 4 studies,37,38,45,56 concomitant coanalgesics were noninterventional trial60 in patients with severe
taken by 14.3% to 54.4% of patients and concom- chronic pain who were receiving tapentadol PR
itant WHO step I analgesics were taken by 55.6% to during routine treatment by a general practitioner
64.5% of patients. Despite the relatively high percen- or internist provided further support for the tolerable
tages of patients taking WHO step I analgesics or use of concomitant analgesics with tapentadol PR. In
coanalgesics, the tolerability profile observed in these that study,60 concomitant analgesics were taken with
studies37,38,45,56 for tapentadol PR was generally tapentadol PR by 48.4% of patients (strong opioids,
better than that observed in randomized, controlled, 3.6%; weak opioids, 6.4%; nonopioids, 44.7%) at
Phase III studies23,24,40 that did not allow additional the final visit. Treatment was well tolerated, with
analgesics or coanalgesics, indicating that the con- adverse drug reactions reported for only 7% of
comitant use of WHO step I analgesics or coanalgesics patients.60
did not have a negative effect on the tolerability of In summary, the results of these studies36–38,45,56,60,80,84
tapentadol PR but also reflecting the lower mean suggest that tapentadol PR has a low potential for
doses of tapentadol PR used in Phase IIIb studies. In pharmacokinetic drug-drug interactions. Pharmacoki-
addition, morphine IR42,85,86 and oxycodone IR86 netic drug-drug interactions mediated by cytochrome
were permitted for the treatment of breakthrough P450 pathways20 or plasma protein binding are
pain concomitantly with tapentadol PR in Phase III unlikely to occur with tapentadol PR.33 There is a
studies in patients with moderate to severe chronic potential for pharmacodynamic interactions with
malignant tumor–related pain. In those studies,42,85,86 CNS-active drugs (see the summary of product char-
tapentadol PR used concomitantly with morphine IR acteristics for full information).33 When tapentadol
and oxycodone IR was well tolerated. Although only PR has been administered with centrally acting
the concomitant use of morphine IR and oxycodone analgesics and coanalgesics,37,38,45,56 selective seroto-
IR for breakthrough pain has been evaluated, these nin reuptake inhibitor– or serotonin norepinephrine
findings suggest that other IR opioids could be safely reuptake inhibitor–type antidepressants, or anticon-
used as well. vulsants,33,36,79,84 the tolerability profile has been
In a randomized, double-blind, Phase IIIb study in found to be comparable with that of tapentadol PR
patients with severe low back pain with a neuropathic alone, in line with the subpopulation studied. In
component,36 the analgesic efficacy of a combination addition, a combination of tapentadol PR and pre-
of tapentadol PR (300 mg/d) and pregabalin (300 mg/d) gabalin36 was found to have a better tolerability
was comparable with that of tapentadol PR (500 mg/d), profile compared with historical trials of other
and the incidence of the composite of dizziness and/or opioid analgesics and coanalgesics.14,15 Taken as a
somnolence was significantly lower with tapentadol whole, these results indicate that tapentadol PR may
PR monotherapy (16.9%) than with the combination be safely coadministered with many other medica-
of tapentadol PR and pregabalin (27.0%; P ¼ tions.
0.0302). Still, incidences of the most common
TEAEs in the combination arm were relatively low ABUSE AND DIVERSION
compared with the rates of adverse effects observed in Abuse and diversion are major concerns for physicians
historical trials of combinations of opioids and prescribing long-term opioid analgesics for the man-
coanalgesics.14,15 Furthermore, the rate of adverse agement of chronic noncancer pain.87–89 An abuse
event–related discontinuations remained comparable liability trial in opioid-experienced patients versus oral
in both treatment groups (tapentadol PR monother- hydromorphone that was early in the clinical develop-
apy, 7.8%; tapentadol PR plus pregabalin combina- ment of tapentadol reported a similar liking potential
tion therapy, 7.5%). Taken together, these results for oral tapentadol. In the United States and Europe,
09
09
10
10
10
10
11
11
United States.91
20
20
20
20
20
20
20
20
3Q
4Q
1Q
2Q
3Q
4Q
1Q
2Q
Quarter/Year
Although caution is warranted when prescribing
tapentadol PR to patients for whom there is a concern Figure 8. Drug diversion rates for oxycodone,
about an elevated risk of drug misuse, abuse, addic- hydrocodone, tramadol, and tapenta-
tion, or diversion,33 results of recent studies indicate a dol IR during the first 24 months of
low level of abuse for tapentadol in practice. In a tapentadol IR availability per 1000
study92 that evaluated the rates of abuse and diversion unique recipients of dispensed drug
of tapentadol IR after its introduction to the US (URDD).90 IR ¼ immediate release.
market using data from a US surveillance system Republished with permission of
Weston Medical Publishing, LLC, from
(the Researched Abuse, Diversion, and Addiction-
Dart RC, Cicero TJ, Surratt HL, et al.92
Related Surveillance [RADARS] system93), rates of
Copyright & 2012; permission con-
tapentadol IR abuse and diversion were low during veyed through Copyright Clearance
the first 24 months after its introduction (Figure 8).92 Center, Inc.
Drug diversion rates were found to be low when either
population and unique recipients of dispensed drug
denominators were used.92 During the first 2 years
after its introduction, no tapentadol IR diversion was tapentadol misuse was also observed in a recent
reported during a 9-month period (from the third retrospective cohort study,96 which found that the
quarter of 2009 to the second quarter of 2010).92 The risk of opioid doctor shopping was 43 times more
diversion rate per 1000 unique recipients of dispensed likely for patients treated with oxycodone than for
drug for tapentadol IR was low (substantially lower those treated with tapentadol.96
than that for oxycodone or hydrocodone) throughout These findings from early clinical experience with
the 2-year evaluation period despite the increase in the tapentadol suggest that it is associated with low rates
number of unique tapentadol IR recipients during that of abuse and diversion in practice. The potential for
time frame.92 Data from that same surveillance system abuse and addiction with tapentadol PR should be
were used to evaluate the street value of selected considered, however, for patients for whom there is a
prescription opioids, including tapentadol, during the concern about an increased risk of misuse, abuse,
fourth quarter of 2012; very few street price reports addiction, or diversion.33 Further data on abuse and
were available for tapentadol during the quarter diversion of tapentadol need to be collected and
surveillance period, indicating limited availability of analyzed. If the currently observed profile is
tapentadol in the illicit market. In that study,94 maintained, tapentadol may offer a safer option in
opioids with a single mechanism of action had this respect for patients requiring strong analgesic
higher street values than drugs with 41 mechanism therapy for their chronic pain.
of action, including tapentadol.94 In a separate
study95 evaluating the rate of abuse of tapentadol IR SUMMARY AND CONCLUSIONS
among US college students during the 2 years after its Tapentadol PR, which represents a proposed new
launch in 2009, the rate of nonmedical use of class of centrally acting analgesic with 2 mechanisms
tapentadol IR was low (7 times lower than that of action, MOR agonism and NRI,16,17 has been in
of oxycodone and 9 times lower than that of practical use for Z3 years in various countries.
hydrocodone) and declined during the 2-year period Tapentadol PR, which has been associated with
despite increasing pharmacy sales. The low rate of improvements in pain and quality of life for patients
with and without a neuropathic component to their and Teva. K.-U. Kern is a consultant or presenter for
chronic pain, may provide clinically meaningful bene- Astellas, Berlin Chemie, Boehringer Ingelheim,
fits over classic opioid analgesics for the long-term BetaPharma, Grünenthal, Lilly, Medi Bayreuth, and
management of severe chronic pain. Furthermore, Mundipharma and received LIIRA grant support for
tapentadol PR treatment has been associated with clinical research from Pfizer. T. Drost and I. Steigerwald
improvements in neuropathic pain symptoms for are employees of Grünenthal GmbH. The authors have
patients with neuropathic pain only.37,45 Tapentadol indicated that they have no other conflicts of interest
PR also has an improved tolerability profile, partic- regarding the content of this article.
ularly gastrointestinal tolerability, compared with
other classic opioid analgesics,23,24,29,30,40,42 which
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