ExP.ert
`Opinion
`
`1.
`
`Introduction
`
`2. Tapentadol: mechanism of
`action
`
`3. Tapentadol IR: clinical studies
`
`4. Conclusion
`
`5. Expert opinion
`
`informa
`
`healthcare
`
`Drug Evaluation
`
`Tapentadol immediate release for
`the relief of moderate-to-severe
`acute pain
`
`Craig T Hartrick
`Director, Anesthesiology Research, William Beaumont Hospital, Department of Anesthesiology,
`3601 W 13 Mile Rd, Royal Oak, MI 48073, USA
`
`Tapentadol is a novel, centrally acting analgesic with two mechanisms of
`action: 1-1-opioid receptor agonism and norepinephrine reuptake inhibition. It
`has demonstrated broad analgesic efficacy across multiple pain models. This
`article reviews the clinical development of tapentadol immediate release (IR),
`including results from Phase II and Ill clinical trials that evaluated the efficacy
`and safety of tapentadol IR in patients with moderate-to-severe acute pain.
`In clinical studies in patients with moderate-to-severe acute postoperative
`pain, osteoarthritis pain and/or low back pain, tapentadoiiR 50, 75 or 100 mg
`every 4-6 h has demonstrated analgesic efficacy similar to that observed with
`the 1-1-opioid receptor agonist oxycodone HCI IR 10 or 15 mg every 4- 6 h.
`However, at doses providing comparable analgesic efficacy, tapentadoiiR has
`been associated with significantly lower incidences of nausea and/or vomiting
`and constipation, and a significantly lower rate of treatment discontinuation
`compared with oxycodone IR. The observed efficacy across different pain
`models and favorable gastrointestinal tolerability profile associated with
`tapentadol IR indicate that this novel analgesic is an attractive treatment
`option for the relief of moderate-to-severe acute pain.
`
`Keywords: acute pain, analgesia, opioid, osteoarthritis, postoperative pain, tapentadol
`
`Expert Opin. Pharmacother. (2009) 10(1 6):2687-2696
`
`1. Introduction
`
`Historically, treatment options for the relief of moderate-to-severe acute pain have
`included opioid analgesics, NSAIDs and COX-2-selective inhibitors [IJ. Despite
`these available treatment options and the development of guidelines to optimize
`pain management practices [2-7], many patients continue to experience unrelieved
`moderate-to-severe pain. For example, in a survey [8] of> 1,000 patients who
`underwelll ambulatory day surgery, - 35% experienced moderate-to-severe pain
`after their release from the hospital, even with prescribed analgesic therapy.
`Unrelieved pain is a significant health problem because it can interfere with patients'
`general activity, mood, walking ability, personal relations and sleep L9J. In addition,
`unrelieved pain can result in an increased risk for deep vein thrombosis, pulmonary
`embolism, coronary ischemia, myocardial infarction, hypoxia, pneumonia and poor
`wound healing [10-12].
`Opioids such a.~ oxycodone and morphine provide effective analgesia for noci(cid:173)
`ceptive pain [13]. However, side effects such as nausea, vomiting, constipation,
`dizziness, pruritus and somnolence are common with the use of pure ).l-opioid
`receptor agonists; these side effects can cause discomfort and distress for patients and
`may contribute to poor patient compliance and discontinuation of therapy [14,15].
`For example, a recent adaptive conjoint analysis [16] of patient preferences for the
`relief of acute pain involving 50 patients undergoing major abdominal surgery
`showed that patients are willing to compromise optimum pain relief in order to
`
`10.1517/14656560903313734 © 2009 lnforma UK Ltd ISSN 1465-6566
`All rights reserved: reproduction in whole or in part not permitted
`
`2687
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`Page 1 of 10
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`Grunenthal GmbH Exhibit 2002
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
`
`

`
`Tapentadol
`
`Box 1. Drug summary.
`
`Drug name
`Phase
`Indication
`Pharmacology
`description
`
`Route of administration
`Chemical structure
`
`Tapentadol IR
`Launched
`Pain
`J..t-Opioid receptor agonist;
`adrenergic transmitter uptake
`inhibitor
`Alimentary, p.o.
`
`~w/,..
`
`Pivotal tnal(s)
`
`0
`Two Phase Ill tnals in patients
`undergoing bunionectomy
`surgery or with degenerative,
`end-stage JOint disease of the
`hip or knee were completed.
`Data suggested it had efficacy
`comparable to strong opioids.
`A Phase Ill trial in outpatients
`w1th lower back pain or pain
`from osteoarthritis of the hip
`or knee was also completed
`
`Pharmaprojects - copyright to Citeline Drug Intelligence (an lnforma
`business)
`Readers are referred to lnforma-Pipeline (http://informa-pipeline.citeline
`com) and C1tel1ne (http://mforma.cltellne.com)
`
`reduce or eliminate unpleasant side effects such as nausea,
`vomiting, pruritus, constipation, sleep disorders and mental
`cloudiness. In addition, physicians are often reluctant to
`prescribe opioids because of the potential risks of side effects,
`tolerance, abuse, withdrawal and liability [17-19]. Patients also
`frequently fail to accurately report the severity of their pain
`and may be unwilling to take opioid analgesics because of
`fears of side effects, tolerance, withdrawal and addiction [20].
`For these reasons, opioids are often prescribed at suboptimal
`doses or are underused [19].
`Certain types of pain may have a neuropathic component
`as well as a nociceptive component [21-23], and opioids are
`not considered first-line therapy for the management of
`neuropathic pain l24J. Neuropathic pain is usually managed
`with tricyclic antidepressants, selective serotonin/norepineph(cid:173)
`rine reuptake inhibitors, anticonvulsants, antiarrhythmics,
`N-methyl-D-aspartate receptor antagonists and topical thera(cid:173)
`pies [22,25,26]. Opioids are frequently combined with these
`types of drugs [27]; however, opioid use is often reserved for
`patients with rdractory neuropathic pain [22,25].
`
`NSAIDs and COX-2 inhibitors are often not sufficiently
`effective for the relief of moderate-to-severe pain [10]. In
`addition, NSAIDs are associated with the potential for seri(cid:173)
`ous gastrointestinal, renal and cardiovascular adverse effects
`including peptic ulceration and upper gastrointestinal tract
`bleeding, renal dysfunction and altered platelet function,
`increased risk of bleeding [2R-30].
`which can
`lead to an
`COX-2 inhibitors are associated with adverse effects on renal
`function and cardiovascular adverse effects including promo(cid:173)
`tion of thrombosis and myocardial infarction [31]. The risk of
`adverse effects associated with NSAlDs and COX-2 inhibitors
`increases when these drugs are used at high doses [32-34].
`Tramadol is an available treatment option for the relief
`of moderate-to-moderately-severe acute pain in adults [35]. It
`has ,LL-opioid receptor agonist, serotonergic and noradrenergic
`activity and may offer clinical advantages over opioids. Clin(cid:173)
`ical studies have suggested a low potential for abuse and
`respiratory depression [35,36]. The analgesic activity of trama(cid:173)
`dol relics on metabolic activation, which can lead to variability
`in pain relief.
`Tapentadol (Box 1) is a novel, centrally acting analgesic with
`two mechanisms of action: ).!-opioid receptor agonism and
`norepinephrine reuptake inhibition [37.38]. The unique mech(cid:173)
`anism of action of tapcntadol may offer advantages over other
`marketed analgesics used for the relief of moderate-to-severe
`pain. Tapentadol has demonstrated efficacy in preclinical
`models of both nociceptive and neuropathic pain r37l. An
`immediate-release (IR) formulation of tapentadol is available
`in the US for the relief of moderate-to-severe acute pain in
`patients ;:o: 18 years of age. In clinical trials [39-43], tapentadol
`IR (50, 75 or 100 mg every 4 - 6 h) has demonstrated an
`improved gastrointestinal tolerability profile compared with
`oxycodone HCl IR (10 or 15 mg every 4 - 6 h) at doses
`providing similar analgesic efficacy. This article reviews the
`clinical development of tapentadol IR, including published
`results from several Phase II and Phase III trials [40-43] that
`show the efficacy and satety of tapentadol IR in different
`models of moderate-to-severe acute pain.
`
`2. Tapentadol: mechanism of action
`
`Tapentadol has several features that help to differentiate it
`from opioids with a single mechanism of action (Table 1).
`lt has moderate ).!-opioid receptor affinity compared with
`morphine and oxycodone [37]. The K;_ value for tapentadol
`is
`based on binding assays using rat brain membranes
`0.1 ).!M, which is significantly weaker than that of morphine
`(K;_ = 0.002 J.!M [rat]) and oxycodone (K;_ = 0.018 J.!M
`[rat]) [3744]. This observed reduction in the ).!-opioid receptor
`binding affinity of tapentadol does not appear to lead to
`reduced analgesic efficacy because its second mechanism of
`action, norepinephrine reuptake inhibitor activity, also con(cid:173)
`tributes to the analgesic efficacy of tapentadol. Norepineph(cid:173)
`rine has been shown to play a role in the endogenous
`descending pain inhibitory system [45], and the analgesic
`
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`Page 2 of 10
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`

`
`Table 1. The mechanism of action and main metabolites of selected analgesics.
`
`Tapentadol IR
`
`Oxycodone IR
`
`Tramadol
`
`Morphine
`
`Mechanism of action
`
`~t-Oploid receptor agonist [38]
`Norepinephrine reuptake inhibitor [38]
`~t-Oploid receptor agonist 1441
`
`~t-Oploid receptor agonist [BoJ*
`Norepinephrine [49]§ and serotonin reuptake inhibitor [81]'11
`~t-Oploid receptor agonist [83]
`
`*Inactive metabolite
`*Associated mainly with the (+)-enantiomer and its metabolite, 0-desmethyltramadol
`§Associated with the (-)-enantiomer
`~Associated mainly with the (+)-enantiomer
`IR: Immediate release
`
`Hart rick
`
`Main metabolites
`
`Tapentadol-0-glucuronide [78]*
`
`Noroxycodone 1791
`Oxymorphone [79]
`0-desmethyltramadol [B2]
`
`Morphlne-3-glucuronide [84]
`Morph1ne-6-glucuronide [84]
`
`efficacy of norepinephrine reuptake inhibitors, such as tricyclic
`and tetracydic antidepressants, has been established in pain
`models where a neuropathic component is involved (i.e.,
`low back pain and pain associated with diabetic peripheral
`neuropathy) [46,47].
`The norepinephrine reuptake inhibitor activity of tapenta(cid:173)
`dol may also provide an 'opioid-sparing' effect, resulting in an
`overall improvement in tolerability compared with ~-opioid
`analgesics. Thus, the two mechanisms of action of tapentadol
`may explain its obsetved analgesic efficacy, which is compa(cid:173)
`rable to that of the ~-opioid receptor agonist oxycodone, but
`with a reduction in side effects commonly associated with pure
`~-opioid analgesics, such as nausea, vomiting, constipation
`and pruritus [40-43].
`Unlike tramadol, which is a racemic mixture of(+) and
`(-) enantiomers, with active metabolites also contributing
`to its analgesic efficacy, tapentadol is a pure enamiomer
`with no active metabolites that contribute to its analgesic
`efficacy [37,48]. The serotonergic 5-HT activity of tramadol is
`associated mainly with the (+)-enantiomer of the parent
`compound; norepinephrine reuptake inhibitor activity is asso(cid:173)
`ciated with the (-)-enantiomer of the parent compound; and
`~-opioid receptor agonism is associated mainly with the
`( + )-enantiomer and its Ml metabolite, 0-desmethyl trama(cid:173)
`dol, which has even greater ~-opioid activity (tramadol:
`f< = 2.1 ~M [mouse]; 0-desmethyl tramadol: f< = 0.0034
`~M [human]) [49,50]. Therefore, as Lramadol is metabolized
`from the parent compound to its active metabolites, the mech(cid:173)
`anism of analgesia changes over time. The clearance rate of
`active metabolites may vary widely from one patient to
`another; this creates the potential for accumulation of high
`concentrations of active molecules, which may require dose
`adjustments and may lead to suboptimal pain management.
`For example, ~ 7% of Caucasians lack the CYP isozyme
`CYP2D6, which is involved in metabolism of ( + )-tramadol to
`( + )-0-desmethyl tramadol [51]. Therefore, these patients are
`poor metabolizers of tramadol [51] and require dose adjust(cid:173)
`ments, which may complicate prescribing for physicians and
`
`negatively affect patient compliance. In contrast, the relative
`contributions of the two mechanisms of action of tapentadol
`do not change over time as the molecule is metabolized, and
`the absence of active metabolites reduces the risk of possible
`side effects due to exposure to these metabolites.
`Another advantage of tapentadol over many other avail(cid:173)
`able analgesics is a low potential for drug-drug interactions.
`Tapentadol is metabolized primarily via Phase II conjugation
`to form glucuronide or sulfate conjugates [52]. The major
`metabolite is tapentadol-0-glucuronide, which is formed via
`reactions with the uridine diphosphate (UDP)-glucuronosyl(cid:173)
`transferase (UGT) enzymes UGT1A9 and UGT2B7 [52]. In
`preclinical in vitro drug~drug interaction studies, the potential
`for clinically relevant interactions between tapentadol and drugs
`that induce or inhibit CYP enzymes was low [52]. This is
`significant because CYP enzymes contribute to the clearance of
`approximately two-thirds of the most commonly prescribed
`metabolized drugs [53], including many drugs with serotonin
`norepinephrine reuptake inhibition activity [54] and pure
`~-opioid agonists including morphine, codeine, oxycodone
`and hydrocodone [55,56]. Further, drug~drug interactions may
`also occur because of displacement of concomitantly admin(cid:173)
`istered medications from protein plasma or serum protein
`binding sites. In vitro studies of tapentadol have shown that
`only 20% of tapentadol is bound to serum proteins, indicating
`that it is unlikely that clinically relevant drug-drug interactions
`will occur as a result of the displacement of concomitantly
`administered medications from plasma proteins [52].
`Tapentadol is rapidly absorbed with a time lO maximal
`concentration of 1.25 ~ 1.5 h [48]. The absolute oral bioavail(cid:173)
`ability of tapentadol is~ 32% [38], which is comparable to that
`of morphine (34%) l57J. In contrast, the oral bioavailability
`of tramadol has been reported to be 68% 1581. Tapentadol,
`which is present primarily in the conjugated form (unconju(cid:173)
`gated to conjugated ratio = 1.24), is excreted almost exclu(cid:173)
`sively (99%) by the kidneys, with 69% excreted as glucuronide
`or sulfate conjugates, 27% as other metabolites and 3% as
`unchanged tapentadol [48].
`
`Expert Opin. Pharmacother. (2009) 10(16)
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`
`Tapentadol
`
`3. Tapentadol IR: clinical studies
`
`Clinical Lrials examining muhiple doses of Lapemadol IR
`across different models of moderate-to-severe acute pain
`have shown that at doses providing similar analgesic efficacy,
`tapentadol IR (50, 75 or 100 mg every 4- 6 h) has a better
`gastrointestinal tolerability profile than oxycodone HCl IR
`( 10 or 15 mg every 4 - 6 h) [39-43]. Details of those clinical
`studies are presented here.
`
`3.1 Postoperative pain
`The initial efficacy of tapentadol for moderate-to-severe pain
`was established in a single-dose study in patients undergoing
`third molar extraction [59]. The efficacy and safety of tapen(cid:173)
`tadol IR were further evaluated in three separate clinical
`studies in patients undergoing primary unilateral first meta(cid:173)
`tarsal bunionectomy surgery [39,42,43]. Orthopedic bunionect(cid:173)
`omy surgery is a well-established postoperative acute pain
`model [60-63]. Elective bunionectomy surgery, which involves
`correction of malformations of the large toe joint by surgically
`repairing the bony and capsular tissue around the joint [60], is
`an appropriate model for the evaluation of analgesic efficacy
`because patients are generally in good overall health, and
`the pain following surgery is usually moderate-to-severe in
`intensity [61]. In addition, since bunionectomy surgery avoids
`the viscera, the procedure reduces the likelihood of gas(cid:173)
`LroimesLinal and respirawry dysfunCLion due LO surgery,
`and a standardized surgical and anesthetic procedure is
`used, which results in less confounding and less interpatient
`variability in pain.
`In a Phase II multiple-dose study [39] that compared the
`efficacy and tolerability of tapentadol IR 50 or 100 mg with
`that of oxycodone HCl IR 10 mg or placebo given every
`4- 6 hover a 72-h period, the mean (standard deviation) sum
`of pain intensity over 24 h on day 2 after randomization was
`significantly lower for tapentadol IR 50 mg (33.6 [1':1.7],
`p = 0.133), tapentadol IR 100 mg (29.2 [15.2], p = 0.0001)
`and oxycodone HCl IR 10 mg (35.7 [17.2], nominal
`p = 0.0365) as compared to placebo (41.9 [17.7]). Explora(cid:173)
`tory efficacy comparisons performed on pain intensity and
`pain relief results from that study suggested that tapentadol
`IR 100 mg provided better analgesic efficacy than oxyco(cid:173)
`done HCl IR 10 mg, and that the efficacy of tapentadol IR
`50 mg was similar to that provided by oxycodone HCl lR
`1 0 mg. The overall incidence of gastrointestinal adverse
`evems (AEs) and Lhe incidence of Lhe mosl commonly
`reported specific gastrointestinal events of nausea, vomiting
`and constipation were all numerically lower in the tapentadol
`IR 50- and 100-mg groups than in the oxycodone HCl IR
`10-mg group (Table 2).
`A Phase III bunionectomy study [43] compared tapentadol
`IR 50, 75 and 100 mg with oxycodone HCl IR 15 mg
`and placebo administered every 4 -
`() h for 72 h following
`surgety in patients (n = 603) with moderate-to-severe pain.
`All active treatments were significantly more effective than
`
`placebo based on the sum of pain intensity difference over
`48 h (SPID48 all p S::: 0.001). A post hoc analysis showed
`that tapentadol IR 100 mg and oxycodone HCl IR 15 mg
`provided equivalent analgesic efficacy; however, the former
`was associated with a significantly lower incidence of nausea
`and/or vomiting than the latter (53 versus 70%, respectively;
`nominal p = 0.007).
`Another Phase III bunionectomy study [42] compared tape(cid:173)
`ntadollR 50 and 75 mg with oxycodone HCllR 10 mg and
`placebo administered every 4 - 6 h following surgery. In that
`study, acetaminophen(< 2 g) was allowed in the first 12 h after
`the first dose of study medication. T apentadol IR 50 and
`75 mg were evaluated using prespecified comparisons for
`efficacy superior to placebo and noninferior to oxycodone
`H Cl IR 10 mg, and tolerability superior to oxycodone H Cl IR
`10 mg. Consistent with the first Phase III bunionectomy
`study [43], all active treatments were significantly more effective
`than placebo based on SPID48 (all p S::: 0.001). The efficacy of
`tapentadol IR 50 and 75 mg was statistically noninferior to
`that provided by oxycodone HCl IR 10 mg based on pre(cid:173)
`specified comparisons of mean SPID48 values. The incidence
`of nausea and/or vomiting was statistically significantly lower
`in the tapentadol IR 50-mg group (35%) than in the oxy(cid:173)
`codonc HCl IR 10-mg one (59%; p < 0.001). The incidence
`of nausea and/or vomiting was numerically lower in the
`tapentadol IR 75-mg group (51 o/o) than in the oxycodone
`HCl IR 10-mg group (59%), buL resuhs for Lhe Lapemadol
`IR 75-mg group were not statistically significant (p = 0.057).
`The most common treatment-emergent AEs reported in that
`study were nausea, vomiting, dizziness, headache, somno(cid:173)
`lence, pruritus and constipation. Tapentadol IR 50 mg was
`associated with lower incidences of all of these treatment(cid:173)
`emergent AEs than oxycodone HCl IR 10 mg (Table 3).
`Tapentadol IR 75 mg was associated with lower incidences
`of nausea, headache and constipation than oxycodone HCl
`IR 10 mg, and with similar incidences of vomiting, dizziness
`and somnolence (Table 3).
`
`3.2 End-stage joint disease
`End-stage joint disease in patients who were candidates
`for joint replacement surgery due to moderate-to-severe
`acute osteoarthritis pain of the hip or knee was chosen as a
`model of short-term acute pain requiring treatment with
`suong analgesics because Lhese paLiems consisLendy repon
`moderate-to-severe pain that requires a relatively constant
`level of analgesia [64]. In addiLion, paLiems awaiLing joim
`replacement surgery are required to discontinue therapy
`with NSAIDs for S::: 2 weeks in preparation for surgery because
`NSAIDs may interfere with coagulation l65,66J. Tapentadol
`IR may be an appropriate short-term treatment option for
`this population, with the advantage of lower incidences of
`gastrointestinal AEs over pure )l-opioid analgesics [67].
`A Phase III study [40] in patients (n = 666) with moderate(cid:173)
`to-severe osteoarthritis hip or knee pain who were candidates
`for joint replacement surgery due to end-stage joint disease
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`
`Hart rick
`
`Table 2. Incidence of gastrointestinal TEAEs in a Phase II study of tapentadol IR in patients with moderate-to-severe
`pain following bunionectomy [39].
`
`Type of TEAE
`
`Placebo
`{%; n = 67)
`
`Tapentadol IR 50 mg
`{%; n = 67)
`
`Tapentadol IR 100 mg
`{%; n = 68)
`
`Oxycodone HCIIR 10 mg
`{%; n = 67)
`
`All Gastrointestinal TEAEs
`
`Nausea
`
`Vomiting
`Constipation
`
`25.4
`
`17.9
`
`1.5
`1.5
`
`56.7
`
`46.3
`
`16.4
`6.0
`
`70.6
`
`66.2
`
`35.3
`7.4
`
`79.1
`
`71.6
`
`38.8
`17.9
`
`Adapted by permission from lnforma Healthcaw Curr Med. Res Opin 25(6): 1551-61, copyright 2009 [42]
`IR: Immediate release; TEAE: Treatment-emergent adverse event
`
`Table 3. TEAEs reported by> 5% of patients in a Phase Ill study of tapentadol IR in patients with moderate-to-severe
`pain following bunionectomy [39].
`
`Type of TEAE
`
`Placebo
`{n = 69), n {%)
`
`Tapentadol IR 50 mg
`(n = 275), n {%)
`
`Tapentadol IR 75 mg
`{n = 278), n {%)
`
`Oxycodone HCI IR 10 mg
`{n = 279), n {%)
`
`Nausea
`Vomiting
`
`Dizziness
`Headache
`
`Somnolence
`Pruritus
`Constipation
`
`12 (17)
`
`0
`7 (1 O)
`11 (16)
`
`2 (3)
`2 (3)
`1 (1)
`
`93 (34)
`34 (12)
`
`41 (15)
`56 (20)
`
`20 (7)
`14 (5)
`22 (8)
`
`IR: Immediate release; TEAE: Treatment-emergent adverse event
`
`127 (46)
`77 (28)
`
`69 (25)
`52 (19)
`
`37 (13)
`23 (8)
`15 (5)
`
`160 (57)
`72 (26)
`
`65 (23)
`73 (26)
`
`33 (12)
`28 (10)
`31 (11)
`
`was conducted to compare the efficacy and tolerability of
`tapentadol IR 50 and 75 mg with oxycodone HCl IR 10 mg
`and placebo. Study medication was administered every 4 - 6 h
`during waking hours for 10 days. All active treatments were
`significantly more effective than placebo based on 5-day SPID
`results (all p < 0.001). Based on a prespecified noninferioriry
`analysis, tapentadol IR 50 and 75 mg both provided efficacy
`comparable to that provided by oxycodone HCl IR 10 mg.
`The most common AEs reported in that study were typical
`of centrally acting analgesics and included nausea, dizziness
`and vomiting. The incidence of nausea and/or vomiting and
`the incidence of constipation were significantly lower for
`both doses of tapentadol IR than for oxycodone HCI IR
`10 mg (nominal p < 0.001 for all comparisons). The odds
`ratios (95% confidence intervals) for nausea and/or vomiting
`for tapentadol IR 50 and 75 mg compared with oxycodone
`HCI10 mgwere 0.21 (0.128, 0.339) and 0.32 (0.204, 0.501),
`respectively. Odds ratios for constipation tor tapentadol IR 50
`and 75 mg compared with oxycodone HCl IR 10 mg were
`0.13 (0.057, 0.302) and 0.20 (0.098, 0.398), respectively. The
`rates of discontinuation due to AEs were lower in the tapen(cid:173)
`tadol IR 50- and 75-mg groups (13 and 18%, respectively)
`than in the oxycodone HCI IR 10-mg group (30%).
`
`3.3 long-term tolerability
`A Phase III study [41] was designed to evaluate the long(cid:173)
`term safety of a flexible dosing regimen of tapentadol IR
`compared with oxycodone IR in patients with low back
`pain or osteoarthritis pain. A 90-day duration of treat(cid:173)
`ment was chosen to cover a period of time that was likely
`to show both the early and late safety effects of treatment
`with tapentadol IR in support of an acute pain indication.
`The use of a flexible dosing regimen was designed to reflect a
`real-world clinical outpatient setting. Low back pain and
`osteoarthritis pain were chosen as pain models because these
`are common condi Lions affecting a significalll percemage of
`the population [GR-70], and pain is often moderate-to-severe
`in intensity.
`A 90-day randomized, double-blind, Phase III study [41]
`was conducted to evaluate the long-term tolerability of
`flexible doses of tapentadol IR 50 or 100 mg compared
`with oxycodone HCI IR 10 or 15 mg administered every
`4 - 6 h in patients (n = 878) with low back pain or
`osteoarthritis knee or hip pain. Gastrointestinal AEs were
`reported by 44% of patients treated with tapentadol IR and
`by 64% of patients treated with oxycodone IR. Incidences of
`specific gastrointestinal AEs were nausea, 18 and 29%;
`
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`
`Tapentadol
`
`vommng, 17 and 30%; and constipation, 13 and 27%, in
`the tapentadol IR and oxycodone IR groups, respectively.
`Nervous system AEs were reponed by 37% of patients in
`both treatment groups. In the tapentadol IR and oxycodone
`IR groups, respectively, incidences of specific nervous sys(cid:173)
`tem AEs were dizziness, 18 and 17%; headache, 11 and 1 Oo/o;
`and somnolence, 10 and 9%. The incidence of pruritus was
`4% in the tapentadol IR group and 12 in the oxycodone IR
`group. Odds ratios indicated that the incidences of somno(cid:173)
`lence and dizziness were similar for tapentadol IR and
`oxycodone lR and that the incidences of nausea, vomiting
`and constipation were significantly less likely with tapen(cid:173)
`tadol IR than with oxycodone IR (nominal p < 0.001 for all
`comparisons; Figure 1).
`Opioid withdrawal symptoms were evaluated in that
`study
`[41] using the Clinical Opiate Withdrawal Scale
`(COWS), which is a clinician-rated scale of perceived opioid
`withdrawal symptoms, and the Subjective Opiate Withdrawal
`Scale (SOWS), which is a patient-reported measure. For the
`COWS, physicians rated the presence and intensity of each of
`the following opioid withdrawal symptoms in each patient
`on a Liken-type scale ranging from 0 to 4 or 5 depending
`on the item: resting pulse, gastrointestinal upset, sweating,
`tremor, restlessness, yawning, pupil size, anxiety or irritabil(cid:173)
`ity, bone or joint aches, gooseflesh skin and runny nose or
`tearing. The total scores ranged from 0 to 48 with a high
`score indicating more severe opioid withdrawal ( < 5 = 'no
`withdrawal', 5- 12 ='mild withdrawal', 13- 24 ='moderate
`withdrawal', 25 - 36 =
`'moderately severe withdrawal'
`and > 36 = 'severe withdrawal'). For the SOWS, patients
`rated with 1 of 5 possible answers (0 ='not at all', 1 ='a little',
`2 = 'moderately', 3 = 'quite a bit' and 4 = 'extremely') each
`of the following 15 items according to how they felt at the
`time they completed the rating sheet: I feel anxious, I feel
`like yawning, I'm perspiring, my eyes are tearing, my nose
`is running, I have goose flesh, I am shaking, I have hot
`flashes, I have cold flashes, my bones and muscles ache, I
`feel restless, I feel nauseous, I feel like vomiting, my muscles
`twitch and I have cramps in my stomach. The total range of
`possible scores was 10 - 60, with a score of 60 indicating
`extremely severe opioid withdrawal.
`Results using the COWS for the subset of patients who
`did not take opioids after discontinuation of study medi(cid:173)
`cation indicated that most patients experienced no opioid
`withdrawal symptoms when measured 2 - 4 days after
`treatment discominuation. The percemage of patients
`who had mild or moderate opioid withdrawal symptoms
`was significantly lower in the tapentadol IR group (17%)
`than in the oxycodone IR group (29%; nominal p < 0.05);
`no patients in either treatment group experienced severe
`withdrawal. Results of the SOWS assessments showed that
`the mean total SOWS score was lower in the tapentadol
`IR group (6.9) than in the oxycodone IR group (8.7);
`the difference between these scores was not statistically
`significant [ 41].
`
`4. Conclusion
`
`For many years, opioids have been the cornerstone for the man(cid:173)
`agement of moderate-to-severe pain, but currently marketed
`pure )..L-opioid agonists are associated with side effects includ(cid:173)
`ing constipation, nausea, vomiting, dizziness, somnolence and
`pruritus, which may restrict treatment and reduce patient com(cid:173)
`pliance, leading to inadequate pain control. The two mechan(cid:173)
`isms of action of tapentadol ()..L-opioid receptor agonism and
`norepinephrine reuptake inhibition) may make it an important
`treatment option for the management of both nociceptive and
`neuropathic pain. Clinical studies to date indicate that tapen(cid:173)
`tadol IR (50, 75 or 100 mg every 4 - 6 h) provides effective
`pain relief, with significantly lower incidences of nausea, vomit(cid:173)
`ing and constipation compared with oxycodone HCl IR
`( 10 or 15 mg every 4 - 6 h) at doses providing similar efficacy
`across different models of moderate-to-severe acute pain.
`
`s. Expert opinion
`
`There has recently been an increase in the use of short-acting
`opioids for the management of non-cancer pain [71]. In a
`survey of trends in opioid use conducted between 2000
`and 2005 [71], a significant increase in the use of opioids
`for > 90 days was observed in patients with arthritis, low back
`and neck pain and headache. Specifically, the use of short(cid:173)
`acting schedule II opioids increased markedly during this
`time period. These findings suggest that there is an increas(cid:173)
`ing market for short-acting analgesic formulations for the
`management of moderate-to-severe pain and other conditions
`with neuropathic components.
`Short-acting formulations of opioid analgesics such as oxy(cid:173)
`codone and morphine are effective for the relief of moderate-to(cid:173)
`severe acute pain [131. However, the most common side effects
`associated with these )..L-opioid agonists include gastrointestinal
`symptoms, such as constipation, nausea and vomiting, which
`may significantly impact treatment compliance and lead to
`discominuation of therapy [14,72]. Over time, patiems may
`learn to tolerate many of the adverse effects associated with
`opioids [72]. However, this is rarely the case with constipation,
`making it a frequent cause of distress and intolerance to ther(cid:173)
`apy with pure )..L-opioid receptor agonists [15,671. An agent with
`a reduced potential for opioid-induced constipation may be
`especially suitable for patients with moderate-to-severe acute
`pain, who may require longer-term opioid therapy.
`T apentadol IR represents such an agent. Results of the
`90-day tolerability study [41] of tapentadol IR compared with
`oxycodone IR for the management of moderate-to-severe
`osteoarthritis pain or low back pain showed that tapentadol
`is well tolerated over time, with incidences of constipation that
`are < 50% of those observed with doses of oxycodone IR pro(cid:173)
`viding similar analgesic efficacy. In addition, discontinuations
`due to the gastrointestinal AEs of nausea, vomiting and
`constipation were notably lower for tapentadol IR (9%)
`than with oxycodone lR (21 o/o).
`
`2692
`
`Expert Opin Pharmacother. (2009) 10(16)
`
`
`
`Page 6 of 10
`
`

`
`Nausea
`
`Vomiting
`
`•
`•
`
`Nausea/vomiting* ~
`
`Hart rick
`
`Oxycodone IR
`TapentadoiiR
`(n = 170)
`(n = 679)
`n(%)
`n (%)
`Odds ratio (95% Cl)
`
`50 (29.4)
`125 (18.4)
`0.542 (0.37- 0.79)
`51 (30.0)
`115 (16.9)
`0.476 (0.32- 0.70)
`190 (28.0)
`78 (45.9)
`0.458 (0.33- 0.65)
`46 (27.1)
`87 (12.8)
`0.396 (0.26- 0.59)
`69(10.2)
`16(9.4)
`1.089 (0.62- 1.93)
`123 (18.1)
`29 (17.1)
`1.076 (0.69- 1.68)
`
`Constipation ~
`
`Somnolence
`
`Dizziness
`
`•
`•
`
`0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
`
`Event incidence for
`tapentadoiiR is lower
`than for oxycodone I R
`
`Event incidence for
`tapentadoiiR is higher
`than for oxycodone IR
`
`Figure 1. Odds ratios and 95% confidence intervals for gastrointestinal and nervous system adverse events associated with
`tapentadol IR versus oxycodone IR from a 90-day tolerability study in patients with moderate-to-severe low back or
`osteoarthritis pain.
`*Composite of nausea/vomiting means an event of nausea or vomiting
`Reproduced from [41]
`IR: Immediate release; Cl: Confidence interval
`
`The improved gastrointestinal tolerability profile of tapen(cid:173)
`tadol IR over oxycodone IR may make tapentadol IR a better
`treatment option than pure )l-opioid agonists for the relief
`of moderate-to-severe postsurgical pain. Nausea and vomiting
`are common side effects following surgery, and opioid use is
`associated with an increased risk for
`these unwelcome
`AEs [73.74]. In a study involving patients in a preope