Tapentadol immediate release: a new treatment
`option for acute pain management
`
`REVIEW
`
`Marc Afilalo 1
`Jens-Uirich Stegmann 2
`David Upmalis 3
`
`'Sir Mortimer B. Davis Jewish General
`Hospital, Montreal, Canada; 'Global
`Drug Safety, Gri.inenthal GmbH,
`Aachen, Germany; 'Johnson &
`Johnson Pharmaceutical Research
`and Development, L.L.C., Raritan,
`New Jersey, USA
`
`Correspondence: Marc Afilalo
`Associate Professor, McGill University,
`Director, Emergency Department,
`Sir Mortimer B. Davis Jewish General
`Hospital, 3755 C6te-St-Catherine
`Road, D-0 I 0, Montreal Quebec H3T
`I E2 Canada
`Tel +I (514) 340-8222 (Ext 5568)
`Fax+l (514) 340-7519
`Emai! marc.afi!a!o@mcgi!!.ca
`
`This article was published in the following Dove Press journal:
`Journal of Pain Research
`7 February 20 I 0
`Number of times this article has been viewed
`
`Abstract: The undertreatment of acute pain is common in many health care settings. Insufficient
`management of acute pain may lead to poor patient outcomes and potentially life-threatening
`complications. Opioids provide relief of moderate to severe acute pain; however, therapy
`with pure J..L-opioid agonists is often limited by the prevalence of side effects, particularly
`opioid-induced nausea and vomiting. Tapentadol is a novel, centrally acting analgesic wilh
`2 mechanisms of action, J..L-opioid receptor agonism and norepinephrine reuptake inhibition. The
`analgesic effects of tapentadol are independent of metabolic acliv ation and tapentadol has no
`active metabolites; therefore, in theory, tapentadol may be associated with a low potential for
`interindi vidual efficacy variations and drug-drug interactions. Previous phase 3 trials in patients
`with various types of moderate to severe acute pain have shown that tapentadol immediate
`release (IR; 50 to 100 mg every 4 to 6 hours) provides analgesia comparable to that provided
`by the pure J..L-opioid agonist comparator, oxycodone HCl IR (10 or 15 mg every 4 to 6 hours),
`with a lower incidence of nausea, vomiting, and constipation. Findings suggest tapentadol may
`represent an improved treatment option for acute pain.
`Keywords: tapentadol IR, acute pain, opioid, gastrointestinal tolerability
`
`Introduction
`Appropriate management of acute pain remains a considerable challenge for health
`care providers. Unrelieved acute pain may cause anxiety, sleep disturbances, and
`2 Acute
`demoralization and may interfere with mental activity and social interactions. 1
`•
`pain can also increase heart rate and blood pressure, suppress immune functioning, and
`reduce pulmonary function, leading to an increased risk of dangerous complications,
`including myocardial ischemia, deep vein thrombosis, pulmonary embolism, hypoxia,
`pneumonia, and stroke.2 In addition to these more severe adverse effects, uncontrolled
`acute pain is also associated with gastrointestinal effects, including the development
`of ileus, nausea, and vomiting. 3
`The psychologic and physiologic effects of uncontrolled acute pain can result in lon(cid:173)
`ger hospital stays and unscheduled readmissions following surgery.4
`5 A retrospective
`•
`analysis of the medical records of 20,817 patients who had undergone same-day
`surgery in 1999 found that pain was the most common reason that patients were
`hospitalized immediately after surge1y or returned to the hospital within 30 days of
`surgery, accounting for 38% of unscheduled postoperative hospital admissions or
`readmissions.4 In addition, prolonged acute pain can cause sensitization ofthe central
`and peripheral nervous systems, leading to the development of chronic pain, which is
`often difficult and costly to treat. 6--S
`
`Journal of Pain Research 20 I 0:3 I 9
`© 2010Afilalo et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
`which permits unrestricted noncommercial use, provided the original work is properly cited.
`
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`Grunenthal GmbH Exhibit 2001
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
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`Afilalo et al
`
`Although guidelines have been developed to improve
`10 pain relief remains suboptimal for
`acute pain management, 9
`•
`many patients.U-16 Surveys conducted among patients who had
`undergone ambulatory surgery indicated that 30W 5 to 40%12
`of patients experience moderate to severe pain following
`discharge. Among hospitalized patients who were receiving
`treatment in various medical wards 14 or who had undergone
`surgcry, 11 the percentages were even higher, with 52%14 to
`80%11 of patients experiencing acute pain; of these patients,
`as many as 86% experienced moderate to extreme pain. 11 The
`undertreatment of acute pain may result from several contrib(cid:173)
`uting factors related to patient care, such as infrequent pain
`assessments, underestimation ofthe severity of pain, concerns
`about side effects associated with analgesic treatment, and
`delays or dose reductions in the administration of analgesics by
`health care providers. 13•14•17- 20 In addition, patients may under(cid:173)
`report acute pain because oflow expectations of pain relief and
`concerns about the adverse effects of analgesic treatment. 19.2 1
`A 2004 survey of patients undergoing major abdominal surgery
`found that many patients were willing to sacrifice pain relief
`for a reduction in the severity of side effects.22
`Current treatment options for the management of acute
`pain include opioid analgesics ( eg, morphine, hydromorphone,
`and oxycodone) and nonopioid analgesics ( eg, acetaminophen,
`acetylsalicylic acid, and nonsteroidal anti-inflammatory drugs
`[NSAIDs]).23 Most NSAIDs are limited by a therapeutic ceil(cid:173)
`ing and are appropriate for the relief of only mild to moderate
`pain.23 In addition, NSAlDs are contraindicated in patients with
`peptic ulcer disease, renal impairment, and any tendency for
`bleeding.24 Cyclooxygenase-2 ( COX-2 )-specific inhibitors do
`not impair platelet function and have an improved gastrointes(cid:173)
`tinal tolerability profile relative to other NSAIDs25
`; however,
`certain COX-2-specific inhibitors have been linked to an
`increase in the risk of cardiovascular side effects, including
`myocardial infarction.26
`Opioids are typically used for the management of
`moderate to severe acute pain,27 but opioid use is limited
`by the occurrence of a range of side effects.28 Opioids exert
`their analgesic effects primarily through agonistic interac(cid:173)
`tions with 11-opioid receptors in neurons in the pain path(cid:173)
`way, which lead to a reduction in neurotransmitter release
`and associated pain.29 However, the agonistic interactions
`responsible for opioid activity are not limited to neurons of
`the pain pathway.23 Opioid receptors are present throughout
`the nervous system, and the interactions of opioids with
`nonanalgesic receptors are responsible for many of the side
`effects associated with opioid treatment.23 For example,
`opioids may induce nausea and vomiting by direct stimulation
`
`of receptors at the chemoreceptor trigger zone and vestibular
`apparatus. 30
`A systematic review31 of randomized controlled trials of
`opioids in postoperative patients found that the most common
`side effects occurring in these patients were gastrointestinal
`side effects, central nervous system (CNS) side effects,
`pruritus, and urinary retention. Pruritus occurred in 18.3% of
`patients who were treated with opioids following surgery and
`was most common with epidural administration of opioids. 31
`Somnolence and sedation were the most commonly reported
`CNS side effects; the incidence of somnolence ranged from
`less than 2% to more than 90%, depending on the route of
`administration and type of opioid used.'~ Gastrointestinal side
`effects, including nausea, vomiting, and constipation, were
`the most common side effects associated with opioid analge(cid:173)
`sia and were reported by 31.0% ofpatientsY Opioid-induced
`postoperative nausea and vomiting (PONY) is associated with
`negative effects on patient outcomes and quality of life, 32
`which may lead to increases in recovery time, duration of
`hospitalization, and cost of medical care.33
`34 The underuse
`•
`of opioid analgesics by health care providers to relieve acute
`pain may be related to attempts to balance analgesia against
`concerns about opioid-induced side effects and subsequent
`deleterious repercussions for patient outcomes.20
`There is a continuing need for a potent analgesic agent that
`will provide adequate relief of acute pain, but with a reduction
`in side effects. Tapentadol is a novel, centrally acting analgesic
`that offers analgesic efficacy that is similar to that provided by
`a pure 11-opioid agonist comparator, but with an improved side
`e±Tect profile, which may represent a significant advancement
`in the management of moderate to severe acute pain.
`
`Pharmacology and
`pharmacokinetics of tapentadol
`Tapentadol (Figure 1) is a centrally acting analgesic with
`2 complementary mechanisms of action, 11-opioid receptor
`agonism and norepinephrine reuptake inhibition.l 5
`36 In opioid
`•
`receptor binding studies, tapentadol was found to have only a
`modest affinity (dissociation constant [KJ = 0.096!1M [rat])l 5
`for the 11-opioid receptor relative to pure 11-opioid receptor
`agonists such as oxycodone (Ki = O.Ol811M [rat]) or morphine
`= 0.002 11M [rat]).37 A similar binding affinity to that
`(K1
`observed in native rat receptors was demonstrated for tapent(cid:173)
`adol at the human recombinant 11-opioid receptor (Ki = 0 .l611M
`[human]).35 Despite the approximately 50-fold difference in
`binding affinity for the 11-opioid receptor relative to mmphine,
`tapentadol demonstrated only a 2- to 3-fold reduction in
`analgesic potency in a series of acute and persistent animal
`
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`Journal of Pain Research 20 I 0:3
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`Page 2 of 9
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`H-CI
`
`Figure I Chemical structure of tapentadol HCI.
`
`pain models.36 This disparity in potency and binding affinity
`for the 11-opioid receptor may be related to the contribution of
`the second mechanism of action, inhibition of norepinephrine
`reuptake, to the analgesic effects oftapentadol. In rat synapto(cid:173)
`somal reuptake assays, tapentadol inhibited the norepinephrine
`reuptake transporter with a Ki of 0.48 ± 0.11 11M and, when
`administered in intraperitoneal doses of 4.64 to 10 mg/kg,
`produced a dose-dependent increase in extracellular levels of
`norepinephrine in the ventral hippocampus of freely moving
`rats to a maximum of 450% above baseline with 10 mg/kg,
`as measured by microdialysis. 35 In contrast to tapentadol,
`morphine administered to rats in intraperitoneal doses of 1 to
`10 mg/kg produced a small, nonsignificant decrease in extracel(cid:173)
`lular norepinephrine levels. 35
`The contributions of both 11-opioid receptor agonism
`and norepinephrine reuptake inhibition to the analgesic
`effects of tapentadol were further elucidated by examining
`the extent to which analgesia was blocked by the selective
`11-opioid receptor antagonist naloxone and the norepinephrine
`a 2-receptor antagonist yohimbine." In an animal model"
`of acute (writhing) pain, it was observed that intravenous
`tapentadol and morphine induced dose-dependent inhibi(cid:173)
`tion of writhing (ED 50 for tapentadol, 0.7 mg/kg; ED 50 for
`morphine, 0.4 mg/kg). When combined with naloxone,
`the antinociceptive effect of morphine (0.681 mg/kg) was
`more potently reduced than that oftapentadol (3.16 mg/kg);
`the ED50 for naloxone antagonism was 0.007 mg/kg when
`combined with morphine and 0.099 mg/kg when combined
`with tapentadol (P < 0.001 fortapentadol vs morphine). Ina
`spinal nerve ligation model of mono neuropathic pain, 35 coad(cid:173)
`ministration of intraperitoneal naloxone (0.3 mg/kg) with
`equianalgesic intravenous doses of tapentadol ( 1 0 mg/kg) or
`
`Journal of Pain Research 20 I 0:3
`
`Tapentadol I R for acute pain
`
`morphine (6.81 mg/kg) reduced the anti-allodynic effect of
`tapentadol from 72% to 42% ofthe maximal possible effect
`(MPE); the anti-allodynic effect of morphine was reduced
`from 83% to 25% ofthe MPE. In contrast, when yohimbine
`(2.15 mg/kg) was administered intraperitoneally in combi(cid:173)
`nation with intravenous doses of morphine (6.81 mg/kg) or
`tapentadol (I 0 mg/kg), the anti-allodynic effect oftapentadol
`was reduced from 81% to 19% of the MPE, whereas the anti(cid:173)
`allodynic effect of morphine was only minimally reduced
`(from 80% to 54% of the MPE). 35 These results indicate that
`both 11-opioid receptor agonist and norepinephrine reuptake
`inhibitor mechanisms are involved in the analgesic effect of
`tapentadol and that, in contrast to morphine, norepinephrine
`reuptake inhibition plays a prominent role in tapentadol(cid:173)
`induced analgesia.
`In addition to contributing to the analgesic activity of
`tapentadol, the opioid-sparing effect of norepinephrine reup(cid:173)
`take inhibition may also contribute to a reduction of adverse
`effects associated with pure 11-opioid agonists.36 Such an
`opioid-sparing effect has been achieved by combining other
`analgesics, such as NSAIDs or COX-2-specific inhibitors,
`with opioids to control acute pain.38 This type ofmultimodal
`strategy achieves an additive analgesic effect by combining
`2 different mechanisms of analgesic activity, but reduces the
`consumption of opioid analgesics and, thereby, the incidence
`of adverse effects associated with 11-opioid agonist activity.38
`For example, in a study of 200 patients undergoing outpatient
`anterior cruciate ligament surgery, patients who received
`peri operative doses ofthe COX-2-specific inhibitor celecoxib
`in addition to oxycodone experienced less pain (P < 0.01)
`in the recovery room, had lower postoperative opioid con(cid:173)
`sumption (P < 0.001), and reported a lower incidence of
`PONY (P < 0.05) than patients taking oxycodone alone. 39
`By combining a second mechanism of analgesic activity with
`11-opioid receptor agonism, tapentadol may offer the benefits
`of multimodal analgesia within a single molecule.
`The analgesic effects of tapentadol are independent of
`metabolic activation, and tapentadol has no active metabolites.40
`Orally administered tapentadol is principally cleared by hepatic
`glucuronidation via the uridine 5' -diphospho-glucuronosyl
`transferases (UGTs) UGT1A9 and UGT2B7, which are
`responsible for approximately 55% oftapentadol metabolism
`in humans.41 The major metabolite oftapentadol, tapentadol-
`0-glucuronide, has no activity at opioid receptors, synapto(cid:173)
`somal reuptake systems, or other binding sites.35 Morphine is
`likewise primarily metabolized by hepatic glucuronidation via
`UGT2B7 to morphine-3-glucuronide (M3G) and morphine-
`6-glucuronide (M6G). 42 Morphine-3-glucuronide has no
`
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`Afilalo et al
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`analgesic activity, but M6G has an affinity for the 11-opioid
`receptor and contributes significantly to the analgesic effect of
`morphine.43 In patients with renal insufficiency, M6G accumu(cid:173)
`lates and may contribute to the higher incidence of morphine
`toxicity observed in these patients.44.45
`Many other opioids, including oxycodone, codeine, dihy(cid:173)
`drocodeine, hydrocodone, and tramadol, are primarily metab(cid:173)
`olized by the cytochrome P450 (CYP) enzymes CYP2D6
`or CYP3A4.46 Mutations in the CYP2D6 gene, which occur
`in approximately I% to 7% of the Caucasian population,
`can either decrease or increase enzyme activity, leading to
`alterations in opioid analgesia. 47 The analgesic effects of
`codeine are highly dependent on conversion of codeine to
`morphine by CYP2D6; a poor CYP2D6 metabolic phenotype
`can suppress codeine analgesia, and an ultra-rapid CYP2D6
`metabolic phenotype can lead to increased opioid effects,
`such as euphoria, dizziness, and visual disturbances. 47
`In addition to the potential for varied individual responses
`to cytochrome P450-metabolized opioids due to genetic
`mutations, opioids metabolized by the cytochrome P450 path(cid:173)
`way are associated with an increased risk for drug-drug interac(cid:173)
`tions. More than half of all drugs are metabolized by CYP3A4,
`and opioids metabolized by this isozyme (including fentanyl,
`buprenorphine, and methadone) are prone to dmg-dmg interac(cid:173)
`tions with antiretroviral agents and antidepressants.48 Opioids
`metabolized by CYP2D6, including codeine, dihydrocodeine,
`and oxycodone, are also associated with a number of drug-drug
`interactions. Substrates of CYP2D6 include antiarrhythmic
`agents, antidepressants, antipsychotics, antiparasitic agents, and
`tamoxifen.48 The analgesic activity of codeine is particularly
`impaired by inhibition of CYP2D6 because the analgesic effects
`of codeine result from the formation of metabolites, including
`morphine and, possibly, codeine-6-glucuronide.48
`In vitro studies41 were used to evaluate the inhibitory or
`inducing etTects of tapentadol on the 7 major C Y P isoforms
`involved in drug metabolism (CYP2D6, CYP3A4, CYPIA2,
`CYP2A6, CYP2C9, CYP2Cl9, and CYP2El). Tapentadol
`did not undergo significant metabolism by CYP enzymes
`and did not inhibit or induce the activity of any of the CYP
`isoforms tested, with the exception of CYP2D6. 41 Limited
`inhibition of CYP2D6 was observed with tapentadol, with
`competitive inhibition occurring with a K, of 181 11M and
`noncompetitive inhibition with a Ki of I ,410 11M.41 The
`Ki values for both competitive and noncompetitive inhibi(cid:173)
`tion are much higher than the expected tapentadol plasma
`concentrations of0.5 to I 11M (following therapeutic dosing),
`indicating that CYP2D6 inhibition by tapentadol is unlikely
`to be clinically relevant.41
`
`Two randomized, open-label studies were performed to
`evaluate the potential for dmg-dmg interactions between
`tapentadol and 3 common analgesics that, like tapentadol, are
`metabolized by UGT pathways (acetaminophen, naproxen, and
`acetylsalicylic acid).49 Mean serum concentrations oftapent(cid:173)
`adol and tapentadol-0-glucuronide were similar after adminis(cid:173)
`tration of tapentadol IR alone and after coadministration with
`acetaminophen and acetylsalicylic acid. A slight increase in
`the serum concentration of tapentadol and a slight decrease
`in the serum concentration of tapentadol-0-glucuronide
`were observed after coadministration with naproxen, but
`these changes were not considered clinically relevant, due
`to the relatively small magnitude of change. Thus, no dosing
`adjustments are needed for administration oftapentadol with
`any of these commonly coadministered analgesics.
`
`Tapentadol IR for moderate
`to severe pain
`The efficacy oftapentadol IRforthe relief of moderate to severe
`pain has been evaluated in 3 randomized, double-blind, phase 3
`studies in patients with postoperative (bunionectomy) pain50.51
`and pain related to end-stage degenerative joint disease52 and
`as a secondary measure in a phase 3 randomized, double(cid:173)
`blind, 90-day safety study. 53 In one of the postoperative pain
`1 patients received tapentadol IR (50, 75, or I 00 mg),
`studies, 5
`oxycodone HCI IR ( 15 mg), or placebo every 4 to 6 hours for
`72 hours following bunionectomy; in the other postoperative
`pain study, 50 patients received tapentadol IR (50 or 75 mg),
`oxycodone HCI IR (I 0 mg), or placebo every 4 to 6 hours
`for 72 hours following bunionectomy. ln the end-stage joint
`disease study, 52 patients received tapentadol IR (50 or 75 mg),
`oxycodone HCI IR ( 10 mg), or placebo every 4 to 6 hours for
`10 days. In the 90-day safety study,53 patients received flexible
`doses oftapentadol IR 50 or 100 mg (up to 600 mg/day) or
`oxycodone HCI 10 mg or 15 mg (up to 90 mg/day) every 4 to
`6 hours as needed for up to 90 days.
`In all 4 phase 3 studies50- 53 of tapentadol IR for acute
`pain, improvements in pain intensity were observed with
`tapentadol IR treatment (50, 75, or 100 mg every4 to 6 hours)
`that were similar to those observed with oxycodone HCI IR
`treatment ( 10 or 15 mg every 4 to 6 hours) based on pain
`intensity measurements on an 11-point numerical rating scale
`(NRS; 0 ="no pain" to 10 ="worst pain imaginable"). For
`example, in the postoperative pain study5° in which patients
`received tapentadol IR (50 or 75 mg) for 72 hours following
`bunionectomy, 901 patients were randomized to treatment.
`In that study, 50 efficacy was evaluated based on the following
`measures: the sum of the pain intensity difference (SPID) over
`
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`Journal of Pain Research 20 I 0:3
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`Tapentadol I R for acute pain
`
`the first 12, 24, 48 (primary efficacy endpoint), and 72 hours of
`treatment; responder rates at 48 hours; and the patient global
`impression of change (PGIC). Based on increases in the mean
`(SD) SPID48
`, significantly greater reductions in pain inten(cid:173)
`sity from baseline were observed with tapentadol IR 50 mg
`(122.2 [98.66]), tapentadol IR 75 mg (143.7 [96.52]), and
`oxycodone HCl IR 10 mg (140.3 [99.52]) than with placebo
`(54.1 [105.74]; P < 0.001 for all comparisons; Figure 2).
`Additionally, the efficacy of both doses oftapentadol IR was
`noninferiorto the efficacy of oxycodone HCl IR 10 mg, based
`on the lower bounds ofthe 2-sided 97.5% confidence inter(cid:173)
`vals for tapentadol IR 50 mg (-36.05) and 75 mg (-12.91 ),
`which were within the prespecified noninferiority margin
`of -48 (1 0% of the total possible value).
`Secondary efficacy measurements supported the results
`ofthe primary efficacy endpoint in this phase 3 postoperative
`pain study. 5° Compared with placebo, significant reductions
`in pain intensity (based on the SPID) were observed for all
`active treatment groups at 12, 24, and 72 hours (P < 0.001
`for all comparisons; Figure 2).
`The distribution of responder rates was also significantly
`different between both tapentadol IR dose groups and placebo
`(P < 0.001) and oxycodone HCl IR 10 mg and placebo
`(P < 0.001; Figure 3). Compared with placebo, a significantly
`greater percentage of patients in all active treatment groups
`reported reductions in pain intensity at 48 hours of at least
`30% (tapentadol IR 50 mg, 77.5%; tapentadol IR 75 mg,
`76.3%; oxycodone HCl IR 10 mg, 75.2%; placebo, 58.0%;
`
`P < 0.004 for all comparisons) and at least 50% (tapentadol
`IR 50 mg, 64.7%; tapentadol IR 75 mg, 64.0%; oxycodone
`HCl IR 10 mg, 64.4%; placebo, 47.8%; P :c:: 0.012 for all
`comparisons).
`For the PGIC, patients rated their overall status since
`beginning study medication on a 7-point scale (1 = "very
`much improved" to 7 ="very much worse"). At the end of the
`study or early discontinuation, a rating of"much improved"
`or "very much improved" on the PGIC was reported by 83%
`of patients in the tapentadol IR 50-mg group, 88% of patients
`in the tapentadol IR 75-mg group, 86% of patients in the
`oxycodone HCl IR 1 0-mg group, and 65% of patients in the
`placebo group. The overall distribution of PGIC scores was
`significantly more favorable for all active treatment groups
`compared with placebo (P < 0.001 for all comparisons).
`
`Safety and tolerability
`of tapentadol I R
`In all 4 studies, 50- 53 the most commonly reported treat(cid:173)
`ment emergent adverse events (TEAEs) for patients who
`received any dosage of tapentadol IR were typical of drugs
`with 11-opioid agonist activity, and there were no major TEAEs
`suggestive of hyper-adrenergism. In the phase 3 studyl0 of
`tapentadol IR 50 and 75 mg in patients with postoperative
`pain following bunionectomy, the most common TEAEs
`(reported by :::o-1 0% of patients in any treatment group) were
`nausea, vomiting, dizziness, headache, somnolence, pruritus,
`and constipation. Tapentadol IR 50 mg was associated with
`
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`Oxycodme HCI TapentadoiiR
`IR 10mg
`50 mg
`
`12 hours
`
`24 hours
`
`48 hours
`
`72 hours
`
`Figure 2 Differences from placebo' in mean SPID scores at 12, 24,48, and 72 hours in patients with moderate to severe pain following bunionectomy treated with tapentadol
`IR 50 or 75 mg or oxycodone HCI IR I 0 mg. 50
`'P < 0.00 I vs placebo for all comparisons.
`Abbreviations: SPID. sum of pain intensity difference: LS.Ieast squares: Cl. confidence interval: IR. immediate release.
`
`Journal of Pain Research 20 I 0:3
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`5
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`Page 5 of 9
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`
`Afilalo et al
`
`100
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`---Placebo (n = 69)
`
`- - - TapentadoiiR 50 mg (n = 275)
`
`TapentadoiiR 75 mg (n = 278)
`
`----- Oxycodone HCIIR 10 mg (n = 278)
`
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`Percent reduction in pain intensity from baseline at 48 hours
`
`Figure 3 Distribution of responder rates based on pain intensity at 48 hours in patients with postoperative pain following bunionectomy: Reproduced from Daniels et al
`(2009). 50 Copyright© 2009 lnforma Healthcare.
`Abbreviation: IR, immediate release.
`
`a lower incidence of all of these TEAEs than oxycodone HCl
`IR 10 mg, and tapentadol IR 75 mg was associated with a
`lower incidence of nausea, headache, and constipation than
`oxycodone HCl IR 10 mg (Figure 4). A significantly lower
`percentage of patients reported nausea and! or vomiting in the
`tapentadol IR 50-mg group (35%) than in the oxycodone HCl
`IR 10-mg group (59%; P < 0.001). Thus, at a dose (50 mg)
`that provided efficacy that was noninferior to that provided by
`oxycodonc HCl IR 10 mg, tapcntadol IR was associated with
`a significantly lower incidence of gastrointestinal adverse
`events than oxycodone IR. A lower percentage of patients in
`the tapentadol IR 75-mg (51%) than in the oxycodone HCI
`lR I 0-mg group (59%) reported nausea and/or vomiting,
`but the difference did not reach statistical significance (P =
`0.057). A low percentage ( <3% in any treatment group) of
`patients reported TEAEs that led to study discontinuation
`in the tapentadol IR 50-mg group (1.1 %), the tapentadol IR
`75-mg group (2.9%), the oxycodone HCI IR I 0-mg group
`(1.8%), and the placebo group (1.5%).
`The 90-day safety study53 permitted an evaluation of the
`long-term safety of flexible doses of tapentadol IR (50 or
`100 mg every 4 to 6 hours) in comparison with flexible doses
`of oxycodone HCI IR (10 or 15 mg every 4 to 6 hours) in
`patients with acute osteoarthritis hip or knee pain or low
`back pain. Similar to the phase 3 postoperative pain study, 50
`the most common TEAEs (occurring in 21 0% of patients
`
`in either treatment group) included gastrointestinal TEAEs
`(nausea, vomiting, and constipation), nervous system TEAEs
`(dizziness, headache, and somnolence), and pruritus. A lower
`percentage of patients in the tapentadol IR group than in the
`oxycodone IR group reported nausea (18.4% vs 29.4%),
`vomiting (16.9% vs 30.0%), constipation (12.8% vs 27.1 %),
`and pruritus (4.3% vs 11.8%). Odds ratios demonstrated
`that patients treated with tapentadol lR were significantly
`less likely than patients treated with oxycodonc IR to report
`nausea (0.542), vomiting (0.476), the composite of nausea
`and/or vomiting (0.458), or constipation (0.396; P < 0.001
`for all comparisons). In addition, a lower percentage of
`patients discontinued from the study because of AEs in the
`tapentadol IR group (20 .8%) than in the oxycodone IR group
`(30.6% ), and patients in the oxycodone IR group discontinued
`significantly earlier than those in the tapentadol IR group
`(nominal P < 0.05; Figure 5). The percentage of patients
`who discontinued from the study due to gastrointestinal
`AEs was lower in the tapentadol IR group (8.8%) than in
`the oxycodone IR group (21.1 %).
`Compared with placebo, tapentadol IR (50 to 100 mg
`every 4 to 6 hours) and oxycodone HCl IR (10 or 15 mg
`every 4 to 6 hours) were associated with a higher incidence
`of TEAEs at all doses studied, and the majority of TEAEs
`increased with increasing dose. 50- 52 However, tapentadol
`IR was associated with a reduction in TEAEs, particularly
`
`6
`
`Journal of Pain Research 20 I 0:3
`
`
`
`Page 6 of 9
`
`

`
`• Placebo
`
`TapentadoiiR 50 mg • TapentadoiiR 75 mg
`
`Oxycodone HCI IR 10 mg
`
`Tapentadol I R for acute pain
`
`Nausea ~-------17
`•1111111111111111111111111111111111111111111111111111114~6
`
`34
`
`. . . . . . . . . . . 57
`
`Vomiting
`
`Dizziness
`
`Headache
`
`Somnolence
`
`Pruritus
`
`12
`
`10
`
`15
`
`16
`
`20
`
`13
`12
`
`28
`
`26
`
`25
`
`23
`
`26
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Percentage of patients
`
`Figure 4 Treatment-emergent adverse events occurring in ::::::I 0% of patients in any treatment group among patients treated with placebo, tapentadol IR 50 or 75 mg, or
`oxycodone HCIIR 10 mg following bunionectomy. 50
`Abbreviation: IR. immediate release.
`
`'0
`Cl)
`:::l c:
`:.;::::;
`c:
`0
`0
`(/)
`(/)._
`'0 ;
`0 >
`J: Cl)
`== Cl)
`(/) ~
`c: >
`-- Cl)
`Cl)
`:.;::::;'0
`co co
`
`0 Cl)
`:::l
`Cl)
`tn'C
`
`c.o ---
`co --c:
`Cl)
`0 s...
`Cl) a..
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`
`10
`
`Number of patients at risk
`Tapentadol IR 679
`548
`Oxycodone IR 170
`122
`
`- - TapentadoiiR
`·-- Oxycodone IR
`
`rl - 1- -+- I +I I+ +-
`
`1 Ill
`
`1111
`
`1 1 11111111
`
`1111
`
`II
`
`IIIII II
`
`70
`60
`50
`40
`30
`20
`Days from first dose date
`
`80
`
`90
`
`504
`110
`
`481
`105
`
`461
`102
`
`442
`100
`
`428
`99
`
`414
`96
`
`404
`92
`
`388
`91
`
`Figure 5 The distribution of times to discontinuation due to adverse events from the 90-day safety study among patients with osteoarthritis hip or knee pain or low back
`pain treated with tapentadoiiR or oxycodone IR. Reproduced from Hale et al (2009). 53
`Abbreviation: IR. immediate release.
`
`Journal of Pain Research 20 I 0:3
`
`7
`
`
`
`Page 7 of 9
`
`

`
`Afilalo et al
`
`gastrointestinal TEAEs and pmritus, relative to oxycodone
`IR in all 4 phase 3 studies. 5°-
`53 The lower incidence of gas(cid:173)
`trointestinal TEAEs observed with tapentadol IRrelative to
`oxycodone IR50
`53 was associated with a lower percentage
`-
`of patients who discontinued treatment because of TEAEs.
`Nausea and vomiting are often associated with the initiation
`of opioid therapy27 and are considered to be among the most
`undesirable adverse effects associated with analgesic therapy. 54
`These opioid-induced gastrointestinal TEAEs may be dose(cid:173)
`limiting and are often severe enough to cause patients to dis(cid:173)
`continue therapy, leading to dismption of pain relief. 55•56
`
`Conclusions
`Tapentadol is a novel, centrally acting analgesic with
`2 mechanisms of action, 11-opioid receptor agonism and
`norepinephrine reuptake inhibition,35
`36 which may contribute
`•
`to an improved gastrointestinal tolerability profile. In patients
`with moderate to severe acute pain of various etiologies,
`tapentadol IR has been shown to offer comparable analgesia
`to that provided by oxycodone IR, with lower incidences of
`gastrointestinal adverse effects and pmritus and lower rates of
`discontinuation due to adverse effects. 5°-53 This combination
`of potent analgesia and tolerability may represent a substan(cid:173)
`tial improvement over current acute pain relief strategies.
`
`Acknowledgments
`Editorial support for the writing of this manuscript was
`provided by Megan Knagge, PhD, of MedErgy, and was
`funded by Johnson & Johnson Pharmaceutical Services,
`L.L.C. The authors were not compensated and retained full
`editorial control over the content of the manuscript.
`
`Disclosures
`D. Upmalis is an employee and shareholder of Johnson &
`Jo:bu~son. J.-U. Stegmann is an employee ofGrfinenthal GmbH.
`
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