2010 nucynta core speaker slides
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2010 nucynta core speaker slides
- 1. An Advance in Multimodal Analgesic Therapy © Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2010 May 2010 02TL10045
- 2. This promotional educational activity is brought to you by PriCara ® , Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc, and is not certified for continuing medical education. The speaker is a paid consultant presenting on behalf of PriCara ® and must present information in compliance with FDA requirements applicable to PriCara ® . Core
- 3. INTRODUCTION TO NUCYNTA ® Core
- 8. DUAL MECHANISM OF ACTION: NOREPINEPHRINE REUPTAKE INHIBITOR AND µ-OPIOID RECEPTOR AGONIST 1. Tzschentke TM et al. J Pharmacol Exp Ther . 2007;323(1):265-276. 2. Vanderah TW. Med Clin North Am. 2007;91(1):1-12. 3. Pertovaara A. Prog Neurobiology . 2006;80(2):53-83. Secondary afferent Primary afferent Pain signal Core Spinal cord Simplified schematic for mechanism of action. *The exact mechanism of NUCYNTA ® (tapentadol) is unknown. Glu + SP Ascending pathway to the brain Descending pathway from the brain NE 2 -AR – μ -OR Tapentadol* + - = glutamate (Glu) = glutamate receptor = substance P (SP) = substance P recepto r = norepinephrine (NE) = alpha2-adrenoceptor ( 2 -AR) = NE reuptake transporter protein = mu-opioid receptor ( -OR)
- 11. NUCYNTA ® : PHASE 3 CLINICAL DATA Core
- 12. TAPENTADOL IR TRIAL DATA: STUDIED IN MORE THAN 3000 PATIENTS OA = osteoarthritis. * All trials except safety were placebo-controlled. 1. Daniels SE et al. Curr Med Res Opin . 2009;25(3):765-776. 2. Daniels S et al. Curr Med Res Opin. 2009;25(6):1551-1561. 3. Hartrick C et al. Clin Ther . 2009;31(2):260-271. 4. Hale M et al. Curr Med Res Opin . 2009;25(5):1095-1104. Core Study* No. of Patients Tapentadol IR (mg) Oxycodone IR (mg) Duration (d) Bunionectomy I 1 603 50, 75, 100 15 3 Bunionectomy II 2 901 50, 75 10 3 End-Stage Joint Disease (OA) 3 674 50, 75 10 10 90-day Safety 4 849 50, 100 10, 15 ≤ 90
- 13. END-STAGE JOINT DISEASE OF THE HIP OR KNEE STUDY: ANALGESIC EFFICACY IN A 10-DAY TRIAL Intent-to-treat population (N=659; all randomized subjects who received at least 1 study drug intake following randomization and had a valid baseline pain assessment) with a mean baseline pain intensity score of 6.7 was randomized to 50 mg or 75 mg of NUCYNTA ® , 10 mg oxycodone IR, or placebo dosed every 4 to 6 hours while patients were awake. The primary efficacy analysis is based on the last observation carried forward (LOCF) imputation method. Adjusted P -values using Hochberg procedure (oxycodone group was not included). SPID is defined as the sum of pain intensity difference and a higher value in SPID indicates greater pain relief. The chart uses the mean SPID calculations vs placebo. These calculations are noted in the original study report. 1. Data on file, J&J PRD, LLC. 2. Hartrick C et al. Clin Ther . 2009;31(2):260-271. Mean Cumulative SPID Score 1 130.6 229.2 236.5 * SPID-5 DAYS (Primary Endpoint) 223.8 * † * † Core * P <.001 for all comparisons vs placebo. 1,2 † Both doses of tapentadol IR were noninferior to oxycodone IR 10 mg (prespecified analysis). ‡ Clinical trials were conducted with immediate release oxycodone, which is the opioid ingredient in Percocet ® , Percodan ® , and OxyIR ® . Percocet and Percodan are registered trademarks of Endo Pharmaceuticals Inc. OxylR is a registered trademark of Purdue Pharma Inc. The higher the SPID score, the greater the pain relief Placebo Oxycodone IR 10 mg ‡ Tapentadol IR 75 mg Tapentadol IR 50 mg N=659 0 50 150 250 100 200
- 14. BUNIONECTOMY STUDIES I AND II: ANALGESIC EFFICACY IN A POSTOPERATIVE PAIN MODEL (3-day trial) 1. Daniels SE et al. Curr Med Res Opin . 2009;25(3):765-776. 2. Daniels S et al. Curr Med Res Opin. 2009;25(6):1551-1561. 3. Data on file, J&J PRD, LLC. Mean SPID Score 24.5 * 119.1 * 139.1 * 167.2 * 172.3 SPID-48 Hours (Primary Endpoint) 54.1 * † 122.2 * † 143.7 * 140.3 Bunionectomy I (N=602) 1 Bunionectomy II (N=901) 2,3 Oxycodone IR 15 mg Median onset of confirmed, perceptible pain relief with tapentadol IR was as early as 32 to 46 minutes ( P≤.005, for all tapentadol IR doses vs placebo onset at 100 min). 1 Intent-to-treat population (N=602 1 or 901 2 ; all randomized subjects who took at least 1 dose of study medication and had a valid baseline pain assessment) with a mean baseline pain intensity score of 7 1 or 7.1 2 was randomized to 50 mg 1,2 , 75 mg 1,2 , or 100 1 mg of NUCYNTA ® , 10 2 mg or 15 1 mg oxycodone IR, or placebo dosed every 4 to 6 hours. Based on analysis of covariance model with treatment and study center as factors and baseline pain intensity score as a covariate. Adjusted P -values using Hochberg procedure (oxycodone group was not included). Higher value in SPID indicates greater pain relief. The chart uses the mean SPID calculations vs placebo. These calculations are noted in the original study report. 3 Core * P <.001 vs placebo. † Both doses of tapentadol IR were noninferior to oxycodone IR 10 mg. Placebo Tapentadol IR 75 mg Tapentadol IR 50 mg Oxycodone IR 10 mg Tapentadol IR 100 mg 0 100 200 50 150 The higher the SPID score, the greater the pain relief
- 15. END-STAGE JOINT DISEASE OF THE HIP OR KNEE STUDY: TREATMENT-EMERGENT ADVERSE EVENTS REPORTED BY ≥1% OF SUBJECTS 1,2 IR = immediate release. *Includes administration site conditions. † Includes subcutaneous tissue disorders. Adapted with permission from Hartrick C et al. 1. Data on file, J&J PRD, LLC. 2. Hartrick C et al. Clin Ther . 2009;31(2):260-271. Core System/Organ Class Dictionary-Derived Term % of Subjects Placebo (n=169) Tapentadol IR 50 mg (n=157) Tapentadol IR 75 mg (n=168) Oxycodone IR 10 mg (n=172) GI Disorders 17 29 40 60 Nausea 5 18 21 41 Vomiting 4 7 14 34 Constipation 2 4 7 26 Diarrhea 3 1 5 1 Nervous system disorders 11 29 41 37 Dizziness 5 18 26 23 Somnolence 1 6 10 12 Headache 6 6 8 3 General* 2 6 8 22 Fatigue 1 1 7 10 Skin † 2 6 8 22 Pruritus 1 2 5 15
- 16. BUNIONECTOMY STUDIES: TREATMENT-EMERGENT ADVERSE EVENTS REPORTED BY ≥5% OF SUBJECTS *Dosing: q4-6h per 24 hours (around the clock). 1. Daniels SE et al. Curr Med Res Opin . 2009;25(3):765-776. 2 . Daniels S et al. Curr Med Res Opin. 2009;25(6):1551-1561. (Blanks indicate <5% incidence or adverse event not reported) Core Bunionectomy I * 1 (3 days) (N=602) Bunionectomy II * 2 (3 days) (N=901) Placebo NUCYNTA ® Oxycodone IR Placebo NUCYNTA ® Oxycodone IR % 50 mg % 75 mg % 100 mg % 15 mg % % 50 mg % 75 mg % 10 mg % Nausea 13 35 38 49 67 17 34 46 57 Vomiting 18 21 32 42 12 28 26 Constipation 7 10 15 8 5 11 Dizziness 5 16 22 31 30 10 15 25 23 Somnolence 12 13 21 10 7 13 12 Headache 7 12 11 12 14 16 20 19 26 Pruritus 9 17 12 5 8 10 Generalized pruritus 7 10 Hyperhydrosis 5 6 Pyrexia 6
- 18. BUNIONECTOMY STUDY II: COMPOSITE INCIDENCE OF NAUSEA AND/OR VOMITING 1,2 Intent-to-treat population (N=901) with a mean baseline pain intensity score of 7.1 was randomized to 50 mg or 75 mg of NUCYNTA ® , 10 mg oxycodone IR, or placebo dosed every 4 to 6 hours. Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. * P <.001 for all comparisons vs placebo. † P< .001 for tapentadol 50 mg vs oxycodone IR 10 mg ( P value adjusted using the Hochberg procedure). 1. Data on file, J&J PRD, LLC. 2. Daniels S et al. Curr Med Res Opin. 2009;25(6):1551-1561 . * N=901 17.4% 35% 59% 51% Composite of Nausea and/or Vomiting Placebo Oxycodone IR 10 mg Tapentadol 75 mg Tapentadol 50 mg Incidence (%) * * † Core 0 30 50 60 20 40 10
- 19. 90-DAY SAFETY STUDY: TREATMENT-EMERGENT ADVERSE EVENTS REPORTED BY ≥2% OF SUBJECTS IR = immediate release. Hale M et al. Curr Med Res Opin. 2009;25(5):1095-1104. Core System/Organ Class Dictionary-Derived Term % of Subjects Tapentadol IR 50 mg or 100 mg (n=679) Oxycodone IR 10 mg or 15 mg (n=170) Gastrointestinal Disorders 44.2 63.5 Nausea 18.4 29.4 Vomiting 16.9 30.0 Constipation 12.8 27.1 Diarrhea 6.6 5.9 Dry mouth 5.3 2.9 Nervous system disorders 36.7 37.1 Dizziness 18.1 17.1 Headache 11.5 10.0 Somnolence 10.2 9.4 Fatigue 5.6 2.4 Skin and tissue 8.5 15.9 Pruritus 4.3 11.8
- 20. NAUSEA AND VOMITING RATES AMONG OPIOID-NAÏVE * VS OPIOID-EXPERIENCED † PATIENTS IN THE 90-DAY STUDY *Opioid use for <5 days/week during the 30 days prior to screening. † Opioid use for ≥5 days/week during the 30 days prior to screening. 1. Hale M et al. Curr Med Res Opin. 2009; 25(5):1095-1104 . 35% Incidence Rates (%) Nausea Vomiting Opioid-Naïve* Nausea Vomiting Opioid-Experienced † Core 18% 39% 14% 23% 22% 16% 21% 40 60 20 50 30 0 10 N=849 Tapentadol IR 50 or 100 mg (n=679) Oxycodone IR 10 or 15 mg (n=170)
- 21. DISCONTINUATION RATES DUE TO ADVERSE EVENTS IN STUDIES ≥10 DAYS: EVENTS REPORTED IN ≥ 2% OF PATIENTS* *Incidence based on number of subjects, not the number of events. Discontinuation rates include patients who discontinued because of 1 or more adverse events. † Dosing: q4-6h during waking hours. ‡ Flexible dosing: q4-6h as needed. IR = immediate release. 1. Hartrick C et al. Clin Ther . 2009;31(2):260-271. 2. Hale M et al. Curr Med Res Opin. 2009;25(5):1095-1104. Core (Blanks indicate <2% incidence or adverse event not reported) Feature End-Stage Joint Disease Study (10 Day) †1 (N=666) 90-Day Safety Study Disease Study ‡2 (N=849) Placebo NUCYNTA ® Oxycodone IR NUCYNTA ® Oxycodone IR % 50 mg % 75 mg % 10 mg % 50/100 mg % 10/15 mg % Total discontinuation rates due to AEs 4 13 18 30 21 31 Nausea Vomiting Constipation 2 4 4 4 13 11 5 5 3 2 11 8 6 Dizziness Somnolence Headache 2 7 2 8 2 9 6 4 2 2 6 3 4 Skin Pruritus (itching) 4 2 Fatigue Asthenia 2 2
- 30. Case Studies
Notas del editor
- This promotional educational activity is brought to you by PriCara ® , Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc, and is not certified for continuing medical education. The speaker is a paid consultant presenting on behalf of PriCara ® and must present information in compliance with FDA requirements applicable to PriCara ® .
- Introduction to NUCYNTA ® Although the exact mechanism of tapentadol is unknown, it includes a dual mechanism of action –norepinephrine reuptake inhibition and mu-opioid agonism. The next few slides will discuss how pain signals are transmitted along the major pain pathways and how the MOA of norepinephrine uptake inhibitors and mu-opioid agonists relate to these pathways.
- Roles of Ascending and Descending Pathways in Pain The initial reception of painful stimuli occurs at the peripheral terminals of nociceptors. 1 When the specialized pain receptors initiate a nerve impulse, it is conducted along the peripheral sensory nerve to the dorsal horn of the spinal cord where it synapses with a secondary sensory neuron. Alternatively, this peripheral neuron may synapse with an interneuron, and the interneuron then synapses with the secondary neuron. Sensory processing (inhibitory and facilitative) at this level determines whether the pain signals will be transmitted via ascending pathways to the brain. 1 Within the brain, pain is perceived and a motor and emotional response is typically evoked. The brain can respond with both facilitative (pain enhancing) and inhibitory (pain decreasing) modulatory controls. 1 These modulatory effects are transmitted through the descending pathways to the spinal cord. Descending inhibition from the brain acts primarily through the release of monoamines, such as serotonin and norepinephrine. The inhibitory mechanisms may reduce or totally block the transmission of nociceptive input to the brain. 1 References Woolf CJ. Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441-451.
- Key Roles of μ -Opioid Agonism and Norepinephrine (NE) Reuptake Inhibition This section will focus on mechanisms of selected analgesics, including important roles for agonists of mu ( μ )-opioid receptors 1 and inhibitors of norepinephrine reuptake 1-3 in modulation of pain. Action of μ -opioids on ascending pathways modulates nociceptive signals and also modulates activation of the descending pathway. 1,3 Norepinephrine reuptake inhibitors increase the concentration of NE in the spinal dorsal horn after its release from neurons in the descending pathways, which inhibits transmission of pain signals. 1-3 References Vanderah TW. Pathophysiology of pain. Med Clin North Am . 2007;91(1):1-12. Delgado PL. Common pathways of depression and pain. J Clin Psychiatry . 2004;65(suppl 12):16-19. Benarroch EE. Descending monoaminergic pain modulation: bidirectional control and clinical relevance. Neurology . 2008;71:217-221.
- Norepinephrine (NE) Has a Key Role in Pain Modulation Descending pathways projecting from cerebral and brain stem structures to the dorsal horn can inhibit (or facilitate) transmission of nociceptive signals to the brain. 1,2 These modulating effects are mediated by the release of serotonin, dopamine, and norepinephrine. 2-4 In preclinical studies, all three monoamines inhibit pain signaling. In addition dopamine and serotonin may facilitate pain signaling. 2-4 Animal studies suggest that the descending noradrenergic system can be activated to suppress the hypersensitivity of nociceptive neurons in the superficial dorsal horn. 2,5 References Woolf CJ. Moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med . 2004;140(6):441-451. Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol . 2006;80(2):53-83. Vanderah TW. Pathophysiology of pain. Med Clin North Am . 2007;91(1):1-12. Benarroch EE. Descending monoaminergic pain modulation: bidirectional control and clinical relevance. Neurology . 2008;71:217-221. Wei F, Dubner R, Ren K. Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation. Pain . 1999;80:127-141.
- Mechanism of Action of Selected Analgesics This slide shows how selected analgesics affect the ascending and descending pathways. Acetaminophen acts by inhibiting central prostaglandin synthesis, resulting in primarily analgesic and antipyretic activity. Similarly, NSAIDs act through inhibition of cyclooxygenase, which decreases peripheral and central prostaglandin synthesis, resulting in analgesic, antiinflammatory, and antipyretic activity. 1 Anticonvulsant drugs, such as gabapentin and pregabalin, reduce presynaptic neurotransmitter release. These agents work in the ascending pathway to inhibit presynaptic release of pain transmitters. 2,3 In addition, the pain relief that these agents provide may also depend in part upon the noradrenergic descending pain pathway. 6 Opioids act at peripheral and spinal levels to limit nociceptive transmission. In addition they function in the cerebral structures and brain stem to prompt the release of norepinephrine by the descending inhibitory pathway. 4 Local anesthetics can block the sodium channels to decrease neural excitability at the receptor level. 3,5 Tricyclic antidepressants, SSRIs, and SNRIs inhibit the reuptake of serotonin and/or norepinephrine in the dorsal horn to varying degrees to modulate descending pain pathways. 3 References Carver A. Pain. In: ACP Medicine. New York, NY: WebMD; 2005:section 11, chap 14. Benarroch EE. Descending monoaminergic pain modulation : bidirectional control and clinical relevance . Neurology . 2008;71:217-221. Knotkova H, Pappagallo M. Adjuvant analgesics. Med Clin North Am . 2007;91(1):113-124. Vanderah TW. Pathophysiology of pain. Med Clin North Am . 2007;91(1):1-12. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Progr. 2006;53:98-109. Tanabe M, Takasu K, Kasuya N, Shimizu S, Honda M, Ono H. Role of descending noradrenergic system and spinal 2 -adrenergic receptors in the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse. Brit J Pharmacol. 2005;144(5):703-714.
- Dual Mechanism of Action: Norepinephrine Reuptake Inhibitor and μ -opioid Receptor Agonist Although the exact mechanism of tapentadol IR is unknown, based on preclinical data and a Phase 1 study, the mechanism of action for tapentadol includes μ -opioid receptor agonism, as well as inhibition of norepinephrine reuptake. 1,2 This animated slide depicts a theoretical signaling pathway sequence by which pain signals from and to the brain are affected by tapentadol through both the descending and ascending pathways, respectively. An incoming nociceptive pain signal leads to the release of chemicals such as substance P and glutamate. These pronociceptive transmitters may propagate a signal via specific receptors, and ultimately to the brain via the ascending pathway. 3 Activation of the descending pathway may inhibit the pain signaling to the ascending pathway by the release of norepinephrine (NE). NE binds and activates alpha-2 adrenergic receptors, which then inhibit the ascending signal stimulated by substance P or glutamate. 3,4 However, NE action may be self-limited by the presynaptic reuptake of NE. Tapentadol IR may exert its analgesic action by affecting at least 2 proteins: the μ -opioid receptor and the NE reuptake protein. 1,2 It may block the incoming signal to the ascending pathway by activating the μ -opioid receptor to reduce release of pronociceptive transmitters. Secondly, tapentadol IR may inhibit NE reuptake protein, making more NE available in the synaptic cleft to alpha-2 adrenergic receptors that will inhibit the pronociceptive receptor–driven ascending signals. References: Tzschentke TM, De Vry J, Terlinden R, et al . Tapentadol hydrochloride. Drugs Future. 2006;31(12):1053-1061. Tzschentke TM, Christoph T, Kögel B, et al. (–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (Tapentadol HCl): a novel μ -opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther . 2007;323(1):265-276. Vanderah TW. Pathophysiology of pain. Med Clin North Am . 2007;91(1):1-12 . Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol . 2006;80(2):53-83.
- Specific Features Tapentadol immediate release (IR) is the first new molecule in over 25 years for the relief of moderate to severe acute pain in patients 18 years of age or older. 1 The exact mechanism of action of NUCYNTA ® is unknown. Tapentadol IR is distinct from many other short-acting opioids on the market due to the following: Tapentadol IR dual mechanism of action: norepinephrine reuptake inhibitor and μ -opioid receptor agonist 1,2 Tapentadol IR parent compound is the active moiety, with no active metabolites 1,3 Ninety-nine percent of tapentadol IR, the parent molecule, and its metabolites are excreted by the kidney. 1,3 Tapentadol IR does not induce or inhibit P450 enzymes. Thus clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur. No clinically significant findings have been found in drug-drug interactions with acetaminophen, aspirin, naproxen, probenecid, omeprazole, and metaclopramide. 1,3 NUCYNTA ® is Schedule II and is available in 3 strengths. 1 References: NUCYNTA ® (tapentadol) [Prescribing Information]. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc. Terlinden R, Ossig J, Fliegert F, Lange L, Göhler K. Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects. Eur J Drug Metab Pharmacokin. 2007;32(3):163-169. Tzschentke TM, Christoph T, Kögel B, et al. (–)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (Tapentadol HCl): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther . 2007;323(1):265-276.
- How to Dose NUCYNTA ®
- NUCYNTA ® : Phase 3 Clinical Data This section will cover the following topics in core slides: Overview of trials on efficacy, tolerability, and safety in more than 3000 patients Efficacy based upon findings from the end-stage joint disease (ESJD) and bunionectomy I/II studies Adverse events for the ESJD and bunionectomy I/II studies Tolerability (ESJD, bunionectomy II) Adverse events in the 90-day safety study AE rates for nausea and vomiting in opioid-experienced and opioid-naïve patients in the 90-day safety study Discontinuation due to adverse events for 2 trials of at least 10 days in duration (ESJD, 90-day safety) Summary key points
- Tapentadol IR Trial Data: Studied in More Than 3000 Patients One bunionectomy study, 1 the end-stage joint disease (osteoarthritis) study, 2 and the 90-day safety study, 3 comprised the phase 3 studies that were part of the NDA submission for FDA review of the tapentadol immediate-release formulation. A second bunionectomy study 4 was performed with similar patient demographics as in the first Daniels et al, 1 and focused on a dose of the active comparator (oxycodone IR 10 mg) that was also used in the end-stage joint disease study by Hartrick et al. 2 The first 3 studies listed in the table above provide data on the safety, tolerability, and efficacy of NUCYNTA ® . The fourth study provides additional safety data. The full adverse events profile of these phase 3 studies for tapentadol IR will be discussed later in the presentation. References: Daniels SE, Upmalis D, Okamoto A, Lange C, Häeussler J. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009;25(3):765-776. Hartrick C, Van Hove I, Stegmann J-U, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009;31(2):260-271. Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009;25(5):1095-1104. Daniels S, Casson E, Stegmann J-U, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for acute pain. Curr Med Res Opin . 2009;25(6):1551-1561.
- End-Stage Joint Disease of the Hip or Knee Study: Analgesic Efficacy in a 10-Day Trial The end-stage joint disease study was a randomized, double-blind, active- and placebo-controlled, parallel-group, multicenter study in outpatients with moderate to severe pain due to chronic osteoarthritis of the hip or knee. The intent-to-treat population (N=659) with a mean baseline pain intensity score of 6.7 was randomized to 50 mg or 75 mg of tapentadol IR, 10 mg oxycodone IR, or placebo dosed every 4 to 6 hours while patients were awake. The intent-to-treat population included all randomized subjects who received any amount of study drug (ie, at least 1 dose of study drug intake following randomization) and had a valid baseline pain assessment. The summary and analysis were based on the last observation carried forward (LOCF) imputation method. P values were adjusted using the Hochberg procedure (the oxycodone group was not included). A higher SPID value indicates greater pain relief. 1,2 The sum of pain intensity difference (SPID) 5-day value was the primary endpoint in this study. 1,2 SPID is a cumulative score that increases with time if the patient reports a reduction in pain intensity. SPID is calculated as the sum of change from baseline in pain intensity at a time point multiplied by the elapsed time from the previous observation. The higher the SPID, the greater the pain relief. Assay sensitivity was validated by the separation of the oxycodone IR 10-mg group from the placebo in the 5-day SPID. 1 All active treatment SPID values were significantly different from placebo ( P <.001). 1,2 Decrease in pain intensity was demonstrated by the 5-day SPID least squares mean difference from placebo 2 : Tapentadol IR 50 mg: 101.2 Tapentadol IR 75 mg: 97.5 Oxycodone IR 10 mg: 111.9 Two different statistical calculations are used to show the efficacy data. The slide graph uses the mean SPID calculations vs placebo. These calculations are noted in the original clinical study report. The placebo-subtracted data are calculated using the SPID least squares mean difference method featured in the final published study. In a prespecified analysis, both doses of tapentadol IR provided analgesic efficacy that was noninferior to that of oxycodone IR 10 mg. 2 References: 1. Data on file, J&J PRD, LLC. 2. Hartrick C, Van Hove I, Stegmann J-U, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009;31(2):260-271.
- Bunionectomy Studies I and II: Analgesic Efficacy in a Postoperative Pain Model (3-day trial) Bunionectomy was a postoperative pain model, in which the efficacy and safety of tapentadol IR were evaluated in 2 randomized, active- and placebo-controlled studies. Intent-to-treat patient populations had mean baseline pain intensity scores of 7.0 1 and 7.1 2 for each of the 2 studies. Dosing of study medication was every 4 to 6 hours around the clock in these inpatients (who were primarily middle-aged women). Only the second study allowed up to 2 grams of acetaminophen as rescue medication during the first 12 hours. 2 Graphs of changes in pain intensity over a 48-hour observation interval are shown for bunionectomy study I 1 on the left and for bunionectomy study II on the right. 2 The primary efficacy measure or endpoint was the SPID 48-hour score. Briefly stated, the higher the SPID score, the greater the pain relief. Let’s look first at bunionectomy study I, which had a total of 602 intent-to-treat patients. All active groups including tapentadol immediate release 50, 75, and 100 mg, and oxycodone immediate release 15 mg provided significantly greater pain relief than placebo ( P <.001) . The bunionectomy II study had a total of 901 intent-to-treat patients. All active groups including tapentadol immediate release 50 and 75 mg, and oxycodone immediate release 10 mg provided significantly greater pain relief than placebo ( P <.001). Finally, with regard to onset of analgesia with tapentadol IR, it was noted in study I that the median time to confirmed perceptible pain relief occurred as early as 32 minutes and ranged from 32 to 46 minutes, which were significantly different from the 100-minute placebo value (P ≤.005). 1 References: 1. Daniels SE, Upmalis D, Okamoto A, Lange C, Häeussler J. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009;25(3):765-776. 2. Daniels S, Casson E, Stegmann J-U, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin . 2009;25(6):1551-1561.
- End-Stage Joint Disease of the Hip or Knee Study: Treatment-Emergent Adverse Events Reported by ≥1% of Subjects The 7 most frequently reported treatment-emergent adverse events in all active treatment groups were dizziness, nausea, vomiting, somnolence, constipation, pruritus, and fatigue. 1 Treatment-emergent adverse event rates (% of patients) were 32% for placebo, 84% for oxycodone IR 10 mg, 52% for tapentadol IR 50 mg, and 71% for tapentadol IR 75 mg. The most common gastrointestinal adverse events in the active treatment groups were nausea and vomiting. 1 Reference: Hartrick C, Van Hove I, Stegmann J-U, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009;31(2):260-271.
- Bunionectomy Studies: Treatment-Emergent Adverse Events Reported by ≥5% of Subjects This table summarizes adverse events seen in at least 5% of subjects in the 2 NUCYNTA ® bunionectomy studies. Blank entries represent incidence below 5%. Gastrointestinal, nervous system, and skin disorders are shown in the table. These adverse events are observed for patients taking opioids. References: Daniels SE, Upmalis D, Okamoto A, Lange C, Häeussler J. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009;25(3):765-776. Daniels S, Casson E, Stegmann J-U, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for acute pain. Curr Med Res Opin . 2009;25(6):1551-1561.
- End-Stage Joint Disease of the Hip or Knee Study: Composite Incidence of Nausea and/or Vomiting Data in this slide illustrate GI tolerability of NUCYNTA ® in the end-stage joint disease study. The safety population (N=666) with a mean baseline pain intensity score of 6.7 was randomized to 50 mg or 75 mg of tapentadol IR, 10 mg oxycodone IR, or placebo dosed every 4 to 6 hours while patients were awake. Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events. Shown here is the composite incidence of nausea and/or vomiting for placebo (n=169), oxycodone IR 10 mg (n=172), tapentadol IR 50 mg (n=157), and tapentadol IR 75 mg (n=168). 1,2 Composite incidence of nausea and vomiting 1,2 : Placebo: 8.3% Tapentadol IR 50 mg: 21.7% Tapentadol IR 75 mg: 29.8% Oxycodone IR 10 mg: 57.0% The 7 most frequently reported treatment-emergent adverse events in all active treatment groups were dizziness, nausea, vomiting, somnolence, constipation, pruritis, and fatigue. References: Hartrick C, Van Hove I, Stegmann J-U, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009;31(2):260-271. Data on file, J&J PRD, LLC.
- Bunionectomy Study II: Composite Incidence of Nausea and/or Vomiting Data in this slide from bunionectomy II illustrate GI tolerability in a postoperative setting. This particular study used the composite incidence of nausea and/or vomiting as a combined primary endpoint along with the 48-hour SPID. The intent-to-treat population (N=901) with a mean baseline pain intensity score of 7.1 was randomized to 50 mg or 75 mg of tapentadol, 10 mg oxycodone IR, or placebo dosed every 4 to 6 hours. 1,2 In this second bunionectomy study, the composite incidence of nausea and vomiting was 1,2 : Placebo: 17.4% Tapentadol 50 mg: 35% Tapentadol 75 mg: 51% Oxycodone IR 10 mg: 59% The incidence figures reported above were based on the number of subjects experiencing at least 1 adverse event, not the number of events. All active treatments were significantly different from placebo ( P <.001). 1 References: Data on file, J&J PRD, LLC. Daniels S, Casson E, Stegmann J-U, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for acute pain. Curr Med Res Opin . 2009;25(6):1551-1561.
- 90-day Safety Study: Treatment-Emergent Adverse Events Reported by ≥2% of Subjects Gastrointestinal, nervous system, and skin disorder adverse events are shown in the table. 1 The rate for nausea was 18.4% for tapentadol IR 50 mg or 100 mg and 29.4% for oxycodone IR 10 mg or 15 mg; the rate for vomiting was 16.9% for tapentadol IR and 30.0% for oxycodone IR; and the rate for constipation was 12.8% for tapentadol IR and 27.1% for oxycodone IR. As you can see in the table, rates of dizziness, headache, and somnolence ranged from 9.4% to 18.1% across the treatment groups. Finally, pruritis was 4.3% for tapentadol IR and 11.8% for oxycodone IR. Reference: Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009;25(5):1095-1104.
- Nausea and Vomiting Rates Among Opioid-Naïve vs Opioid-Experienced Patients in the 90-day Study In this study, about half the patients were opioid-naïve and half were opioid-experienced. The definition of “opioid-experienced” was opioid use for 5 days or more per week in the month before patients were screened for this study. Here, the incidence of nausea and vomiting rates are shown. While the data were not analyzed statistically, they illustrate that these side effects tended to be higher in opioid-naïve patients. In opioid-naïve patients, nausea or vomiting were 22% or 18% respectively with tapentadol IR, and 35% or 39% with oxycodone IR. The data were published by Hale et al. However, this publication did not report any other adverse events as a function of prior opioid experience. Reference: Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009;25(5):1095-1104.
- Discontinuation Rates Due to Adverse Events in Studies ≥10 Days: Events Reported in ≥2% of Patients Discontinuation rates from 2 studies of at least 10 days’ duration are summarized in this table. 1,2 Percentages of patients are shown for the incidence of adverse events as a reason for discontinuation. Subjects could report more than 1 reason for discontinuation. In the end-stage joint disease study, total discontinuations ranged from 13% to 18% for tapentadol immediate release 50 mg to 75 mg, and 30% for oxycodone immediate release 10 mg. 1 In the 90-day study, total discontinuations were 21% for subjects randomized to tapentadol immediate release and 31% for subjects randomized to oxycodone immediate release. 2 Most AEs related to discontinuation were GI events. 1,2 Reference: Hartrick C, Van Hove I, Stegmann J-U, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009;31(2):260-271. Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009;25(5):1095-1104.
- IMPORTANT SAFETY INFORMATION Like other drugs with mu-opioid agonist activity, NUCYNTA ® is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment. NUCYNTA ® is contraindicated in patients who have or are suspected to have paralytic ileus. NUCYNTA ® is also contraindicated in patients currently using or within 14 days of using monoamine oxidase inhibitors (MAOIs) due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.
- IMPORTANT SAFETY INFORMATION (cont) Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. NUCYNTA ® should be administered with caution to the elderly, debilitated patients, and patients with conditions accompanied by hypoxia, hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA ® may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered and NUCYNTA ® should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid agonist-induced respiratory depression.
- IMPORTANT SAFETY INFORMATION (cont) Patients receiving other mu-opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with NUCYNTA ® may exhibit additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, coma or death may result if these drugs are taken in combination with NUCYNTA ® . When such combined therapy is contemplated, a dose reduction of one or both agents should be considered. Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, NUCYNTA ® should not be used in patients susceptible to the effects of raised cerebrospinal fluid pressure such as those with head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical course of patients with head injury due to effects on pupillary response and consciousness. NUCYNTA ® should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.
- IMPORTANT SAFETY INFORMATION (cont) NUCYNTA ® is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty. NUCYNTA ® can be abused in a manner similar to other mu-opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA ® in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. All patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction. NUCYNTA ® may be abused by crushing, chewing, snorting or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death.
- IMPORTANT SAFETY INFORMATION (cont) Experience with NUCYNTA ® overdose is very limited. Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to reestablishment of a patent airway and institution of assisted or controlled ventilation when overdose of NUCYNTA ® is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Patients should be cautioned that NUCYNTA ® may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. This is to be expected especially at the beginning of treatment, at any change of dosage as well as in combination with alcohol or tranquilizers. NUCYNTA ® has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. NUCYNTA ® should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.
- IMPORTANT SAFETY INFORMATION (cont) The development of a potentially life-threatening serotonin syndrome may occur with use of SNRI products, including NUCYNTA ® , particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg nausea, vomiting, diarrhea). Withdrawal symptoms may occur if NUCYNTA ® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering NUCYNTA ® .
- IMPORTANT SAFETY INFORMATION (cont) Pregnancy Category C. There are no adequate and well-controlled studies of NUCYNTA ® in pregnant women. NUCYNTA ® should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus. NUCYNTA ® is not recommended for use in women during and immediately prior to labor and delivery. Neonates whose mothers have been taking NUCYNTA ® should be monitored for respiratory depression. NUCYNTA ® should not be used during breastfeeding. NUCYNTA ® is not recommended in patients with severe renal or hepatic impairment. NUCYNTA ® should be used with caution in patients with moderate hepatic impairment. Like other drugs with mu-opioid agonist activity, NUCYNTA ® may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. The most common adverse events are nausea, dizziness, vomiting, somnolence and headache.
- Summary The conclusions for NUCYNTA ® are summarized here.
- Principles of Pain Assessment A careful medical history and physical examination is an important part of any pain assessment. A complete pain history should include information on the onset, timing, intensity, and location of the pain. Also ask about any aggravating or relieving factors or whether there are any symptoms that the patient associates with the pain. Consideration of the patient’s physical, psychological, and psychosocial condition should start with the initial evaluation and continue through therapy. Particularly at an initial assessment, relevant medical and drug history should be evaluated for a history of possible alcohol or drug dependence and the possible management problems involved. These examinations may uncover the underlying cause of pain and, at the very least, assure the patient that the pain complaints are being taken seriously. Finally, both physician and patient should agree on realistic expectations from therapy. This list is comprehensive. For today’s talk, we will focus on how to assess the quality of pain symptoms, which may help selection of appropriate pharmacologic therapy. Since pain is highly subjective, use of an assessment tool, such as a rating scale of 0 to 10 (where a rating of 0 is no pain, and 10 represents worst pain imaginable), can help quantify the severity of pain. The terminology that the patient uses to describe the pain may help you assess the quality or nature of the pain. The rest of the items on this list should be customized, where needed, for the medical condition in question (eg, injury vs acute pain related to a chronic condition). Reference Carver A. Pain. In: ACP Medicine. New York, NY: WebMD; 2005:section11, chap 14.