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Tapentadol Therapy to Manage Moderate-to-Severe Pain:

Key Considerations for NursingPaul Arnstein, PhD, RN-BC, ACNS-BC, FAAN

Kathleen Broglio, DNP, ANP-BC, ACHPN

Acknowledgement

• Drs Arnstein and Broglio would like to thank

Dr. Iwona Bucior (Former Medical Science

Writer for Depomed) for providing about

information about Tapentadol from preclinical

and clinical studies

Disclosures - Arnstein 2014 - 2015

• Scientific & Nurse Practitioner Advisory Panels:– Sterling Labs; – Zogenix; Janssen: Purdue; Mallinckrodt; AstraZeneca

• Author & editorial honoraria/royalties:– Gannet publications – F.A. Davis Publishers

• Speaking honoraria:– Nurse Practitioner Healthcare Foundation – American Pain Society: (FDA-REMS content)

• Expert Legal Testimony:

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Disclosures - Broglio• Speaker’s Bureau:

– Genentech, Mallinkrodt, Teva• Advisory Boards:

– Purdue Pharmaceuticals, Janssen, Zogenix,Mallinkrodt

• Consulting:– Purdue Pharmaceuticals, EMMI solutions

• Royalties:– UpToDate

Objectives

• Describe the place of opioid therapy in thetreatment of pain

• Distinguish the properties of tapentadol from those of other opioids

• Design a comprehensive pain managementplan

Pain affects the whole personSevere or persistent pain sends ripples through the

nervous system, invading the person’s whole life…personality…& relationship with the world

Pain

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Duty to relieve pain & suffering

• Health professionals have an ethical duty – To alleviate suffering – To provide competent & humane services

• Uncontrolled acute pain hurts…. – Impairs immune function (post-op infection)

– Impairs metabolism (insulin resistance hyperglycemia)

– Impairs respirations (atelectasis, PNA)

– Exposes to hazards of immobility– Changes nervous system sensitivity (development of chronic pain)

Harmful Effects of Chronic Pain• CNS remodeling with 5-10% gray matter loss

– Reversible with better pain control

• Long-term exposure to potential risky drugs• Health care expenditures average $10,000/pt./yr.

• Increase in all-cause mortality in 10 years – 50%higher risk; (3x if pain severe)

• Chronic pain is a common reason for:– Seeking health care, – Specialist consultation– Risk of developing depression

Potential Harm from Analgesics•Leading cause of drug-related hospitalization

–25% involving older adults related NSAID toxicity–>1 million opioid-related hospitalizations (CMS)

•1 million older adults/yr go to ED for ADEs– 9% involve opioids and 8% nonopioid analgesics

•Opioids leading cause of overdose deaths– 2012 Rx opioid overdose deaths 16,007 (38% of fatal ODs)

– 77% Benzodiazepine deaths – also had opioids– 65% antiepileptic/anti-parkinson deaths w/ opioid

CDC/NCHS, (2015) National Vital Statistics System, Mortality FileFranceschi et al., (2008) Drug Saf, 31(6):545-56 Jones, (2013) Pharmaceutical Overdose Deaths, United States, 2010. JAMA, 309 (7): 657-659Samhsa.gov/data/2k10/TDR013AdverseReactionsOlderAdults/AdverseReactionsOlderAdults_HTML.pdfYoung (2014) CQ Healthbeat. Medicare Sees Most Growth in Opioid-Related Hospitalizations

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Expected opioid effects

• Analgesia

• Side effects

• Tolerance

– Diminution of one or more opioid effects

• Physical dependence

– Abstinence syndrome

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Undesirable Opioid Effects

–Respiratory depression, bronchospasm

–Sedation, dizziness, ataxia, visual disturbances

–Nausea / vomiting, constipation

–Urinary retention, sexual dysfunction

–Itching, skin rash

–Immune, hormonal or neurological problems

–Psychosocial problems

–Behavioral / existential problems

Rx Analgesic Sales & Deaths

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Are opioids indicated?

• Indicated– Moderate-severe acute pain (?15-30 days)– Cancer pain / severe pain at end of life– Chronic non-cancer pain benefits>risks (controversial)

• Not Indicated– True allergy– Untreated addiction disorder (relative contraindication)

– Unmonitored environment if IV/Neuraxial route– Drug diversion confirmed

Avoiding Overdose• Patient selection based on risk• Lower risk by drug selection (highest to lowest risk /Rx1)

– Methadone, morphine, hydrocodone, fentanyl, hydromorphone, oxycodone, buprenorphine

– Tramadol and Tapentadol

• General & tailored dosing– Most overdose deaths include >1 drug– Rx poisonings 8% non-opioids; 9% opioids2

1. CDC (2012) MMWR July 12 61(26);493-4972. Bronstein (2010) Clin Toxicol (Phila). 2010 Dec;48(10):979-1178.

WHO* 3-Step Approach to Relief

Pain

Pain persists or increases

Pain persists or increases

Non-opioids for mild to moderate pain± Adjuvant

Opioids for moderate to severe pain± Non-opioid ± Adjuvant

Stronger, higher dose opioids for severe pain. ± Non-opioid ± Adjuvant

(e.g. Non-drug &/or Interventional Rx)

Adjuvant examples

Drugs• Gabapentin

• Duloxetine

Interventions• Nerve blocks

• Neuroablation

Non-drug• Heat or cold

• Distraction

• Coping

• Acupuncture

*Originally published by the World Health Organization (1986) for cancer pain

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2015 Cancer Pain Guideline Update• Greater use of adjuvants before opioid escalation• Added assessment of risk factors for opioid abuse• Avoid certain drugs in renal compromised patient

– Morphine, Codeine, Hydrocodone, Hydromorphone, Oxymorphone

• Added indications for opioid rotation– Physical factors including route of administration – Insurance coverage, formulary & cost impact

• Added monitoring of aberrant drug behaviors– Monitor both patient and family

• Added information on ER/LA REMSNational Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain.Version 2.2015 Accessed July 15, 2015. http://www.nccn.org/professionals/physician_gls/PDF/pain.pdf.

ASA Guidelines: Acute Pain

American Society of Anesthesiologists. Practice Guidelines for Acute Pain Management in the Perioperative Setting: An Updated Report by the American

Society of Anesthesiologists Anesthesiology. 2012;116(2):248-273.

• Assess potential risks/benefits of therapy options• Select lowest risk approach

– Peripheral Nerve Blocks– Neuraxial Analgesia– PCA / Opioids

• Use Multimodal opioid-sparing approaches– Non-opioid analgesics– Local Anesthetics– Adjuvant therapies

Risks & Benefits of Acute Opioids

Thorson D, Biewen P, Bonte B, et al. Institute for Clinical Systems Improvement. Acute Pain Assessment and Opioid Prescribing Protocol. https://www.icsi.org/_asset/dyp5wm/Opioids.pdf. Accessed July 30, 2015.

High Benefit

Low Benefit

High Risk

Low Risk

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Teach Patients• Medication ~ necessary but alone is insufficient• Use right drug for right discomforts in right way

– Analgesics: lowest dose, shortest time– Adjuvants, Give adequate trial

• Avoid interactions;– 1 prescriber – 1 pharmacy – Know foods, drugs, herbs, alcohol that can interact

http://healthtools.aarp.org/drug-interaction

• With opioids– Always use opioid sparing methods– Always be concerned about safe storage/disposal– Never sell or give opioids to another person

Balance Opioid Benefits / RisksAHRQ report on chronic opioid

therapy efficacy & risks• 39 of 4,209 studies met quality standards

– Differences in definitions & measures preclude the ability to deduce comparative effectiveness & risks

– Strength of evidence was rated no higher than low• Lack evidence to know benefits & harms• Most patients do not develop drug problems

– opioid abuse 0.6% to 8%– Rates of dependence were 3.1 % to 26%– aberrant drug-related behaviors 5.7% to 37.1%

Chou R, Deyo R, Devine B, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. AHRQ Report No. 218. Agency for Healthcare Research and Quality; September 2014. Accessed on lin 10/4/14 at http://www.effectivehealthcare.ahrq.gov/ehc/products/557/1971/chronic-pain-opioid-treatment-report-140929.pdf

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Initiating Opioids for Chronic PainInitial treatment as a therapeutic trial

May last from several weeks to several months

Decision to proceed w/ long-term treatment should be intentional & based on careful

consideration of outcomes during the trial

Progress toward meeting therapeutic goals

Presence of opioid-related AEs

Changes in underlying pain condition

Changes in psychiatric or medical comorbidities

Identification of aberrant drug-related behavior, addiction, or diversion

Chou R, et al. J Pain. 2009;10:113-30

Universal precautions for chronic opioid therapy

• Make a diagnosis with appropriate differential • Psychological assessment (including risk of addiction)

• Informed consent & treatment agreement • Pre-treatment assessment of pain level & function • Trial of opioid therapy with adjunctive therapy• Reassessment of pain score and level of function • Regularly assess the four A’s of pain medicine • Periodically review pain diagnosis & comorbidity• Documentation

• Recognize & document aberrant behavior– In addition to patient self-report also use:

• State PDMPs, where available• UDT

– Positive for nonprescribed drugs– Positive for illicit substance– Negative for prescribed opioid

• Family member or caregiver interviews• Monitoring tools such as the COMM, or PDUQ• Medication reconciliation (e.g., pill counts)

Monitor Adherence & Behavior

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Interpretation of UDT ResultsDemonstrates recent use

• Most drugs in urine have detection times of 1-3 d• Chronic use of lipid-soluble drugs: test positive for ≥1 wk

Does not diagnose• Drug addiction, physical dependence, or impairment

Doesn’t provide enough info to determine• Exposure time, dose, or frequency of use

Does not diagnose diversion• More than presence or absence of drug in urine

May be maladaptive drug-taking behavior• Bingeing, running out early• Cessation of insurance, financial difficulties, etc.

Positive Result

Negative Result

How Worried are You?

• Patient’s UDT (IA)results:– Negative for opiates– Negative for

benzodiazepines– Positive for PCP– Positive for cannabinoids

Patient is prescribed Hydrocodone 20mg/day; Buprenorphine patch 20mg/week

Alpraxolam 0.5mg TID; Venlafaxine 225mg Daily Confirm (GC/MS) because

IA doesn’t reliably identify non-opiate opioids

IA doesn’t identify Alpraxolam Venlafaxine ~give false + PCP Omeprazole ~give false + for

cannabinoids1st Minute: Write down … What finding is least worrisome

for Aberrant Behaviors? 2nd Minute: Compare notes with neighbor

Switching to an ER/LA Opioid? • Reason for switching to ER/LA Opioids

• Continuous, around-the-clock opioid analgesic is needed for an extended period of time

• No alternative therapy is likely to pose as favorable a balance of benefits to harms

• May be used in lowest dose for non-tolerant:• Extended release morphine, oxycodone, hydrocodone:• Tapentadol ER; Buprenorphine transdermal system

• Only for opioid-tolerant patients (any dose)• Fentanyl, methadone, oxymorphone, hydromorphone

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Abuse Deterrent Formula TypesPhysical/ Chemical Barrier

Prevents chewing or crushingPrevents ability to extract drug chemically

Agonist/Antagonist Combinations

Antagonist (e.g. naloxone) added to prevent euphoriaSequestered antagonist released if altered

Aversion Sequestered substances (irritant) combined to produce an unpleasant effect if altered

Delivery systems that resist abuse

Delivery system difficult to manipulate, (e.g. ER - IM injections; SubQ implants)

Prodrug Converts to active form in GI Tract

United States Food and Drug Administration. (2013) FDA’s Efforts to Addressthe Misuse and Abuse of Opioids. Available online

Case Study• EW 64 y.o. man with hypertension and insulin dependent

diabetes mellitus• Chronic pain conditions: Severe low back pain with radicular

symptoms, diabetic peripheral neuropathic pain, severe osteoarthritis right knee planning for total knee replacement

• Poor response to acetaminophen, nonsteroidal anti-inflammatory drugs, topical analgesics, corticosteroidinjections, physical therapy, and exercise

• Tricyclic antidepressant contraindicated, had side effects from SNRIs and gabapentinoids

Would tapentadol be an appropriate analgesicoption for both acute and chronic pain ?

Tapentadol Mechanism of Action• Exact mechanism of action unknown• Centrally acting synthetic analgesic• Dual mechanisms of action

– Mu-opioid receptor agonist – Norepinephrine reuptake inhibitor

• Synergistic action for pain reduction• Dual mechanism may affect tolerance

developmentTzschentke TM, et al. J Pharmacol Exp Ther. 2007; 323(1):265-276. Schröder W, et al. J Pharmacol Exp Ther. 2011;337(1):312-320.

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Mechanism of Action (2)

• Tapentadol similar binding to norepinephrinereuptake inhibitor as venlafaxine (SNRI)

• Tapentadol dose escalation show minimalincrease in serotonin levels

Take away: May have less serotonergic effects

Tzschentke TM, et al. J Pharmacol Exp Ther. 2007;323(1):265-276.

Indications

• Tapentadol IR– Moderate to severe acute pain in adults

• Tapentadol ER– Management of pain severe enough to require

daily around the clock opioid therapy– Painful diabetic peripheral neuropathy in adults

that is unresponsive to alternative treatment• Only opioid in US approved for this indication

NUCYNTA. Janssen Pharmaceuticals, Inc. 2011; NUCYNTA ER. Janssen Pharmaceuticals, Inc. 2014

Postoperative Pain

• Bunionectomy– All doses of tapentadol (50 mg, 75 mg and 100

mg) or oxycodone 15 mg significantly improved pain intensity (p<0.001) compared with placebo at 48 hours

– Incidence of nausea and/or vomiting was significantly less with tapentadol IR 75 mg (41%) when compared with oxycodone IR 15 mg (70%)

Daniels SE, et al. Curr Med Res Opin. 2009;25(3):765-776.

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Postoperative Pain

• Bunionectomy– No significant differences in pain relief between

oxycodone 10 mg and tapentadol IR 50 mg– Significant difference in nausea/vomiting between

tapentadol 50 mg (35% and oxycodone 10 mg (59% ) but no significant differences seen withtapentadol 75 mg and oxycodone 10 mg

Daniels S, et al. Curr Med Res Opin. 2009;25(6):1551-1561.

Acute pain

• Osteoarthritis pain in end-stage joint disease– Tapentadol 50 mg or 75 mg significant pain

reduction when compared to placebo, no significant difference in efficacy when comparedto oxycodone 10 mg

– Nausea, vomiting, constipation significantly less (p<0.001) when compared to oxycodone 10 mg

Hartrick C, et al. Clin Ther. 2009;31(2):260-271.

Chronic Pain

• Osteoarthritis of knee1 and chronic low backpain2

– Tapentadol ER 100 mg- 250 mg BID produced significant reductions in pain intensity and overall impression of change at 12 weeks

– Less nausea, vomiting and constipation whencompared to oxycodone ER

1Afilalo M, et al. Clin Drug Investig. 2010;30(8):489-505. 2Buynak R, et al. Expert Opin Pharmacother. 2010;11(11):1787-1804.

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Diabetic Peripheral Neuropathic Pain

• Two RCT studies Tapentadol ER1,2

– 53.6%1 and 55.4%2 with greater than 30%improvement in pain at week 12.

– 37.8%1 and 40.4%2 with greater than 50%improvement in pain at week 12

• Pooled analysis 100-250 mg BID effective-meaningful reductions pain intensity3

1Schwartz S, et al. Curr Med Res Opin. 2011;27(1):151-162. 2 Vinik AI, et al. Diabetes Care. 2014;37(8):2302-2309. 3Schwartz S, et al. Clin Drug Investig. 2015;35(2):95-108.

Chronic Cancer Pain

• Tapentadol ER - No significant difference inefficacy when compared to Morphine ER 40-100 mg BID1

• Tapentadol ER- Morphine CR dose ratio was 2.5:1

• Tapentadol ER 25-200 mg bid similar inefficacy oxycodone CR 5-40 mg bid2

• Tapentadol (mean daily dose 190 mg)significant reductions pain intensity3

1Kress HG, et al. Pain Physician. 2014;17(4):329-343. 2Imanaka K, et al. Curr Med Res Opin. 2013;29(10):1399-1409. 3Mercadante S, et al. Curr Med Res Opin. 2012;28(11):1-5.

Dosing

• Tapentadol IR – 50 mg, 75 mg or 100 mg q4h – max dose 700 mg

day one, 600 mg subsequent days• Tapentadol ER

– 50 mg q12h – opioid naïve; titrate by 50 mg every 3 days

– Maximum dose 500 mg daily

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Equianalgesia

• Osteoarthritis Pain or Low Back PainMorphine Tapentadol ER (start)≤ 100 mg/d 50 mg BID

101 to 160 mg/d 100 mg BID> 160 mg/d 150 mg BID

Steigerwald I, et al. Clin Drug Investig. 2013;33(9):607-619 Galvez R, et al. Adv Ther. 2013;30(3):229-259.

Equianalgesia (2)

• Chronic painMorphine equivalent Tapentadol ER (start)< 80 mg/d 50 mg BID80 to < 120 mg/d 100 mg BID120 to < 160 mg/d 150 mg BID160 to < 200 mg/d 200 mg BID≥ 200 mg/d 250 mg BID

Schwittay A, et al. J Pain Palliat Care Pharmacother. 2013;27(3):225-234.

Equianalgesia (3)• Cancer pain

Morphine Equivalent1 Tapentadol ER20 to 30 mg/d 50 mg BID

> 30 to 40 mg/d 75 mg BID> 40 to 60 mg/d 100 mg BID> 60 to 90 mg/d 150 mg BID> 90 to 120 mg/d 200 mg BID

• Morphine to tapentadol switch 1:4.52

1Imanaka K, et al. Clin Drug Investig. 2014;34(7):501-511. 2Mercadante S, et al. Curr Med Res Opin. 2013;29(6):661-666.

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Side effects• Gastrointestinal: Nausea, Vomiting,

Constipation• Nervous System: Dizziness, Somnolence• Skin: Pruritis• In studies chronic low back pain and

osteoarthritis Tapentadol ER less incidence of above side effects when compared toOxycodone CR

Afilalo A, et al. Clin Drug Investig. 2010;30(8):489-505. Buynak R, et al. Expert Opin Pharmacother. 2010;11(11):1787-1804.

Limitations• Dose limits

– Daily ceiling dose 500 mg ER and 600 mg IR• Risk for serotonin syndrome

– Although mostly norepinephrine reuptake, some serotonergic effects – caution when using with serotonergic agents

• Contraindicated with use of monoamineoxidase inhibitors in last 14 days

• Avoid when history of seizuresNUCYNTA. Janssen Pharmaceuticals, Inc. 2011; NUCYNTA ER. Janssen Pharmaceuticals, Inc. 2014

DESIGNING A COMPREHENSIVE TREATMENT PLAN

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Case Study (cont.)• EW undergoes a total knee replacement and

receives a regional nerve block prior to surgery, IV acetaminophen and as neededopioid analgesics

• When transitioning to oral agents EW startstapentadol IR therapy at a dose of 50 mg every4 as needed for pain

• Physical therapy is initiated• He attends a session on cognitive behavioral

therapy

Multimodal Therapy

• Guidelines for postoperative pain and chronicpain recommend multimodal therapy

• The use of opioids are only one part of thecomprehensive plan for both acute and chronicpain– risks must be balanced with benefits

Selected References• Afilalo M, Etropolski MS, Kuperwasser B, et al. Efficacy and safety of tapentadol extended release compared with

oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study. Clin Drug Investig. 2010;30(8):489-505.

• Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled phase III study. ExpertOpin Pharmacother. 2010;11(11):1787-1804

• Daniels SE, Upmalis D, Okamoto A, Lange C, Häeussler J. A randomized, double-blind, phase III study comparingmultiple 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 JU, Oh C, Okamoto A, Rauschkolb C, Upmalis D. 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 MedRes Opin. 2009;25(6):1551-1561.

• Galvez R, Schafer M, Hans G, et al. Tapentadol prolonged release versus strong opioids for severe, chronic low back pain: results of an open-label, phase 3b study. Adv Ther. 2013;30(3):229-259.

• Hartrick C, Van Hove I, Stegmann JU, 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

• Imanaka K, Tominaga Y, Etropolski M, et al. Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Curr Med Res Opin. 2013;29(10):1399-1409.

• Imanaka K, Tominaga Y, Etropolski M, et al. Ready conversion of patients with well-controlled, moderate to severe, chronic malignant tumor-related pain on other opioids to tapentadol extended release. Clin Drug Investig. 2014;34(7):501-511

• Kress HG, Koch ED, Kosturski H, et al. Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. Pain Physician. 2014;17(4):329-343.

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References• Mercadante S, Porzio G, Aielli F, et al. Opioid switching from and to tapentadol extended release in cancer patients:

conversion ratio with other opioids. Curr Med Res Opin. 2013;29(6):661-666

• Mercadante S, Porzio G, Ferrera P, et al. Tapentadol in cancer pain management: a prospective open-label study. Curr MedRes Opin. 2012;28(11):1-5.

• NUCYNTA. Tapentadol Immediate-release Oral Tablets [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011.

• NUCYNTA ER. Tapentadol Extended-release Oral Tablets [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2014.

• Schröder W, Tzschentke TM, Terlinden R, et al. Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther. 2011;337(1):312-320.

• Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151-162.

• Schwartz S, Etropolski MS, Shapiro DY, et al. A pooled analysis evaluating the efficacy and tolerability of tapentadol extended release for chronic, painful diabetic peripheral neuropathy. Clin Drug Investig. 2015;35(2):95-108.

• Schwittay A, Schumann C, Litzenburger BC, Schwenke K. Tapentadol prolonged release for severe chronic pain: results of a noninterventional study involving general practitioners and internists. J Pain Palliat Care Pharmacother. 2013;27(3):225-234.

• Steigerwald I, Schenk M, Lahne U, et al. Effectiveness and tolerability of tapentadol prolonged release compared with prior opioid therapy for the management of severe, chronic osteoarthritis pain. Clin Drug Investig. 2013;33(9):607-619.

• Tzschentke TM, Christoph T, Kogel B, et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrumanalgesic properties. J Pharmacol Exp Ther. 2007;323(1):265-276.

• Vinik AI, Shapiro DY, Rauschkolb C, et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy andtolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care. 2014;37(8):2302-2309.