Clinical Therapeutics/Volume 35, Number 11, 2013

Review Article

Medication Pain Management in the Elderly: Uniqueand Underutilized Analgesic Treatment Options

Timothy J. Atkinson, PharmD1; Jeffrey Fudin, PharmD1,2,3,4; Abhinetri Pandula, MD1,5;and Maira Mirza3

1Stratton Veterans Affairs Medical Center, Albany, New York; 2American Academy of Pain Management;3Albany College of Pharmacy and Health Sciences, Albany, New York; 4Department of Pharmacy Practice,University of Connecticut School of Pharmacy, Storrs, Connecticut; and 5Department of Medicine, AlbanyMedical Center, Albany, New York

Accepted for publication September 11, 2013.http://dx.doi.org/10.1016/j.clinthera.2013.09.0080149-2918/$ - see front matter

Published by Elsevier HS Journals, Inc.

ABSTRACT

Background: By 2030, the US population of adultsaged Z65 years will increase by 480%, and theseadults will account for nearly 20% of the US population.In this population, the decline of multiple physiologicprocesses and diseases collectively influence treatmentoptions. Physiologic changes, drug–drug interactionsresulting from polypharmacy, and drug–disease interac-tions combine to make elderly patients more sensitive tothe adverse events (AEs) associated with medications, allof which must be considered in drug selection.

Objective: This article focuses on select underutilizedmedication options for analgesia that may providesignificant advantages in the elderly population aboveand beyond commonly prescribed conventional choices.

Methods: We performed a complete review of theliterature using the search terms pain management,elderly, opioids, NSAIDs, topical NSAIDs, levorpha-nol, buprenorphine transdermal, and tapentadol. Da-tabases searched included PubMed, Google Scholar,Ovid, and Athens. Package inserts were utilized forapproval dates, indications, and formulations avail-able. We looked at reviews of agents to identifyimportant studies for consideration that searchesmay have missed. Pharmacology and pharmacokineticdata were taken from randomized trials focusing inthis area. Pivotal Phase III trials were utilized fordiscussion of clinical trial experience and to summa-rize efficacy and AEs. For purposes of validity, onlypeer-reviewed literature was included.

Results: There were limited data that specificallyoutlined analgesic drug selection and highlighted saferalternatives for the elderly patient based on

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polypharmacy risks, end-organ deterioration, and/ordrug choices that presented less risk. We focused onunique opioid alternatives: levorphanol, which offersseveral therapeutic advantages similar to methadonebut without the pharmacokinetic and drug–interactionpitfalls associated with methadone; tapentadol, associ-ated with significantly less gastrointestinal distress andconstipation; and transdermal buprenorphine, an ago-nist/antagonist with less risk for the toxicities associ-ated with conventional opioids and with compliancebenefits. Topical NSAIDs are discussed as a viabletherapeutic option. Specific attention to a more desir-able tolerability profile, including avoidance of druginteractions, end-organ dysfunction, and gastrointesti-nal bleed with topical NSAID agents versus their oralcounterparts is discussed, including the ability toachieve superior tissue levels for appropriately selectedinflammatory conditions.

Conclusion: It is incumbent that providers considerthese options as part of an analgesic armamentariumin an effort to maximize therapeutic benefit andminimize risks in the increasing elderly patient pop-ulation. (Clin Ther. 2013;35:1669–1689) Publishedby Elsevier HS Journals, Inc.

Key words: analgesia, buprenorphine transdermal,elderly, levorphanol, opioids, pain management,tapentadol, topical NSAIDs.

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INTRODUCTIONOver the next 15 years, the number of adults agedZ65 years will increase by 80% and account fornearly 20% of the total population.1 “Baby boomers,”born between 1949 and 1964, will reach age 65 years,and the elderly will compose the largest percentage ofthe total population. The fastest-increasing age groupis that aged Z85 years as life expectancy continues toincrease, with average life expectancies of 80.8 years inwomen and 75.7 years in men.2 It is vital that healthcare professionals familiarize themselves with thisunique population and employ evidence-based treat-ment strategies shown to ensure maximum efficacyand tolerability.

The decline of multiple physiological processes(Table I), even in the absence of disease, combinedshould logically influence treatment options. Decreasedgastric secretions, intestinal motility, and vitamin Dreceptors lead to loss of appetite, malnutrition, anddecreased bone density.3,4 Increased arterial thickeningand rigidity elevate cardiac risk, while decreased elas-ticity in the lungs potentially exacerbates breathingdisorders.5,6 Memory impairment and cognitive declineprogress as neurons become less resilient to stress overtime.7 Reduced hepatic and renal blood flow limitmetabolism and filtration, increasing the risk foraccumulation of toxic substances.8 In fact, 49% of all

Table I. Summary of physiologic changes with aging.

Organ System

General Body fat ↑, muscleMusculoskeletal Arthritis ↑, myalgiaCardiovascular Ejection fraction ↓

cardiac output ↓,response to β-adrearterial wall thicknelastin ↓,endothelial nitrix oarterial distensibilitvascular inflammat

Respiratory Chest wall rigidity ↑ventilation/perfu

Gastrointestinal Transit time ↑, amHepatic Liver cells ↓, bloodRenal Blood flow ↓, eGFR

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hospitalizations attributed to the adverse events (AEs)associated with medications occur in the elderly.9

Physiologic changes, drug–drug interactions resultingfrom polypharmacy, and drug–disease interactionscombine to make elderly patients more sensitive tothe AEs of medications.3

Effective pain management in the elderly is chal-lenging. The elderly may be afflicted with a myriad ofpainful conditions, including osteoarthritis, degener-ative joint disease, rheumatoid disorders, cancer, post-herpetic neuralgia, fibromyalgia, and diabetic neuro-pathy. According to the Institute of Medicine,10

although pain is the most common reason forphysician consultation, nearly 100 million Americanshave chronic pain. The clinical concern for AEsamong the elderly places them at increased risk forundertreatment of their pain.

The purpose of this review is to highlight the use ofseveral treatment options that are underutilized de-spite demonstrated advantages in the general popula-tion, but most particularly in elderly patients. Opioids,for example, may actually afford the safest alternativein many cases in elderly patients compared to oralanti-inflammatories, certain antidepressants, or anti-convulsants. Moreover, the unique pharmacology ofcertain opioids make them advantageous in certainpainful disorders frequently encountered within this

Changes

mass ↓, total body water ↓s ↑,

nergic stimuli ↓,ess ↑,

xide synthetase activity ↓,y ↓,ion and thrombotic events ↑, functional residual capacity (FRC) ↑, elastic recoil ↓,sion mismatch ↑ount of lymphoid tissue ↓, vitamin D receptors↓flow to the liver ↓↓, accuracy of calculating GFR ↓

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population. We present evidence to support the use ofeach agent discussed, but have selected these specifictreatment options also based on experience in ourpain clinic. The following discussion is not intended asan endorsement of any medication and, as always,treatment should be patient specific.

MATERIALS AND METHODSWe performed a complete review of the literatureusing the search terms pain management, elderly,opioids, NSAIDs, topical NSAIDs, levorphanol, bu-prenorphine transdermal, and tapentadol to ascertainwhich analgesic drugs are most commonly used in theelderly population . Databases searched includedPubMed, Google Scholar, Ovid, and Athens. Therewere limited data that specifically outlined analgesicdrug selection and highlighted safer alternatives forthe elderly patient based on polypharmacy risks, end-organ deterioration, and/or drug choices that specifi-cally presented less risk for any of these reasons. Weincluded meta-analyses, randomized studies, case re-ports, commentaries, and case–control studies of allanalgesics searched. Package inserts were utilized forapproval dates, indications, and formulations avail-able. We looked at reviews of agents to identifyimportant studies for consideration that searchesmay have missed. Pharmacology and pharmacokineticdata were taken from randomized trials focused onthis area, whereas other references helped point us inthe right direction. Pivotal Phase III trials were utilizedfor discussion of clinical trial experience and tosummarize efficacy and AEs. Case reports were notrelied on except for in the examination of references.We specifically looked for pivotal trials of agentsnewly approved by the US Food and Drug Admin-istration—tapentadol, buprenorphine transdermal,and diclofenac epolamine 1.3% topical—so that wecould critique their validity. For the purposes ofvalidity, only peer-reviewed literature was included.

In terms of organization, we introduce each agent,year of FDA approval, currently approved indications,and available formulations. We review relevant phar-macology and pharmacokinetics that make each par-ticular agent unique, convey understanding of how itworks, provide evidence-based data supportingunique characteristics, and specifically highlight issuessuch as drug interactions that are particularly notablein this subject and population. Clinical trials focusedon efficacy and tolerability, age of the population

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studied, discontinuation rates, and any other pertinentanalysis are summarized. Finally, we summarize howall of these issues collectively and individually couldbe significantly advantageous in the elderlypopulation.

RESULTSDiclofenac Epolamine 1.3% Topical Patch

Use of NSAIDs in the elderly population, beyondthat seen in the general population, is complicated bythe substantial risks for gastrointestinal (GI) bleed,ulcerations, perforations, nephrotoxicity, and cardio-vascular morbidity and mortality.3 The prevalence ofserious GI AEs with oral NSAIDs is 15%, and GIevents are at least twice as likely in people aged 460years.11 A recent study by the Coxib and TraditionalNSAID Trialists’ Collaboration confirmed these risksand suggested that serious GI and cardiovascular AEsmay be dose and plasma concentration dependent.12

Consequently, prescribers frequently avoid one of themost effective therapeutic medication classes in theelderly specifically due to safety concerns. The pastdecade has seen an effort to provide NSAID therapywith increased tolerability in elderly patients, with ashift from oral to topical NSAIDs.13 In fact, in 2006,topical NSAIDs were recommended therapies in 7 of 9published guidelines.14 Limitations of topical NSAIDsinclude cost, erratic local absorption, variable depth ofpenetration, inaccuracy of dosing, variable wear timesthat may require frequent applications, and anuncomfortable oleaginous feeling.15

An estimated 50% of all NSAID prescriptions arewritten for osteoarthritis.11 Osteoarthritis is the mostprevalent pain condition in the United States, affecting27 million people, and is also the most commonlydiagnosed type of arthritis. Approximately 10 million(38%) people with osteoarthritis are aged Z60 years,and this number is expected to reach 67 million by 2030because of the aging population.13 Diclofenac is by farthe most utilized NSAID worldwide and has becomeavailable in 4100 countries since its introduction in1974.16 Diclofenac is currently available in severaltopical gels and 1 topical solution. In 2007, thediclofenac epolamine 1.3% topical patch (DETP) wasFDA approved for the topical treatment of acute paindue to minor sprains, strains, and contusions.17,18 Incontrast, the patch has been approved in Europe since1993 and was available in 43 countries in 2008, andstudies suggest significant pain relief in chronic

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conditions such as knee osteoarthritis and epicondylitis(tennis elbow).19–21 In a pooled analysis of 5 DTEPtrials in acute injuries, efficacy over placebo was shownin terms of pain control in the back, shoulder, foot, andelbow as measured on a visual analog scale (VAS).18

The DETP patch affords steady drug concentrationsdirectly at the site of injury. The topical patch wasdesigned as a drug-in-matrix system impregnated withdiclofenac 180 mg containing 129.7 mg of diclofenacacid (comparable to 140 mg diclofenac sodium) and50.3 mg of epolamine salt.22–24 Epolamine salt is usedto increase cell permeability by solubilizing lecithin, amajor constituent of cell membranes, thereby increasingits hydrophilic and lipophilic potencies.22,23 The dis-tinction between topical and transdermal patches isimportant: Topical dosage formulations are meant topenetrate skin and tissue but not enter into the plasmain significant concentrations, whereas transdermal prod-ucts are designed to achieve therapeutic concentrationsin systemic circulation, merely using cutaneous tissue asa vehicle for delivery.15,21,22 At the end of the 12-hourdosing interval, 5% of the total diclofenac dose isabsorbed into the tissue; after 24 hours of DETPexposure, 18 mg have potentially been released fromthe patch.23

In terms of pharmacokinetics, the oral terminal half-life of diclofenac is 1 to 2 hours, whereas the half-liferemains 9 to 12 hours with the topical patch, indicatinglocal drug accumulation within a tissue reservoir.22,25,26

Diclofenac accumulation beneath the patch allows forgreater local tissue concentrations with topical NSAIDscompared with oral NSAIDs.22,27–29 Other factorscontributing to lower diclofenac tissue concentrationsafter oral compared with topical administration includehigh protein binding (99%), extensive first-pass metab-olism (E50%), and a low volume of distribution (1.3L/kg).17 Studies have shown that pain relief occurs asearly as 1 hour after DETP placement, but minimalplasma concentrations appear 2 to 8 hours after patchapplication, depending on the rate of cutaneousabsorption, which can be highly variable amongindividuals.11,22 Some patients may not respond at all,presumably at least in part due to lack of skinpenetration and penetration depth.30 The systemicexposure of DETP is 1% of oral exposure following a75-mg oral diclofenac dose.22 The steady-state plasmaconcentrations are also significantly lower (1–3 ng/mL)and therefore are unlikely to result in cyclooxygenase-1–mediated effects that interfere with platelet aggregation

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or compromise gastric protection.17 For example, theminimum concentration of diclofenac necessary toinhibit platelet aggregation was 300 ng/mL (4%) byarachidonic assay.22 At 400 ng/mL, diclofenac canreduce platelet aggregation by 41%.22 The low plasmaconcentrations result in an improved tolerability profileand increased attractiveness for utilization in elderlypatients.21,22

Although disingenuous, the FDA requires thatmanufacturers incorporate standard NSAID precau-tions into the labeling despite stating in their ownmedical review that 100 patches worn simultane-ously would equal 1 diclofenac oral dose of 150mg.26 In clinical trials, the most common AEsreactions were cutaneous application-site reactions(pruritus, burning), which occurred more with pla-cebo (8%, 1%) than with treatment (5%, o1%),and which, in the authors’ opinion, most likely werea result of the anti-inflammatory effect of DETP.17

The only GI event reported was nausea, theprevalence of which was not statistically differentversus placebo.21,31 From 1993 to 2008, postmarket-ing surveillance revealed that 46 million patientsworldwide received the DETP and that AEs werereported in 108 patients, the majority of which wereskin reactions or lack of efficacy. Six were serious GIevents (bleeding or ulcer), none of which demon-strated a causal relationship to DETP.21

DETP is an attractive option for targeted andconsistent drug delivery over a specific area, withfew or no AEs. As a class, topical NSAIDs are effectiveand underutilized and compare well against othertherapeutic options. The Osteoarthritis Research Soci-ety International published a meta-analysis in 2010 toevaluate and compare available treatment options forhip and knee osteoarthritis.14 Therapeutic optionswere assigned an effect size based on the publishedliterature. Opioids and intra-articular corticosteroidinjections provided more pain relief, yet topicalNSAIDs were more effective in improving functionand stiffness, with a more favorable AE profile(Figure 1). Compared with acetaminophen, the mostcommonly used medication for osteoarthritis pain,topical NSAIDs provide 3 times the effect size in painrelief, improved function, and reduced stiffness.14

Topical NSAIDs cannot target central and peripheralpain mechanisms like oral NSAIDs, and they areinappropriate for neuropathic pain, widespreadmusculoskeletal pain, and chronic low back pain

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0.78

0.58

0.44

0.14

0.310.36

Opioids Topical NSAIDs IA corticosteroid Acetaminophen

0.2

0.09

0.49

0.250.16

Function StiffnessPain Relief

Figure 1. Effect size of pharmacologic intervention in knee osteoarthritis. IA ¼ Intra-articular.14

T.J. Atkinson et al.

due to boney arthritis (vs muscle spasm), in whichpenetration may be inadequate.30,32 For many elderlypatients unable to use oral NSAIDs, topical NSAIDs,including DTEP, should be considered to providetargeted pain relief, reduce stiffness, maximize func-tion, and mitigate oral NSAID risks.

LevorphanolLevorphanol is the “forgotten opioid” and perhaps

is not prescribed nearly often enough in the hospiceand palliative-care settings or for neuropathic painsyndromes requiring opioids.33,34 Despite being avail-able for use in the United States since 1953, it isrelatively unknown or unfamiliar to the majority oftoday’s prescribers.35 The complex pharmacokineticsof, and lack of experience among contemporarypractitioners with, levorphanol diminish its usabilityas a first-line agent, yet its unique attributes could fillan important niche in the management of pain. Forelderly patients with persistent neuropathic pain,levorphanol can be particularly useful, especially asan alternative to methadone, the use of which hasrecently increased for this same indication.33,36

Use of opioids for chronic noncancer pain remainscontroversial for a variety of reasons, including mixedevidence, risk for addiction, increasing opioid-relateddrug overdoses (especially when polypharmacy is afactor), and lack of long-term efficacy and tolerabilitydata.37–42 An increased emphasis on the undertreatmentof pain in the 1990s spurred significant research into itsmechanisms and resulted in increased opioid prescrib-ing.43,44 One result of this effort was the characterizationof N-methyl-D-aspartate (NMDA) receptors and theirrole in both chronic, but more particularly neuropathic,

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pain.34 Neuronal hyperexcitability and overstimulationleads to excitatory signals from L-glutamate andL-aspartate, which activate NMDA receptors, theresults of which could be hyperalgesia, allodynia, andpotential neuroplasticity.45,46 In vitro and animal modelshave demonstrated that antagonizing NMDA receptorscan theoretically reverse the aspects of chronic pain andneuronal hyperexcitability, and potentially mitigateopioid tolerance.46–50 An enormous research effort intoNMDA antagonists, particularly ketamine, high-dosedextromethorphan, and memantine, followed. The re-sults have been mixed in clinical trials becausetreatment-emergent AEs are often encountered beforeany therapeutic benefit. One such combination, mor-phine/dextromethorphan, made it to Phase III trialsbefore lack of benefit and psychological AEs led todiscontinuation.51 The NMDA receptor inhibition ofseveral opioids have been studied, and while mostdemonstrate no activity, some of the dehydroxylatedphenanthrenes of the morphinan type and theirenantiomers (levorphanol, dextrorphan, levomethor-phan, dextromethorphan), as well as the diphenyl-heptanes (methadone, propoxyphene), appear to haveconsiderable affinity for NMDA receptors.47

Levorphanol is mechanistically similar to metha-done; both are potent agonists of the m-opioid recep-tor, both are noncompetitive antagonists at theNMDA receptor, and both inhibit the reuptake ofserotonin (5-HT) and norepinephrine (NE).34,52–54

There are, however, differences. Levorphanol is a morepotent NMDA antagonist, similar to ketamine, withgreater affinity for the NMDA and m-opioid receptors.Levorphanol has decreased affinity for the 5-HT andNE receptors compared with methadone.47,52 But

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unlike methadone, levorphanol is also considered a fullagonist at the κ-opioid receptor, with high affinity forthe κ1 and κ3 receptor subtypes. κ3 is believed to bethe primary κ receptor involved in analgesic activity.55

κ receptors are associated with dysphoria and sedationyet are theorized to have fewer overall AEs. However,at this time, there are no available selective agonists forthe κ receptor.54,56

Levorphanol is roughly 4 to 8 times more potentthan morphine and is available as a 2-mg tablet.33,35 Itis 40% protein bound and crosses the blood–brainbarrier with cerebral spinal fluid concentrations of60% to 70% of corresponding plasma concentra-tions.57 The half-life (11–16 hours) of levorphanol islonger than its duration of analgesia (6–15 hours),allowing for potential drug accumulation with long-term dosing until steady-state concentrations arereached (80 hours).57 This obstacle is similar to thatseen with methadone but is not nearly as problematicwith regard to cytochrome P450 (CYP) metabolism.Nonetheless, dose increases are not recommendedmore frequently than every 4 days, and althoughlevorphanol is typically dosed every 6 to 8 hours, theinterval may need to be extended in the setting ofhepatic or renal impairment, where drug accumulationis possible (Table II). Accumulation is a more signi-ficant problem with methadone, as the disparitybetween its duration of analgesia (8–12 hours) andvariable half-life (15–60 hours) could easily result indrug overdose, particularly if one adds doses forbreakthrough pain while the methadone continues tosequester within body tissues because of its highvolume of distribution.34,60

In 2009, methadone represented 2% of all writtenprescriptions for opioids but 430% of opioid-relateddeaths—more than twice the amount with any otheropioid.61 There were nearly 6 times as many metha-done overdose deaths in 2010 as there were in 1999,and this increase was driven mainly by an increase inprescriptions for pain.62 The risk for drug accu-mulation is countered by patience in titration anddose adjustments and does not alone account for theserious risks of methadone. Three key factors makemethadone particularly dangerous. First, methadoneundergoes 3A4 (and other isozyme) metabolism via thehepatic CYP system, leading to a myriad of drug–druginteractions that can potentially increase methadoneserum concentrations to unsafe levels.35,60 Second,methadone can prolong the QTc interval, leading to

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life-threatening cardiac arrhythmias, especially whencombined with other proarrhythmic drugs.35,53 Third,methadone is a P-glycoprotein substrate, which waselucidated recently to have clinically significant inter-actions with HIV treatments and other medications,coupled with enhanced passage through P-glycopro-tein–dependent transfer across the blood–brain bar-rier.63 Consider the genetic polymorphic differences inany patient population with its resultant variability,and methadone may make even the most experiencedpractitioners nervous. In contrast, levorphanol meta-bolism is similar to other dehydroxylated phenan-threnes (oxycodone, hydromorphone, oxymorphone,hydrocodone) in that it results in a 3-glucuronideproduct that is renally excreted. Levorphanol is notmetabolized by the CYP system, lacks the cardiactoxicity associated with methadone, and is not aknown substrate of P-glycoprotein. As a result, levor-phanol presents several advantages over methadone inany patient, but particularly in elderly patients receiv-ing multiple medications.53,57,60–63

Rowbotham et al36 studied levorphanol in 81patients with neuropathic pain in an 8-week random-ized, double-blind study in which the median patient agewas 65 years (range, 32–91 years). Patients wereallowed to self-titrate according to reduction in painand occurrence of AEs within specified dosing limitsidentified for safety. Patients were randomized to low-dose (mean, 2.7-mg/d) or high-dose (mean, 8.9-mg/d)therapy, with a primary end point of overall reductionin pain, as measured using a visual analog scale (VAS)ranging from 0 to 100. A 36% overall reduction in painscores was reported in the high-dose group; 21%reduction in the low-dose group. Older age or earlieronset of pain did not correlate with a smaller reductionin pain scores. A total of 59 patients (73%) completedthe study, 12 of 15 (80%) of those who withdrew dueto AEs were in the high-dose group, 3 patients report-edly withdrew due to lack of efficacy, and 7 of the 10patients with central pain after stroke or focal braininjury did not complete the study. Considering that theinvestigators allowed participants to continue treatmentwith antidepressants (30%), NSAIDs (30%), and anti-convulsants (14%), the overall pain reductions representefficacy above and beyond standard therapy for neuro-pathic pain. Investigators monitored as patient painscores returned to baseline following study completionand levorphanol taper which strongly indicates treat-ment efficacy.36 Armed with an appreciation for the

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Table II. Pharmacology, pharmacokinetics, equivalence, and titration of levorphanol and methadone.

Levorphanol33,35,36,47,52,57–59 Methadone47,52,58–60

PharmacologyOpioid agonist activity μ, κ1, κ3 44 κ2 μNE reuptake blockade ✓ ✓NMDA inhibition ✓ ✓

PharmacokineticsHalf-life 11–16 h 15–60 hDuration of action 6–15 h 4–8 hMetabolic pathway Phase II glucuronidation to levorphanol-

3-glucuronide3A4-, 2B6-, 2C19-mediated N-demethylation to EDDP

Opioid chemistry Dehydroxylated phenanthrene DiphenylheptaneDosing

PO equivalent dose to30mg/day of PO morphine

4 mg 7.5 mg

Suggested starting dose inopioid naïve patients

1 mg (1/2 � 2-mg tablet) PO 3 or 4times daily (maximum daily startingdose, 4 mg); titrate up by up to 25%weekly, ie, if starting at 1 mg PO 4times daily in the first week, increaseto 1 mg PO 5 times daily at secondweek

2.5 mg (1/2 � 5-mg tablet) PO threetimes daily (maximum daily startingdose, 7.5 mg); titrate up by up to 25%weekly, ie, if starting at 2.5 mg PO 3times daily first week, increase to 2.5mg PO 4 or 5 times daily at secondweek (note: as the dose increases,percentage of upward titrationdecreases due to complexpharmacokinetics)

EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene; NE = norepinephrine; NMDA = N-methyl-D-aspartate.

T.J.

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unique pharmacokinetics of levorphanol, prescribersmay consider with confidence a trial of this “forgottenopioid” in appropriate patients.

Buprenorphine PatchThe buprenorphine transdermal system (BTDS) was

FDA approved in 2010 for the management of moderateto severe chronic pain in patients requiring a continuous,around-the-clock opioid analgesic for an extended timeperiod.64 Injectable buprenorphine was approved in1981 for acute pain, and in 2002 sublingualbuprenorphine was approved for substance abusetreatment.65–67 BTDS was the first buprenorphine prod-uct approved in the United States for chronic pain;however, it has been available internationally since2001.68 An international perspective is useful foraiding in understanding the relative potencies of theBTDS strengths available. In Europe, the BTDS dosageformulations available are 20 mg (35 mg/h), 30 mg (52.5mg/h), and 40 mg (70 mg/h), requiring a patch changeevery 72 hours.69 The US-approved BTDS formulationsare 5 mg (5 mg/h), 10 mg (10 mg/h), and 20 mg (20 mg/h), changed every 7 days. Of particular interest is thatthe highest available strength and delivery rate in theUnited States is equivalent to the lowest strengthavailable in Europe.

Buprenorphine is a semisynthetic derivative of thenaturally occurring opium alkaloid thebaine. 69,70 Exten-sive first-pass metabolism (95%) made oral dosage

350

300

250

200

150

100

50

00 1 2 3 4 5 6 7 8 9 10 11 12

Butran

Time

Con

cent

rati

on (

pg/m

L)

Figure 2. Plasma buprenorphine concentrations with tweekly for 3 weeks (N ¼ 36).

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formulations impractical, and therefore, prior to BTDS,the only available dosage formulations were injectableand sublingual (45%).71 Buprenorphine was available foryears in Europe as a sublingual dosage formulationindicated for pain long before it was considered for thetreatment of substance abuse. It is classified as a partialagonist/antagonist because it demonstrates partialagonism at the μ-opioid receptor, but with antagonistactivity at δ- and κ-opioid receptors.72–74 Buprenorphineis highly lipophilic, with extensive distribution into tissuesand passage across the blood–brain barrier.75 BTDS has along half-life (up to 32 hours) and may require at least 21hours to achieve therapeutic serum concentrations.76

Buprenorphine is metabolized into its active metabo-lite, N-dealkylbuprenorphine or norbuprenorphine, viaoxidative CYP3A4 isozyme but has not been consideredclinically relevant since the publication of drug-interactionstudies employing ketoconazole.77

The receptor-binding kinetics of buprenorphine areunique. Buprenorphine has high affinity for the μ-opioid receptor but associates (30 minutes) and dis-sociates slowly (166 minutes) and incompletely (50%)from opioid receptors.73 Analgesia is achievable with5% to 10% saturation at μ-opioid receptors, but theminimum effective concentration for analgesia is 100pg/mL, which in pharmacokinetic studies was achiev-able with BTDS 10 mg/h (Figure 2).69,78–80 Receptorsaturation is particularly important with buprenor-phine because its high affinity and robust binding

13 14

s 10 mcg/hour, every 7 days X 3 (N=36)

ButransRemoval

(d)15 16 17 18 19 20 21 22 23 24 25 26

he administration of buprenorphine 10 mg/h once

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T.J. Atkinson et al.

capacity make displacement by other opioids, includ-ing naloxone, difficult or impossible. For example,2 ng/mL of buprenorphine can displace an equalconcentration of fentanyl from 90% opioid receptors,yet compared with fentanyl, it requires 40 times theamount of naloxone to reverse buprenorphine.73 Toblock the effects of heroin or other opioid use, completereceptor saturation is the goal for products intended totreat substance abuse, such as buprenorphinehydrochloride or buprenorphine/naloxone. A 16-mgdose of buprenorphine/naloxone occupies 79% to95% of available opioid receptors and a 32-mg doseof buprenorphine/naloxone is capable of blocking theeffects of 120 mg of morphine for 429.5 hours.81,82

These properties are believed to result in reducedaddiction potential, with less euphoria at onset andfewer withdrawal effects on discontinuation.69,82 BTDSwas approved based on 3 pivotal Phase III randomized,double-blind trials in patients with chronic low backpain (2 trials) and osteoarthritis (1 trial). In the firststudy, opioid-naive patients were enrolled for a run-inperiod in which tolerability of BTDS was determined(patients were randomized to receive BTDS, initiated at5 mg/h for 3 days and increased to 10 mg/h, or placebo);patients were discontinued before randomization ifBTDS was poorly tolerated. After 12 weeks of treat-ment, the primary end point, average pain over theprevious 24 hours as measured on a 10-point VAS, wassignificantly improved compared with placebo (P o0.01).83 In the second study, opioid-experienced pa-tients were also enrolled in a run-in period to evaluatetolerability of a 20-mg/h dose, after initiation on 10 mg/h, and were discontinued if unable to tolerate; patientswere otherwise randomized to BTDS 20 mg/h, imme-diate-release (IR) oxycodone 40 mg/d, or BTDS 5 mg/h(utilized as an active-control group). After 12 weeks, theprimary end point (average pain over the previous24 hours as measured on a 10-point VAS) wassignificantly improved with BTDS 20 mg/h and oxy-codone IR 40 mg/d compared with BTDS 5 mg/h (both,P o 0.001); the difference between BTDS 20 mg/h andoxycodone IR 40 mg/d was not significant.84 The thirdtrial compared BTDS to sublingual buprenorphine inpatients with hip or knee osteoarthritis over 7 days.Although both groups showed a nearly 50% reductionin pain scores, the BTDS group demonstrated a morefavorable AE profile.85

The AE profiles of opioids are generally problematicin elderly patients, who are particularly sensitive to

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common AEs.86 Buprenorphine is believed to have anincreased safety profile compared with other opioids,and BTDS in particular has been associated withdecreased nausea, vomiting, and constipation at leastin part as a result of transdermal delivery, whichavoids direct contact with GI opioid receptors andlinear serum concentrations that avoid peak andtrough kinetic profiles.69,87,88 Unlike with otheropioids, buprenorphine-induced respiratory depressionhas a ceiling effect at low therapeutic concentrations,resulting in increased tolerability.72,89 In a postmarket-ing surveillance study published in Europe, 13,179patients were enrolled for moderate to severe pain afterfailing previous opioid therapy or experiencing intol-erable AEs. One half of the patients were aged 470years, but age did not affect efficacy, as 80% ofpatients reported either very good or good pain relief,and an additional 9% reported satisfactory. In addi-tion, every patient was started on the 37.5-mg/h dose,and only 18% of patients required an increased dose.At the end of the study, 70% of patients elected tocontinue therapy with BTDS. The most common AEswere nausea (4%), dizziness (1.9%), vomiting (1.6%),and constipation (1%).90 Adverse reactions from PhaseIII clinical trials in the United States were similarly low,with application-site reactions to the patch occurringmost frequently in roughly 17% of patients to as muchas 29% with the highest dose (20 mg/mL). In theopioid-naive trial, AEs occurring at rates higher thanthat with placebo (Treatment group – Placebo group)included constipation (3%), dizziness (3%), nausea(2%), and vomiting (2%).83 The opioid-experiencedtrial demonstrated that many of the AEs are dosedependent (BTDS 20 mg – BTDS 5 mg)—nausea (4%),vomiting (3%), constipation (3%), dizziness (3%),somnolence (3%), and headache (6%).84

The Initiation and Titration Guide provided by themanufacturer may be confusing to providers attempt-ing a patient trial of BTDS because it utilizes morphine-equivalent (MEQ) conversions that are conservative,reports atypical equianalgesic dose conversions ofcommon opioids, and does not reflect evidence-basedpotencies for buprenorphine.91 Although equianalgesicopioid dose conversion is admittedly inconsistent, andthe manufacturer cautiously provides equivalencies,listing hydrocodone as having twice the potencycompared with generally accepted morphine con-versions is conservative to the point of duplicity(Table III). Codeine and oxycodone conversions are

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Table III. Proposed equianalgesic conversions for buprenorphine in terms of morphine-equivalent doses.Values are milligrams.

Drug

Buprenorphine Dose (MEQ)

5 mg/h (o30 mg) 10 mg/h (30–80 mg) 20 mg/h (480 mg*)

Guide91 EB92–98 Guide91 EB92–98 Guide91 EB92–98

Hydrocodone o15 o30 15–40 30–80 440* 480Oxycodone o15 o20 15–40 20–55 440* 455Tramadol o300 o300 300–400 300–400 N/A N/ACodeine o90 130–200 90–250 130–530 4250* 4530EB Morphine Equivalent Doses

of Buprenorphine TransdermalSystems by Strength

1:7599,100 9 18 361:11099,100 13.2 26.4 52.8

EB = evidence-based; MEQ = morphine equivalent.*Per guide, buprenorphine may not be appropriate.

Clinical Therapeutics

debatable, but hydrocodone is generally accepted asequivalent to morphine or, in some sources, slightly lesspotent.92–98 The conversions from the guide were alsoutilized in the Phase III trial in opioid-experiencedpatients.84 This simple conversion has a significantimpact on the study, as 62% of the patients enrolledwere on stable doses of hydrocodone prior to the study.Utilizing their conversion, the mean MEQ prior toenrollment (51.6 mg) corresponds to hydrocodone 25.8mg, which, according to their titration guide, should bea 5-mg/h patch, but patients unable to tolerate 20 mg/hwere discontinued from the study. The recommendedMEQs seem to favor the 5-mg/h patch, which was notstudied except as an ineffective control, whereas the 20-mg/h patch, the focus of the opioid-experienced trial,appears in the guide to be unavailable or contra-indicated based on the MEQ conversions. Also, con-verting hydrocodone 25.8 mg MEQ to oxycodone 17.2mg (20:30) or 12.9 mg (15:30), depending on accept-able conversion ratios, represents 2.3 to 3.1 times thedaily dose utilized by patients prior to the study. Such alarge increase would not be advisable in clinicalpractice, and it therefore is no surprise that the oxy-codone group had favorable results.

Moreover, in light of the previous discussion, care-ful analysis and consideration are particularly

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imperative for any opioid from any manufacturerwhere conversion estimates are conservative, especiallyif one uses an opioid conversion calculator. Conver-sion calculators generally use fixed mathematic con-version equations; therefore, a conservative doseestimate in one direction is liberal in the oppositedirection.101

BTDS is an ideal dosage formulation for elderlypatients with chronic pain due to a better safety profile,improved compliance with 7-day wear time, and lowaddiction potential, as reflected by its status as aschedule III opioid, which affords up to 5 refills. BTDSdemonstrated efficacy in osteoarthritis and low backpain, which are the 2 most common pain conditionsreported in the elderly. For all of these reasons, BTDSis an attractive option for stable elderly patients.

TapentadolTapentadol is an opioid that possesses unique

pharmacology and certain attributes that make itparticularly useful in the elderly. Tapentadol is avail-able as an IR tablet or solution, and was FDAapproved in 2009 for the management of moderateto severe acute pain.102 An extended-release (ER) tabletwas approved in 2011 for the management of moder-ate to severe chronic pain and later gained approval

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specifically for diabetic neuropathy requiring continu-ous, around-the-clock opioid analgesic for an extendedperiod of time.103 Shortly after tapentadol approval inthe United States, the drug was approved in theEuropean Union. The focus of Phase III trials wasconditions common in elderly patients, including hip orknee osteoarthritis, chronic low back pain, and diabeticperipheral neuropathy. In fact, tapentadol is the onlyopioid currently FDA approved for use in patients withneuropathic pain.103 Tapentadol IR is available invarious strengths (50, 75, 100 mg) scheduled every 4to 6 hours, and ER available strengths (50, 100, 150,200, 250 mg) are scheduled twice daily. ERformulations were found to be bioequivalent to IR,resulting in a simple 1:1 conversion and allowing foreasy dose conversions.104 However, the maximumdaily dose of the ER formulation is 500 mg per 24hours, unlike that of the IR formulation, which is 600mg per 24 hours, other than the first day of therapy,which allows for 700 mg to provide an analgesicloading dose.

The research effort into mechanisms of pain reliefduring the 1990s, mentioned previously, focused onresearch into the influence of centrally mediated mono-aminergic transmission and its influence on chronic andneuropathic pain.105,106 Clinical evidence has demon-strated that increasing extracellular concentrations of5-HT and NE in descending pain inhibitory pathwaysexerts an analgesic effect.47,52 NE is the monoamineprimarily involved in attenuating pain signals and isparticularly useful in neuropathic pain.107,108 As aresult, serotonin–norepinephrine reuptake inhibitors(venlafaxine, duloxetine, milnacipran) and dopamine–norepinephrine reuptake inhibitors (bupropion) havelargely replaced tricyclic antidepressants in the treat-ment of neuropathies, particularly in the elderly, due to

Table IV. Differences between tramadol and tapentadol

Properties Tramadol

Mu binding affinity 6000� less than mMetabolism Significant CYPDrug interactions See aboveNeuroamine activity 5-HT/NE

5-HT = serotonin; CYP = cytochrome P450; NE = norepinephr

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significant anticholinergic activity, which places themon the Beers list.109 Important detriments of tricyclicantidepressants include sedation, QTc prolongation,and anticholinergic effects (xerophthalmia, xerostomia,urinary retention, constipation).

Polypharmacy is a significant concern in the elderlypopulation, in which the average number of medica-tions often exceeds 10, resulting in a higher prevalenceof drug interactions, duplication of therapy, and lack ofcompliance.110 However, in pain management, rationalpolypharmacy or utilizing multiple medications withvariable pharmacologic mechanisms at low doses mayoffer analgesic efficacy while minimizing AEs.53

Clinically, it appears that combining an opioidagonist with a monoamine reuptake inhibitor has anopioid-sparing effect that would be expected to in-crease pain relief and minimize AEs.52,106,111,112

Ideally, a single medication capable of combining bothmechanisms could be identified, and the first product ofpharmacologic research into this possibility wastramadol.

Tapentadol and tramadol are the currently appro-ved agents combining m-opioid agonism and mono-amine reuptake inhibition, so comparisons areinevitable (Table IV). Tapentadol was intentionallydesigned to overcome tramadol’s barriers toefficacy.106 Racemic tramadol possesses both NEand 5-HT reuptake inhibition combined with insig-nificant affinity for opioid receptors (6000 times lessthan morphine) but is highly dependent on metabolicactivation for increased potency at opioid receptors.O-desmethyl-tramadol (M-1), the major analgesicmetabolite, has 200-fold greater affinity for m-opioidreceptors and results in 6 times more analgesia thanracemic tramadol.113–115 Unfortunately, M-1 requiresCYP2D6 metabolism for activation, which 5% to

.

Tapentadol

orphine 18� less than morphineConjugation, O-glucuronideSee aboveNE, almost no 5-HT

ine.

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Table V. Adverse-events profiles of tapentadol and oxycodone in Phase III clinical trials. Values are percentages of patients.

Study

GI CNS

Nausea Vomiting Constipation Dizziness* Somnolence* Headache*

Tapentadol Oxycodone Tapentadol Oxycodone Tapentadol Oxycodone Tapentadol Oxycodone Tapentadol Oxycodone Tapentadol Oxycodone

IRHartrick et al119(end-stage joint disease)

18 41 7 34 4 26 18 23 6 12 6 3

Daniels et al120(post-bunionectomy)

49 67 32 42 10 15 31 30 21 10 12 14

Hale et al121(LBP andOA)

18 29 17 30 13 27 18 17 10 9 NA NA

ERBuynak et al122 (LBP) 20 35 9 19 14 27 12 17 13 16 20 17Afilalo et al123 (knee OA) 22 37 5 18 19 37 18 19 11 20 15 15Schwartz et al124 (DPN) 14 — 7 — 6 — 8 — NA — 5 —Wild et al125 (LBP andOA, LT safety andefficacy)

18 33 7 14 23 39 15 19 15 11 13 8

CNS = central nervous system; DPN = diabetic peripheral neuropathy; GI = gastrointestinal; IR = immediate release; LBP = low back pain; LT = Long-term;OA = osteoarthritis; ER = extended release.*CNS side effects.

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Table VI. Unique therapeutic options for pain in elderly patients.

Drug Mechanism in Pain Efficacy Metabolism Advantages Special Considerations

Buprenorphine64,69,71–75,77 m-Opioid agonist,κ-opioidantagonist

General painsyndromes

N-dealkylation tonorbuprenorphine viaCYP3A4 (slightlyactive);glucuronidation ofboth metabolite andparent compound

Prevents withdrawalsymptoms; easycompliance (1 patch/wk); antidepressive/antianxiety effects

May take up to 72 h toreach steady state

Diclofenac patch17–21 Anti-inflammatory Musculoskeletal,somatic pain

Sulfate and glucuro-nidate conjugates ofmetabolites andeliminated throughurinary and biliaryexcretion

Localized nonsteroidalactivity; very littlesystemic absorption;found effective forsprains, strains,contusions, knee OA,epicondylitis

Oral NSAIDs limited inelderly due to possiblecomplications of GIbleed, nephrotoxicity,cardiovascular events

Levorphanol33,35,36,47,53,57 m-Opioid agonist;κ-opioid agonist;NMDAantagonist; NEreuptakeinhibitor

Neuropathic painand general painsyndromes

Glucuronidation tolevorphanol-3-glucuronide (inactive)

Treatment of neuropathicpain; additional analgesicbenefits via- κ-opioidagonist; no QTcprolongation; alternativeto methadone; no DIwith CYP340 system

Long half-life (�15 h);slow titration; only 2-mg oral dose available

Methadone35,53,63,129,130 m-Opioid agonist;NMDAantagonist; NEreuptakeinhibitor

Neuropathic painand general painsyndromes

Major: N-demethylationto EDDP (inactive) viaCYP3A4, -2B6, -2C19

Treatment of neuropathicpain; multiple formsavailable; (IV/IM/oralsolution)

Can cause QTcprolongation; multipledrug interactions(including P-gpsubstrate and 3A4inducer); variable/longhalf-life (8–59 h); highvolume of distribution;slow titration

(continued)

T.J.

Atkinsonet

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Table VI. (continued).

Drug Mechanism in Pain Efficacy Metabolism Advantages Special Considerations

Tapentadol53,102,106,126,127,131m-Opioid agonist;NE reuptakeinhibitor

Neuropathic pain Major: glucuronidationto O-glucuronide;minor: methylation toN-desmethyl-tapentadol via 2C9/2C19

No major druginteractions; no activemetabolites; less GI upset(compared tooxycodone); no risk ofserotonin syndrome; noQTc prolongation

May be expensive

Tramadol53,113,114,116 m-Opioid agonist;NE reuptakeinhibitor

Neuropathic pain O-demethylatedmetabolite viaCYP2D6 (active); 10other metabolites(inactive)

Alternative to opioidintolerant patients;affects mood via 5-HTreuptake inhibitor

6000� less potent thanmorphine; Risk ofserotonin syndrome/seizure; Prodrugrequires activation; 5%–15% of whitepopulation are “poormetabolizers” due to2D6 metabolism

5-HT = serotonin; CYP = cytochrome P-450; DI = drug interactions; EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene; GI = gastrointestinal; NE =norepinephrine; NMDA = N-methyl-D-aspartate; OA = osteoarthritis; P-gp = P-glycoprotein.

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15% of the white population lacks, and can beantagonized by 2D6 inhibitors, including specificserotonin reuptake inhibitors, quinidine, and amitrip-tyline, preventing effective analgesia.116,117 Finally,the potential risk for serotonin syndrome when com-bining tramadol’s serotonergic reuptake inhibitionwith other agents that increase serotonin may limitits clinical utility.118

In contrast, comparing tapentadol to morphine,binding assays demonstrated that tapentadol has 18times less affinity for m-opioid receptors, but func-tional analgesia was 2 to 3 times less potent in animalstudies.106 In Phase III clinical trials, tapentadol wascompared to oxycodone and was determined to be5 times less potent (50 mg tapentadol equivalent to10 mg oxycodone and 100 mg tapentadol equivalentto 20 mg oxycodone), supporting the increased pot-ency observed in animal trials.119–125 The combinedsynergy of m-opioid receptor agonism with NE reup-take inhibition was further confirmed in animalmodels because naloxone and yohimbine, a potentα2-adrenergic antagonist, both demonstrated onlypartial inhibition of tapentadol in pain models.106

Another advantage to the dual mechanism of action oftapentadol is the delayed development of tolerancecompared with that of morphine; tolerance tomorphine developed 2.5 times faster than did that totapentadol.106

Tapentadol has no active metabolites, and all an-algesic properties are retained in the nonracemic parentcompound. Tapentadol undergoes hepatic metabolismvia phase II conjugation, with 13% as CYP substratesthat are not considered clinically relevant.126

Tapentadol selectively inhibits NE reuptake, with anaffinity and potency comparable to those of venlafaxine,thereby increasing efficacy while avoiding the potentialrisk for serotonin syndrome.106 In pharmacokineticstudies, maximum serum concentrations of tapentadolwere 2.5-fold higher in 3 patients with moderate hepaticimpairment (Child-Pugh score Z9) than in healthysubjects.127 Dose adjustment may be required formoderate to severe hepatic impairment and can beachieved by increasing the dosing interval to every 8hours, starting at lower doses, and with cautious doseincreases. Tapentadol has a low risk for druginteractions and does not depend on metabolicactivation for efficacy, and its dual mechanism ofaction results in reduced AE profile compared withthose of other opioids.

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A reduced AE profile affords the elderly populationa significant advantage because their sensitivity to theAEs associated with conventional opioids often leadsto intolerance, lack of compliance, and treatmentfailure.3 The elderly population was well representedin Phase III clinical trials of tapentadol ER, with nearly25% of overall participants aged Z65 years.122–125 GIAEs (nausea, vomiting, constipation) are the mostcommon overall AEs associated with opioid use, andthose associated with the use of tapentadol are con-sistently close to half (Table V121–127) of those re-ported with oxycodone.128 The CNS effects (dizziness,somnolence, headache) of tapentadol are comparableto those of oxycodone and should be monitored toavoid an increased risk for falls. Overall, tapentadolrepresents a therapeutic advantage over other opioidsin the elderly population due to its unique mechanismof action, low potential for drug interactions, andsignificantly reduced AE profile.

DISCUSSIONFurther studies are needed to validate analgesic out-comes for topical versus oral NSAIDs in the elderly interms of both safety and efficacy; methadone versuslevorphanol to further validate safety particularly dueto methadone CYP450 or P-glycoprotein interactions.While we have data on tapentadol and buprenorphinein the elderly, each measured against oxycodonealone, it would be helpful to have larger trials using“summed pain intensity difference” (SPID) for each ofthese agents against more commonly used opioidssuch as oxycodone IR, hydrocodone IR, tramadol,and other opioids.

We have identified the rationale, various pitfallsand opportunities that exist for currently availableanalgesic therapies which could be particularly ad-vantageous in the elderly patient, but that are oftenoverlooked. Interestingly, although we focused thediscussions on certain therapies, they range from veryold drugs, to very new drugs with varying pharma-ceutical delivery options. Finally, we present a sum-mary in Table VI for consideration whencontemplating these unique therapeutic options forthe elderly patient.

CONCLUSIONSIt is incumbent that providers consider DETP, levor-phanol, BTDS, and tapentadol as part of an analgesicarmamentarium in an effort to maximize therapeutic

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benefit and to minimize risks in the increasing elderlypatient population. Moreover, providers must con-tinue to assess various contemporary medicationoptions for this population as new drugs and dosageformulations become available.

ACKNOWLEDGMENTSDr. Atkinson was the primary researcher and author forall sections of the paper including figures and tables andcoordinated the activities of all other participants.Dr. Fudin was the subject matter expert who selectedagents to research, primary editor, author of paragraphsin introduction and conclusion, and creator of levor-phanol table. Dr. Pandula researched and developedphysiologic changes in elderly, introduction adaptedfrom her work, and creator of the table for physiologicchanges in the elderly. Ms. Mirza contributed to thetapentadol section, created the final summary table, andworked on formatting all tables for consistency.

CONFLICTS OF INTERESTThis commentary is the sole opinion of the authorsand does not reflect the opinion of employers, em-ployee affiliates, and/or pharmaceutical companiesmentioned or specific drugs discussed. It was notprepared as part of the official government duties ofDrs. Atkinson, Fudin, or Pandula as clinicians.

Dr. Fudin is a member of the speakers’ bureau atCadence Pharmaceuticals, Cumberland Pharmaceuticals,Janssen Pharmaceuticals, Millennium Laboratories, andPurdue Pharma. He is a consultant to Practical PainManagement in the development of an Online OpioidCalculator. He provides expert testimony but has nopending cases involving any of the drugs discussed.

The authors have indicated that they have no otherconflicts of interest with regard to the content of thisarticle.

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Address correspondence to: Timothy J. Atkinson, PGY-2 Pharmacy PainManagement Resident (Stratton VA Medical Center), 113 Holland Ave,Albany, NY 12208. E-mail: timothy.atkinson@va.gov

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