PAIN MANAGEMENT IN THE OLDER ADULT: QUALITY OF LIFE STILL MATTERS!

PAIN MANAGEMENT IN THE OLDER ADULT: QUALITY OF LIFE STILL MATTERS! Thomas R. Vetter, MD, MPH Vice Chair, Division Director of Pain Medicine Maurice S. Albin Professor of Anesthesiology and Perioperative Medicine Professor of Gerontology, Geriatrics and Palliative Care University of Alabama at Birmingham Thomas R. Vetter, 2015 MY TWO PERTINENT DISCLOSURES 1. I do not have a financial relationship or interest with any proprietary entity producing healthcare goods or services in conjunction with this presentation. 2. I will be discussing the off-label, adult use of FDA-approved pharmaceuticals. Such use requires a thorough review of the published literature in adults, especially in the older adult population. MY LEARNER OBJECTIVES Characterize the epidemiology of pain in older adults Review geriatric pain and mood assessment methods Define health-related quality of life Describe the factors complicating and barriers to more effective pain management in the older adult Recognize importance of analgesic genetic polymorphism Apply multimodal pain management in older adults Justify the use of opioids in older adults Debate the American Geriatric Society Beers Criteria for potentially inappropriate medication use in older adults 1

THE AGING UNITED STATES POPULATION THE SILVER TSUNAMI 80 70 Number of Americans > 65 years (millions) 72.1 60 50 40 30 20 10 0 54.8 40.3 31.2 35 25.5 16.6 9 3.1 4.9 1900 1920 1940 1960 1980 1990 2000 2010 2020 2030 4.1% 13.1% 19.3% Administration on Aging: A Profile of Older Americans: 2011. Washington, DC: U.S. Department of Health and Human Services; 2011: 1-16. PREVALENCE OF PAIN IN OLDER PERSONS Pain most common in older segments of the population Marked age-related increase in prevalence of persistent pain of 20% 80% until later middle age (50 65 years), then a plateau in oldest old (85+ years) Headache, abdominal pain, (new onset) back pain, and chest pain all peak during later middle age Exception is pain associated with degenerative joint disease (e.g., osteoarthritis) that shows an exponential increase until at least 90 years of age. Helme RD, Gibson SJ. The Epidemiology of Pain in Elderly People. Clin Geriatr Med 2001;17:417 31. Gibson SJ, Weiner D, eds. Pain in the Elderly. Seattle: International Association for the Study of Pain, 2005 Gibson SJ, Lussier D. Prevalence and Relevance of Pain in Older Persons. Pain Med. 2012 Apr;13 Suppl 2:S23-6. IMPACT OF PAIN IN OLDER PERSONS The remarkable increase in longevity is a triumph of modern medicine and improved public health; however, an increased lifespan is only a blessing if one can stay healthy, active, and engaged. Bothersome or unremitting pain represents a major threat to quality of life in all persons Gibson SJ, Lussier D. Prevalence and Relevance of Pain in Older Persons. Pain Med. 2012 Apr;13 Suppl 2:S23-6. 2

HEALTH-RELATED QUALITY OF LIFE Health-related quality of life (HRQoL) is a multi-dimensional concept that includes domains related to physical, mental, emotional and social functioning. Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Measure 10-items: Assess global physical, mental and social HRQoL through questions on self-rated health, physical HRQoL, mental HRQoL, fatigue, pain, emotional distress, social activities, and roles. Healthy People 2020. About Healthy People. Foundation Health Measures. Available at http://healthypeople.gov/2020/about/qolwbabout.aspx and www.healthypeople.gov/sites/default/files/hrqolwbfullreport.pdf SELF-REPORTED PAIN SCALES Verbal Descriptor Scale (VDS) Numerical Rating Scale (NRS) Herr K. Pain assessment strategies in older patients. J Pain. 2011 Mar;12(3 Suppl 1):S3-S13. ASSESSMENT OF PAIN IN OLDER PERSONS Identify assessment tool a patient can easily use Institutions should have several tool options available for use with older adults. If the use of Numeric Rating Scale (NRS) is questionable, the Verbal Descriptor Scale (VDS) or pain thermometer have been shown to be the most preferred and easiest to understand tools and are recommended for literate patients. Hadjistavropoulos T, Herr K, Turk DC, Fine PG, Dworkin RH, et al. An Interdisciplinary Expert Consensus Statement on Assessment of Pain in Older Persons. Clin J Pain. 2007 Jan;23(1 Suppl):S1-43. 3

ASSESSMENT OF MOOD Screening for depression and anxiety very important Patient Heath Questionnaire 9-Item Depressive Symptom Screener (PHQ-9) Generalized Anxiety Disorder 7-Item Scale (GAD-7) Well validated measures Can be quickly completed Thus measure at every visit Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: A Systematic Review. Gen Hosp Psychiatry. 2010 Jul-Aug;32(4):345-59. BARRIERS TO EFFECTIVE GERIATRIC PAIN MANAGEMENT: HEALTH CARE PROVIDERS Fear that prescribing, dispensing and administering drug will lead to patient substance abuse or addiction Risk of disciplinary action by federal or state regulators Concern about multiple comorbidities and concomitant use of medications ( polypharmacy ) Concern about excessive side effects from opioids and other analgesic medications Conventional belief that pain medication should be reserved for patient with only moderate-to-severe pain Inadequate awareness and education about pain and patient specific pain management therapies Failure to re-evaluate patient s pain status as underlying disease process progresses Fine PG. Treatment Guidelines for the Pharmacological Management of Pain in Older Persons. Pain Med. 2012 Apr;13 Suppl 2:S57-66. Ly L: Pain Management in Older Adults; Available at www.fresno.ucsf.edu/norcal/downloads/painmgmtolderadults.pdf BARRIERS TO EFFECTIVE GERIATRIC PAIN MANAGEMENT: PATIENTS AND/OR FAMILY Ideology that pain builds character or is just part and parcel of getting old Desire to be a good patient or to avoid additional testing both resulting in underreporting of pain Cognitive/sensory impairments with difficulties in diagnosing pain and assessing treatment effectiveness Lack of social capital, physical accessibility to pain treatment or cost of drugs and other interventions Belief that narcotics will cause mental confusion, personality change, and drug seeking behaviors Fear that use of opioid analgesics will lead family and friends to view the patient as druggie (stigma) Fear that a younger generation family member will divert ( steal ) the medication Fine PG. Treatment Guidelines for the Pharmacological Management of Pain in Older Persons. Pain Med. 2012 Apr;13 Suppl 2:S57-66. Ly L: Pain Management in Older Adults; Available at www.fresno.ucsf.edu/norcal/downloads/painmgmtolderadults.pdf 4

Choosing an analgesic treatment will largely depend on the cause and intensity of pain and other individual patient factors, such as the presence of comorbidities, drug drug interactions, drug disease interactions, adherence to therapy, and cost. Even though older patients are generally at a heightened risk of adverse events, pharmacologic therapy can be safely initiated, and be effective, when all risk factors are taken into consideration. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological Management of Persistent Pain in Older Persons. J Am Geriatr Soc. 2009 Aug;57(8):1331-46. Fine PG. Treatment Guidelines for the Pharmacological Management of Pain in Older Persons. Pain Med. 2012 Apr;13 Suppl 2:S57-66. Rastogi R, Meek BD. Management of Chronic Pain in Elderly, Frail Patients: Finding a Suitable, Personalized Method of Control. Clin Interv Aging. 2013;8:37-46. CYP2D6 ISOENZYME One of the cytochrome (CYP) P450 isoenzymes CYP2D6 responsible for Phase I O-demethylation Converts inactive pro-drug into active metabolite Codeine Hydrocodone Oxycodone CYP2D6 CYP2D6 CYP2D6 CYP2D6 Morphine Hydromorphone Oxymorphone Tramadol O-D Tramadol Oxycodone, hydromorphone & oxymorphone do not require metabolism to be active analgesics. Oxymorphone has 40X higher affinity for µ opioid receptor than oxycodone. Zichterman A: Opioid Pharmacology and Considerations in Pain Management, US Pharmacist 32.5 (2007): 77-87. CYP2D6 GENETIC POLYMORPHISM CYP2D6 is critical for opioid effectiveness and toxicity. Patients are classified into the following four categories of CYP2D6 activity, from highest to lowest functioning: Ultra-rapid metabolizer (UM) Extensive or normal metabolizer (EM) Intermediate metabolizer (IM) Poor metabolizer (PM) 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians classified as PM 4-6% of Caucasians, 3-6% of African-Americans and 2% of Asian-Americans classified as UM Caraco Y. Genes and the Response to Drugs. N Engl J Med. 2004 Dec 30;351(27):2867-9. Gardiner SJ, Begg EJ. Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice. Pharmacol Rev. 2006 Sep;58(3):521-90. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41(2):89-95. 5

PHARMACOVIGILANCE: A REVIEW OF OPIOID-INDUCED RESPIRATORY DEPRESSION IN CHRONIC PAIN PATIENTS PubMed search 1980-2012: 42 cases of opioid-induced respiratory depression (OIRD) in chronic pain Cases published pre-2000 predominantly involved morphine in cancer patients Cases published post-2000 predominantly involved methadone or transdermal fentanyl in non -cancer pain patients Specific OIRD factors also varied Elevated opioid plasma levels due to renal impairment and sensory deafferentiation in pre-2000 cases versus Elevated plasma levels due to CYP450 drug metabolism in post-2000 cases Dahan A, Overdyk F, Smith T, Aarts L, Niesters M. Pharmacovigilance: A Review of Opioid-Induced Respiratory Depression in Chronic Pain Patients. Pain Physician. 2013 Mar-Apr;16(2):E85-94. KEY DRUG-DRUG INTERACTIONS CYP2D6 also metabolizes TCAs, SSRIs, SNRIs, mexiletine, lidocaine, ondansetron, beta-blockers, and tamoxifen Drugs that are weak inhibitors of cytochrome P-450 isozymes e.g., citalopram, escitalopram, sertraline, and venlafaxine would be expected to have fewer drug-drug interactions. Hansten and Horn: Pharmacy Times July 2005; http://www.hanstenandhorn.com/hh-article07-05.pdf Lacy C, Armstrong L, Goldman M, Lance L: Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. Drug Information Handbook, 15th ed. LexiComp Inc., Hudson, OH, 2007; 1899-1912. THE BASIC PAIN TREATMENT SCHEMA: BASIS FOR RATIONALE POLYPHARMACY FOR CHRONIC PAIN If possible, we seek to treat all four levels of the chronic pain process 6

CLASSES OF CHRONIC MEDICATIONS FOR MULTIMODAL ANALGESIA Therapeutic Class Antidepressants (TCAs, SNRIs, SSRIs, NDRI, TeCA/NaSSA) Antiepileptics/Anticonvulsants Anti-arrhythmics Topical formulations Analgesics NMDA antagonists GABA-A and B antagonists Alpha-2 agonists Muscle relaxants Drugs Amitriptyline, nortriptyline, imipramine, desipramine; venlafaxine, duloxetine, milnacipran; citalopram, paroxetine, sertraline; bupropion; mirtazapine Carbamazepine, oxcarbazepine, phenytoin, topiramate, lamotrigine, levetiracetam, gabapentin, and pregabalin Lidocaine, mexiletine Lidocaine, capsaicin, diclofenac NASIDs, tramadol, opioids Ketamine, dextromethorphan, methadone Clonazepam and baclofen Clonidine, tizanidine Baclofen, dantrolene, tizanidine, methocarbamol American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological Management of Persistent Pain in Older Persons. J Am Geriatr Soc. 2009 Aug;57(8):1331-46. PARADOX OF PAIN MANAGEMENT IN U.S. Institute of Medicine (IOM) concluded that pain is not optimally managed in the U.S. and that effective treatment of chronic pain will require a coordinated national effort to transform how the public, policy makers, and health care providers view the condition. Each day, 46 people die from an overdose of prescription opioids in the U.S. CDC Director Dr. Tom Frieden: Prescription drug overdose is epidemic in the United States. All too often, and in far too many communities, the treatment is becoming the problem. Institute of Medicine (2011) : Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research. www.cdc.gov/vitalsigns/opioid-prescribing/ Alabama is at the epicenter of opioids 143 opioid prescriptions 100 people This color-coded U.S. map shows the number of painkiller prescriptions per 100 people in each of the fifty states plus the District of Columbia in 2012. www.cdc.gov/vitalsigns/opioid-prescribing/ 7

OPIOIDS FOR CHRONIC PAIN IN THE OLDER PATIENT Hydrocodone Requires CYP2D6 hydromorphone 2.5 mg, 5 mg, 7.5 mg or 10 mg + 325 mg APAP 2.5 mg + 167 mg APAP/5 ml elixir for a start low/go slow effort Oxycodone Active parent prodrug 2.5 mg, 5 mg, 7.5 mg or 10 mg + 325 mg APAP or without APAP 5 mg/5 ml solution for start low/go slow Hydromorphone Active parent prodrug 2 mg hydromorphone = 5 mg of oxycodone 2, 4, 8 mg tablets or 1 mg/1 ml liquid Oxymorphone Fewer drug interactions ( cleaner ) + less active metabolites 5 mg, 10 mg without APAP Fe ntanyl Transdermal route has lower diver sion risk Rapid tolerance and hence frequent escalating dose Difficult to convert back to oral equivalent opioid once on higher daily dose Methadone Excellent oral bioavailability Highly protein bound with sustained clinical/side effects Prolonged QTc possible at surprisingly low doses of 30 mg/day OXYMORPHONE IN GERIATRIC PATIENTS: THE OPTIMAL OPIOID? Oxymorphone extensively metabolized in the liver primarily by UGT-2B7 to oxymorphone-3-glucuronide Does not significantly induce or inhibit CYP-2C9 or CYP-3A4 activity in healthy adults Based on available clinical trials, oxymorphone is a safe and effective opioid analgesic with similar dose-dependent side effects as other opioids. Because it is metabolized predominantly by non- CYP-450 mechanisms, oxymorphone should have fewer drug drug interactions with agents that are metabolized by those common pathways. Pergolizzi JV, Raffa RB, Gould E. Considerations on the Use of Oxymorphone in Geriatric Patients. Expert Opin Drug Saf. 2009 Sep;8(5):603-13. TRAMADOL: NEW 1 ST LINE PRIOR TO USE OF PURE MU AGONIST OPIOID? SNRI with weak mu-receptor agonist properties Musculoskeletal pain but also a global analgesic Use endorsed by the American Geriatric Society Schedule IV per DEA as of August 18, 2014 High side effect profile: dizziness/vertigo, nausea/vomiting, constipation, headache, somnolence Follow liver function tests with long-term, chronic use because reversible elevation can occur Avoid using (at least at higher doses) with all TCAs, probably all the SSRIs, and hydrocodone to avoid tramadol accumulation and attendant risk of grand mal seizure 0.5 to 1 mg/kg PO q 6 to 8 hours PRN 50 mg scored immediate release tablet at a sliding dose of 25 mg, 50 mg, 75 mg or 100 mg 8

TOPICAL VERSUS ORAL NSAIDS FOR CHRONIC PAIN Cochrane: 7688 participants in 34 studies from 32 publications Randomized, double blind studies where at least one treatment was a topical NSAID product (cream, gel, patch, solution) Direct comparison of topical NSAID with an oral NSAID did not show any difference in efficacy Topical NSAIDs can provide good levels of pain relief Topical diclofenac solution is equivalent to that of oral NSAIDs in knee and hand osteoarthritis, but there is no evidence for other chronic painful conditions. Incidence of gastrointestinal adverse events is reduced with topical NSAIDs compared with oral NSAIDs. Dilcofenac: Flector patch q 12 hours or Voltaren gel QID Alabama Medicare covers Voltaren gel but not Flector patch. Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs for Acute Pain in Adults. Cochrane Database Syst Rev. 2010 Jun 16;(6):CD007402. Derry S, Moore RA, Rabbie R. Topical NSAIDs for Chronic Musculoskeletal Pain in Adults. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007400. ANTIDEPRESSANTS AS ANALGESICS Tricyclic antidepressants 2º amines: nortriptyline and desipramine preferable Nortriptyline 5 mg/5 ml solution for gradual titration Initial low-dose (5 to 10 mg) and monitor side effects ECG to r/o WPW and prolonged QTc blood level at 0.5 mg/kg to r/o being slow metabolizer Lowest number needed to treat (NNT) of 2.2 for neuropathy Serotonin norepinephrine reuptake inhibitors Less α 1 -adrenergic blockade/anticholinergic effects than TCAs Venlafaxine: Dose of > 200 mg/day needed for analgesia Duloxetine: Generic available in U.S. as of December 2013 Selective serotonin reuptake inhibitors Paroxetine and citalopram may have analgesic properties when used in combination with other medications (e.g., an opioid) Dharmshaktu P, Tayal V, Kalra BS. Efficacy of Antidepressants as Analgesics: A Review. J Clin Pharmacol. 2012 Jan;52(1):6-17. ANTICONVULSANT ANALGESICS I Central calcium channel (α2δ) blockers Gabapentin (Neurontin ) 100 mg, 300 mg, or 400 mg capsule; 600 mg or 800 mg tablet 250 mg per 5 ml solution geriatric option to start low/go slow Initially 50 to 100 mg tid, increased gradually to 300 mg tid, then as needed and tolerated to 600 to 900 mg tid GFR 30-59 (BID), 15-29 (QD), <15 (1 dose post-dialysis) Pregabalin (Lyrica ) 25, 50, 75, 100, 150, 200, 225, and 300 mg hard-shell capsules 20 mg per 1 ml solution geriatric option for start low/go slow FDA-approved only for fibromyalgia, diabetic neuropathy, and PHN Initially 25 to 50 mg bid increased gradually to 150 mg bid and as needed to maximum of 300 mg bid May require 2 to 3 weeks for onset of efficacy Need to be taken on scheduled basis not PRN 9

THE GABAPENTANOIDS Gabapentin Exhibits saturable gastric absorption Less predictable nonlinear (zero-order) pharmacokinetics Blood levels can be monitored Therapeutic range: 2-10-20 μg/ml Pregabalin Plasma levels proportionately increase with increasing dose Linear (first order) pharmacokinetics Blood levels are not available 95+% excreted unchanged renally: CrCl periodically in patients at risk for CKD Less organ toxicity than other anticonvulsants however Dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attention) Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A Comparison of the Pharmacokinetics and Pharmacodynamics of Pregabalin and Gabapentin. Clin Pharmacokinet. 2010 Oct;49(10):661-9. ANTICONVULSANT ANALGESICS II Carbamazepine (Tegretol ) Topiramate (Topamax ) Lamotrigine (Lamictal ) Oxcarbazepine (Trileptal ) Peripheral and central Na channel blocker 150 mg, 300 mg and 600 mg tablets 300 mg per 5 ml oral suspension Adults: 300 mg bid target dose of 900 mg bid 3% incidence of hyponatremia (< 125) in adults Sedation common at higher doses especially in the older population, so start with liquid @ low dose AMERICAN GERIATRIC SOCIETY BEERS CRITERIA FOR POTENTIALLY INAPPROPRIATE MEDICATION USE IN OLDER ADULTS Dr. Mark Beers recognized more than 2 decades ago that the prevention of adverse drug events in older adults is crucial to the public health of this vulnerable population. Although not without limitations, the Beers Criteria have done more than any other tool in the past decade to improve the awareness of and clinical outcomes for older adults with polypharmacy and for the most vulnerable older adults at risk of adverse drug events. Accomplished this because of their explicit nature, simple application for non-pharmacy experts, and wide dissemination. The Beers Criteria remain simultaneously one of the most used and most controversial sets of medication criteria in the world. Fick DM, Semla TP. 2012 American Geriatrics Society Beers Criteria: New Year, New Criteria, New Perspective. J Am Geriatr Soc. 2012 Apr;60(4):614-5. 10

2012 AMERICAN GERIATRIC SOCIETY BEERS CRITERIA: PAIN MEDICINES Therapeutic Category or Drug Tertiary TCAs Amitriptyline, Imipramine Alpha agonists, central Clonidine But Tizanidine is not listed Benzodiazepines Clonazepam Non selective NSAIDs Etodolac, Meloxicam, Nabumetone Skeletal muscle relaxants Carisoprodol, Cyclobenzaprine, Metaxalone, Methocarbamol Opioids Hydrocodone, Oxycodone Antiepileptic drugs Gabapentin, Pregabalin Rationale Recommendation Quality of Evidence Highly anticholinergic, sedating, and cause Orthostatic hypotension High risk of adverse CNS effects; may cause bradycardia and orthostatic hypotension Increase risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents Increase risk of GI bleeding and peptic ulcer disease in high risk groups (But no specific mention of increased risk of MI, CVA or worsening of CHF) Most muscle relaxants are poorly tolerated by older adults because of anticholinergic adverse effects, sedation, risk of fracture; effectiveness at dosages tolerated by older adults is questionable Not included on 2012 AGS Beers Criteria Not included on 2012 AGS Beers Criteria Avoid High Strong Avoid Low Strong Avoid High Strong Avoid chronic use unless other alternatives are not effective Moderate Strength of Recommendation Strong Avoid Moderate Strong American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2012 Apr;60(4):616-31. None None 11