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Caveats for Treating Chronic Pain in Older Adults Cynthia Feucht, PharmD, BCPS, CGP October 21, 2016 Objectives Describe physiological and pharmacokinetic changes in the elderly that impact the use of opioids. Discuss alternative (non-controlled) options for treating chronic pain in older adults. Describe polypharmacy and its potential consequences in older adults. Change is Inevitable… Physiological Changes Aging is a more important predictor of PK/PD changes compared to age itself! Physiologic changes can influence PK/PD PK (ADME) are more measurable Increases the risk of adverse effects Constipation, confusion, falls Elliot D. Pharmacokinetics and pharmacodynamics in the elderly. In: Schumock G, Brundage D, Dunsworth T, Fagan S, Kelly H, Rathbun R, et al., eds. Pharmacotherapy Self-Assessment Program, 5th ed. Lenexa, KS: American College of Clinical Pharmacy, 2004:115-126. Trivia Question Approximate loss of organ function per year after the age of 30 is: 0.9% 3% 5% 7.5% Absorption Atrophy of gastric cells Increase in gastric pH Decrease in gastric acid secretion Delayed gastric emptying May alter rate (but note extent) of EC or SR product absorption May increase contact time for drugs http://hubpages.com/education/Absorption-of-drugs-how-drugs-are-absorbed-in-the-body-ePharmacology Elliot D. Pharmacokinetics and pharmacodynamics in the elderly. In: Schumock G, Brundage D, Dunsworth T, Fagan S, Kelly H, Rathbun R, et al., eds. Pharmacotherapy Self-Assessment Program, 5th ed. Lenexa, KS: American College of Clinical Pharmacy, 2004:115-126. Distribution Increase in body fat Lipid soluble drugs: Vd Increased concentration and half-life for lipid soluble drugs Effect: delayed drug elimination Examples: Benzodiazepines, tricyclic antidepressants http://www.fat2fitradio.com/wp-content/uploads/2008/04/elderly.jpg Distribution Decrease in total body water Water soluble drugs: Vd drug plasma concentrations & diffusion to receptor sites ↑ Example: morphine, digoxin http://www.alistwellnesscenter.com/images/proportionofwater.gif Elliot D. Pharmacokinetics and pharmacodynamics in the elderly. In: Schumock G, Brundage D, Dunsworth T, Fagan S, Kelly H, Rathbun R, et al., eds. Pharmacotherapy Self-Assessment Program, 5th ed. Lenexa, KS: American College of Clinical Pharmacy, 2004:115-126. Metabolism Liver mass reduction of ~ 25-35% Similar reduction in hepatic blood flow Can lead to ↓ drug metabolism & ↑ drug effect High hepatic extraction ratio agents May bioavailability due to altered first pass metabolism Examples: morphine, amitriptyline, hydromorphone http://hepatitiscnewdrugresearch.com/liver-disease-in-elderly-patients.html Sera L, et al. Clin Geriatr Med 2012;28:273-286. Elliot D. Pharmacokinetics and pharmacodynamics in the elderly. In: Schumock G, Brundage D, Dunsworth T, Fagan S, Kelly H, Rathbun R, et al., eds. Pharmacotherapy Self-Assessment Program, 5th ed. Lenexa, KS: American College of Clinical Pharmacy, 2004:115-126. Metabolism Phase I reactions (oxidation) Impact of lifestyle factors In vitro tests demonstrate inter-patient variability No clear association for age-related decline Alcohol intake Tobacco abuse Caffeine intake Impact of disease-related dysfunction http://medicineworld.org/images/blogs/old-man-smoking-432510.jpg Elliot D. Pharmacokinetics and pharmacodynamics in the elderly. In: Schumock G, Brundage D, Dunsworth T, Fagan S, Kelly H, Rathbun R, et al., eds. Pharmacotherapy Self-Assessment Program, 5th ed. Lenexa, KS: American College of Clinical Pharmacy, 2004:115-126. Excretion Progressive age-related decline ~1% decline/yr after the age 50 Scr poor marker of kidney function Muscle mass loss, ↓ tubular function Assess function using CrCl / eGFR Can lead to ↓ drug clearance ↑ risk for side effects http://www.kidneyfoundationofcentralpa.org/images/kidney.gif Elliot D. Pharmacokinetics and pharmacodynamics in the elderly. In: Schumock G, Brundage D, Dunsworth T, Fagan S, Kelly H, Rathbun R, et al., eds. Pharmacotherapy Self-Assessment Program, 5th ed. Lenexa, KS: American College of Clinical Pharmacy, 2004:115-126. Davis M, et al. Drugs Aging 2003;20(1):23-57. Opioids and ADME Absorption: usually not affected by aging Distribution: Highly lipid soluble: fentanyl & methadone Hydrophilic: Codeine, hydrocodone, oxycodone, & tramadol Morphine & hydromorphone Lexi-Comp, Inc. (Lexi-Drugs®). Lexi-Comp. Accessed September 19, 2016 Davis M, et al. Drugs Aging 2003;20(1):23-57. Opioids and ADME Typically exhibit high first pass metabolism: Morphine, hydromorphone, oxymorphone & tapentadol May see ↑ drug bioavailability in elderly Clinically significant active metabolites: Morphine, codeine, meperidine, tramadol, hydrocodone, oxymorphone Avoid in hepatic failure: codeine, tramadol, meperidine Preferred (severe): Morphine, fentanyl & methadone Lexi-Comp, Inc. (Lexi-Drugs®). Lexi-Comp. Accessed September 19, 2016 Davis M, et al. Drugs Aging 2003;20(1):23-57. Opioids and ADME Primary renal excretion: Morphine, hydromorphone, codeine, fentanyl, tramadol, oxycodone, hydrocodone: adjust dose in mild to moderate renal failure Meperidine: avoid use Tapentadol: avoid with CrCl < 30ml/min Generally safe to use in moderate renal failure: Hydromorphone, fentanyl Methadone (moderate to severe) Lexi-Comp, Inc. (Lexi-Drugs®). Lexi-Comp. Accessed September 19, 2016 Davis M, et al. Drugs Aging 2003;20(1):23-57. Dean M. J Pain & Symptom Manage 2004;28(5):497-504. Opioid Caveats Poor CYP 2D6 metabolizers: Affects ~ 5-10% of the caucasian population Also 1-2% of Southeast Asians Tramadol & codeine → lack of efficacy due to reduced conversion to active metabolites Oxycodone, hydrocodone → prolonged effect due to decreased metabolism https://memegenerator.net/instance/19879024 Wilkinson G. N Engl J Med 2005;352(21):2211-2221. Davis M, et al. Drugs Aging 2003;20(1):23-57. Opioid Caveats: Methadone Variable pharmacokinetics: Duration of analgesia ↑ with prolonged administration Half-life range: 8-59 hrs (avg. 20-35) Multiple drug interactions QTc prolongation & risk for torsades: Risk factors: other QTc prolonging meds, ↓ K/Mg, elderly, female, structural heart disease, congenital long QT syndrome Obtain baseline EKG and risk stratify Avoid if QTc > 500 msec. http://www.apsf.org/newsletters/html/2011/spring/01_opioid.htm Lexi-Comp, Inc. (Lexi-Drugs®). Lexi-Comp. Accessed September 19, 2016. Lugo R, et al. J Pain & Palliative Care Pharmacother 2005;19(4):13-24. Owens R, et al. Clin Infect Dis 2006;43:1603-1611. Trivia Question Which of these men has influenced how we treat older adults? https://images-na.ssl-images-amazon.com/images/I/21AgpWqWMYL._UX250_.jpg https://mibiz.com/media/k2/items/cache/ebe2497a9810ac1c751277b6aacb6b9b_XL.jpg http://media.mlive.com/kzgazette_impact/photo/8911853-large.jpg Criteria Regarding Opioid Use START/STOPP Criteria Avoid high-potency oral or transdermal opioids as 1st line therapy in those with mild pain Use high-potency opioids in mod-severe pain where Tylenol, NSAIDS & low-potency opioids are either inappropriate or ineffective Beers Criteria Avoid meperidine: safer alternatives exist Avoid opioids in those with history of falls/fractures Avoid total of ≥ 3 CNS-active meds due to risk for falls American Geriatrics Society 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc 2015. O’Mahony D, et al. Age Ageing 2015;44:213-218. https://ipspotlight.files.wordpress.com/2014/11/17187698_s.jpg Guiding Principles Establish mutually acceptable comfort goals Use of combined nonpharmacological & pharmacological therapy Initiate Adjust with low dose dosing for organ impairment / drug interactions Reassess frequently / titrate cautiously Davis M, et al. Drugs Aging 2003;20(1):23-57. Pharmacological Management of Persistent Pain in Older Adults. J Am Geriatr Soc. 2009;57:1331-1346. http://images.addictionblog.org/cherrycake/wp-content/uploads/2016/02/Is-methadone-safe-1.png What Do Older Patients Want: Preferred Lansbury G. Disabil Rehab 2000;22(1-2):2-14. http://www.epainassist.com/images/Article-Images/home-remedies-arthritis.jpg http://mymedsupply.com/wp-content/uploads/2015/03/Hot-and-Cold-Therapy-Shoulder.jpg http://salonpas.us/wp-content/uploads/2016/01/FamilyShot-FS-Gel-Spray-GelPatch-NHP-Trans-01262 016a-Small-2.jpg http://www.dignicareins.com/wp-content/uploads/2013/12/Nursing-Home-Insurance-The-Benefits-of-Socialization-for-the-Elderly.jpg What Do Older Patients Want: Least Preferred Lansbury G. Disabil Rehab 2000;22(1-2):2-14. http://www.reputehealthcare.com/eldercare.html http://www.consumerreports.org/content/dam/cro/news_articles/health/71262728_health_pills.jpg http://scrubbing.in/encouraging-the-elderly-to-exercise/ Alternative Approach: Nonpharmacological Physical therapy Heat, massage, stretching TENS unit PHN & acute/chronic pain Behavioral therapy Meditation, relaxation, prayer, music therapy, biofeedback Pain Management Alternatives Over-the-Counter Topical counterirritants Topical lidocaine Acetaminophen Oral NSAIDs Prescription Topical / oral NSAIDs Lidocaine patch Tricyclic antidepressants Duloxetine Anticonvulsants http://www.browardcountypainclinics.com/wp-content/uploads/2012/12/pain-relief21.jpg Topical OTCs Counterirritants: induces a less intense pain to counteract a more severe one Examples: methyl salicylate, camphor, menthol, capsaicin, trolamine salicylate Up to 3-4 applications per day Don’t apply heat or wrap bandage tightly Multiple formulations: cream, ointment, gel, patch Names don’t change but ingredients often do! http://salonpas.us/wp-content/uploads/2012/02/family-of-products-small.jpg https://audubonparkwellness.brimhallwebsite.com/istore/4233_biofreeze__pain_cream.html http://www.icyhot.com/wp-content/uploads/2014/01/pro_img03.jpg Newest OTC ingredient: Lidocaine Lidocaine 4% patch • 1 patch/day; ~ $50/mo. supply • Available OTC & in other formulations Lidocaine 5% patch • Up to 3/day, may cut patches & apply to several areas • Rx: PHN; often used off label for LBP & OA http://www.aspercreme.com/img/portfolio/lidocaine-patch-slider-1-sm.jpg https://www.walgreens.com/images/drug/0163481068706.jpg NSAIDS: OTC & Rx Analgesic, anti-inflammatory & antipyretic In a variety of combination products: Aleve PM (NSAID + antihistamine) Vimovo (NSAID + PPI) Treximet (NSAID + triptan) Vicoprofen (NSAID + opioid) In 2000: 70% over age 65 took NSAIDs at least once weekly http://neuropathyandhiv.blogspot.com/2016/01/nsaids-like-ibuprofen-and-advil-can-be.html#.V-1IXIWcGEY NSAID Mechanism of Action http://www.voltarengel.com/HCP/images/charts/MOA_chart.jpg Herndon C, et al. Pharmacotherapy 2008;26(6):788-805 NSAID Gastrointestinal Toxicity • Nausea & bloating Common Serious • Heartburn & epigastric pain • Colonic ulceration & perforation • Gastric or duodenal ulcers • 20-40% of users Herndon C, et al. Pharmacotherapy. 2008;28(6):788-805. http://infohealth.net/wp-content/uploads/2013/04/ulcer-s.jpg http://www.health.harvard.edu/blog/can-heartburn-medication-cause-cognitive-problems-201603219369 Additional NSAID Toxicity Nephrotoxicity • 1-5% incidence • Risk factors: concurrent diuretic or ACE inhibiror & underlying renal disease Fluid Retention • Result of increased sodium reabsorption • Can lead to weight gain & exacerbate HTN & HF CNS • Rare: confusion, psychosis, aseptic meningitis • Risk factors: older age & lipophilic NSAID Herndon C, et al. Pharmacotherapy 2008;28(6):788-805. NSAIDs and Cardiovascular Risk FDA Warning July 2015 Precision Trial Started 2006, ended 2016 Compared celecoxib to naproxen and ibuprofen Combined endpoint: CV death Nonfatal MI, CVA Hospitalization for UA, TIA Revascularization http://blog.affordablehealthinsurance.org/2015/08/fda-says-that-taking-advil-motrin-and.html#.V-w-3oWcGEY https://clinicaltrials.gov/ct2/show/NCT00346216 Scarpignato C, et al. BMC Medicine 2015;13:1-22. Guideline Recommendations….. ACR (2012) Hand OA: oral and topical NSAIDs including trolamine salicylate Avoid NSAIDs (exception: celecoxib) for chronic use unless other alternatives are not effective & patient can take PPI HF & CKD: avoid NSAIDs and COX-2 inhibitors Gastric/duodenal ulcers: avoid non-selective NSAIDs Age ≥ 75: topical preferred Knee & Hip OA: oral NSAIDs and topical NSAIDs (knee) Beers (2015) Age ≥75: topical preferred Hochberg M, et al. Arthritis Care and Research. 2012;64(4): 465-474. American Geriatrics 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2015. Topical NSAIDs Diclofenac gel Indication: OA Application 4 times daily Dose differentiated by lower/upper extremity Diclofenac solution Indication: Knee OA Two strengths / product type Systemic bioavailability: ~1% Preferred in elderly! http://www.onlinepharmacynz.com/images/products/414-299-Voltaren_Emulgel.jpg Lexi-Comp, Inc. (Lexi-Drugs®). Lexi-Comp. Accessed September 29, 2016 http://www.pennsaid.com/img/hcp_2.0_img1.png Adjuvant Agents Antidepressants Serotonin-norepinephrine reuptake inhibitors (SNRIs) Tricyclic antidepressants (TCAs) Anticonvulsants Gabapentin, pregabalin Origination in treatment of cancer pain Useful for neuropathic pain May be used alone or with another agent Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57:1331-1346. http://chronicpainreliefoptions.com/wp-content/uploads/2016/08/np3.jpg Duloxetine Pros Useful when concomitant depression/anxiety Indicated for diabetic neuropathy & chronic musculoskeletal pain Trial benefits: reduction in pain & improved physical functioning Cons Side effects: N/V/D, dizziness, fall risk, hyponatremia Must taper to avoid withdrawal symptoms Avoid in mod-severe renal failure Makris U, et al. JAMA 2014;312(8):825-836. Chappell A, et al. Pain 2009;146(3):253-260. http://pharmamkting.blogspot.com/2008/08/cymalta-buzz-machine-is-at-full.html Tricyclic Antidepressants Useful for a variety of indications Depression Diabetic neuropathy Migraine prophylaxis Chronic pain Small study in older adults found equal efficacy in diabetic PN when compared to pregabalin & duloxetine http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/ Boyle J, et al. Diabetes Care 2012;35(12):2451-2458. TCAs: Comparison Profile AntiSedation OSH cholinergic Seizures Conduction abnormalities Amitriptyline* Doxepin* ++++ +++ ++++ ++++ +++ ++ +++ +++ +++ ++ Desipramine Nortriptyline ++ ++ ++ ++ ++ + ++ ++ ++ ++ Teter CJ, Kando JC, Wells BG. Chapter 51. Major Depressive Disorder. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com.ezproxy.ferris.edu/content.aspx?bookid=689&Sectionid=45310502. Accessed September 30, 2016 TCAs and Beers Criteria Avoid: highly anticholinergic, sedation and cause orthostasis Avoid if history of: Syncope, delirium, dementia, cognitive impairment, falls/fractures, & BPH Often related to anticholinergic properties American Geriatrics 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2015. Caveats for TCA Use Use secondary amines: Less anticholinergic effects, fewer associated falls, less confusion & ↓ risk for OSH Use low dose at bedtime (sedation) Caution use in: BPH, urinary retention, constipation, CV disease, 2nd /3rd degree heart block, prolonged QTc interval, severe liver disease, seizure disorder & closed angle glaucoma http://lionsheartcounseling.com/wp-content/uploads/2015/08/small-pills1.jpg Davis M, et al. Drugs Aging 2003;20(1):23-57. Pregabalin & Gabapentin Indications • Diabetic neuropathy, PHN, fibromyalgia, seizure d/o • Off-label: restless leg syndrome, hot flashes Side Effects • Dizziness, sedation, peripheral edema, weight gain • Dry mouth, blurred vision, ataxia, fatigue, tremor Precautions • Heart failure, fall risk, concurrent CNS active meds • Dose adjust when CrCl < 60 ml/min Lexi-Comp, Inc. (Lexi-Drugs®). Lexi-Comp. Accessed September 29, 2016 Davis M, et al. Drugs Aging 2003;20(1):23-57. Medication Use in the Elderly Cross sectional survey of 3005 elderly (57-85 yrs) At least 5 Rx medicines: 29% Concurrent OTC use: 46% Concurrent dietary suppl.: 52% At least 5 dietary supplements: nearly 1 in 8 Qato D, et al. JAMA 2008;300(24):2867-2878) What is Polypharmacy? Conditions Medications Medications Chronic pruritis Restoril 15mg qhs Hydroxyzine 25mg bid Chronic cough Lamictal 100mg qhs Ativan 0.5mg tid prn Diabetes mellitus type 2 Effexor XR 150mg qd Tussionex 5ml bid prn Hypertension Detrol LA 4mg daily Vicodin 5/500mg bid prn Urinary incontinence Cymbalta 20mg daily Motrin 800mg tid prn Insomnia Catapres 0.3mg qhs Depression / anxiety Diovan 40mg daily Osteoarthritis Activella 1/0.5mg daily Sleep apnea Omeprazole 20mg daily GERD Melatonin 5mg qhs Personality disorder Polypharmacy Medication Count Arbitrarily defined Often > 5 medicines Unnecessary Use Range 2-9 Controversial May be appropriate if multiple disease states Shah B, et al. Clin Geriatr Med 2012;28:173-186. http://www.wur.nl/en/project/pandemics.htm Not clinically indicated Lack of indication Suboptimal Duplication More practical approach Consequences http://www.slideshare.net/EdricPawChoSing/epidemiology-of-polypharmacy-and-potential-drugdrug-interactions-among-pediatric -patients-in-icus-of-us-childrens-hospitals Shah B, et al. Clin Geriatr Med 2012;28:173-186. Prescribing Optimization Method Designed to optimize medication use in older adults Six questions: Is the patient undertreated & is additional therapy indicated? Does the patient adhere to current regimen? Which drug(s) can be withdrawn or is inappropriate? Which adverse effects are present? Which clinically relevant interactions could be expected? Should the dose frequency or drug form be changed? Drenth-van Maanen A, et al. Drugs Aging 2009;26(8):687-701. Gokula M, et al. Clin Geriatr Med 2012;28:323-341. http://askapharmmedicationreview.com/uploads/3/6/3/2/3632226/2322479.jpg?200 Managing Older Adults Customize therapy for each patient Monitor & reassess for efficacy & toxicity Many adverse effects mimic underlying disease processes Consider any symptom an ADR until proven otherwise! Minimize withdrawal effects by tapering dose Steinman M, et al. JAMA 2010;304(14):1592-1601. http://www.health-heart.org/NoBadCholesterol.jpg