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Pain When It Matters Most

Pain When It Matters Most

KHCHA Annual Meeting 9/20/18 - Workshop H2

Transitions in Life Managing Pain When it Matters Most

Michael F Dandurand PharmD, BCGP, FACA

Objective

● Intro to pain ● Assessment ● Principles of pain control ● Opioid analgesics

1 Pain

● Occurs 70% of patients with cancer ● Occurs 65% of patients with non- malignant disease

Definition

● “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”- International Association for the Study of Pain' ● Whatever the patient says it is!

2 Types of Pain

● Nociceptive o Specific pain receptors are stimulated o Includes somatic and visceral

● Neuropathic o No specific receptors stimulated o AKA nerve pain o Burning and electrical feel

Pain Tolerance

Lowered by: ● Discomfort ● Boredom ● Insomnia ● Sadness ● Fatigue ● Depression ● ● Introversion ● Fear ● Social abandonment ● Anger ● Mental isolation

3 Pain Tolerance

Raised by: ● Relief of symptoms ● Sleep ● Elevation of mood ● Rest or physiotherapy ● Finding meaning and ● Relaxation therapy significance ● Explanation/support ● Social inclusion ● Understanding/empathy ● Support to express ● Diversion emotions

Pain Assessment

● Patient is central to pain assessment ● Diagnose the cause of pain ● Take detailed history of the pain ● Use patient self-assessment

4 Pain Scales

healthonecares.com Regular monitoring with: queri.research.va.gov ● Visual analogues scales ● Numerical scales ● Wong-Baker Faces Pain Scale

WHO Analgesic Ladder

Step 1 (pain less than 3/10)

Step 2 (pain 3-6/10)

Step 3 (pain over 6/10)

ntnu.edu

5 WHO Analgesic Ladder

● Start at step according to pain severity ● Choose drug based pain severity, not disease stage ● Use strong opioids when steps 1 and 2 analgesics fail ● Choose analgesic of different potency if pain relief failed ● Treat moderate-to-severe pain with opioid analgesics

Adjuvant Analgesics Adjuvant analgesics can be added at any stage Drugs Indication

NSAID ● Bone pain ● Soft tissue infiltration ● Hepatomegaly

Corticosteroids ● Raised intracranial pressure ● Soft tissue infiltration ● Nerve compression ● Hepatomegaly ●Bone Pain

Antidepressants and ● Nerve compression or infiltration ● Paraneoplastic neuropathies

Ketamine (special use only) ● Refractory pain ●Neuropathic pain ● Ischaemic limb pain

6 Pain Management Principles

● Goal: patients pain free at rest and during activity ● Analgesics scheduled, not PRN in continuous pain ● Pain is easier to prevent than relieve ● Additional pain medication prior to activity ● Simplest regimen, least drugs used, appropriate form, and interval ● Ensure treatment goals regularly ● Provide patient information about treatment ● Encourage patient involvement

1st-line Treatment Recommendations

● Oral sustained-release morphine for maintenance in patients requiring strong opiates ● Transdermal patches not for first line ● If patient’s pain cannot be controlled with first line therapy after optimization, revise treatment

7 1st-line Treatment for Breakthrough Pain

● Offer immediate-release morphine, if tolerable ● Fentanyl not for first-line rescue medication

timeinc.net

1st-line Treatment Recommendations: Transdermal When oral option is intolerable ● Transdermal Options: Fentanyl and Buprenorphine ● Use lowest cost transdermal patches ● Initiate after patient’s pain stabilize, due to long titration period ● Convert opiate doses with caution

8 1st line Recommendations: Subcutaneous

When oral opioids are not tolerable: ● Use subcutaneous opioids with the lowest cost Sample Options: ● Morphine ● Hydromorphone ● Fentanyl

Opioids Potency Effect of Opioid Receptors Weak Opioids Pure Partial Codeine Morphine Buprenorphine Meperidine HYdromorphone Oxymorphone Oxycodone Fentanyl Methadone Strong Opioids Agonist-antagonist Pure Antagonists Morphine Pentazocine Naloxone Hydromorphone Nalbuphine Naltrexone Oxymorphone Butorphanol Methylnaltrexone Oxycodone Fentanyl Methadone

9 Codeine

● Mild-to-moderate pain treatment ● Weak affinity for opioid receptor ● About 10 percent metabolized to morphine ● Available as single and in combination with acetaminophen or aspirin ● Also indicated as antitussive

Tramadol

● Binds weakly to opioid receptors, inhibit uptake of and norepinephrine, and promotes serotonin release ● Caution with other serotonin uptake inhibitors ● Available as combination with acetaminophen or single agent as immediate or long-acting

10 Hydrocodone ● Similar structure to codeine ● Weakly binds to opioid receptor ● Moderate-to-severe pain ● Commercially available as combination

Meperidine

● Synthetic opioid ● Less potent, shorter duration of action than morphine ● Seizure risk ● Not for long term, elderly, or renally impaired patients

11 Morphine

● Backbone of first-line therapy ● Standard of opioid comparison ● Moderate-to-severe pain ● Available in multiple formulations

Misconceptions of Morphine Explained

Patients normally believe: ● It is very addictive ● Respiratory depression issue ● Significant tolerance develops ● Morphine is stupefying

12 Recommendations for Starting Morphine

● Initiate 4-hourly doses of normal-release morphine tablets or elixir ● Allow extra doses for “breakthrough pain” PRN ● After 24 hours, total the day’s intake and divide by 6 to get the dose for every 4 hours. ● Regular starting dose for 4-hourly is 5-10 mg morphine

Maintenance dose of Morphine

● After pain stabilized, use sustained release preparations ● Breakthrough pain not associated with unusual acvity should be treated with morphine at ⅙ total daily dose

13 Oxycodone ● 25-50% more potent than morphine ● Oral only ● Available in combinations with acetaminophen, ibuprofen, and aspirin ● Immediate and long-acting available

Hydromorphone ● Semisynthetic derivative of morphine ● 7-11 times more potent than morphine ● Oral and parenteral

14 Oxymorphone

● Active metabolite of oxycodone ● More potent than oxycodone ● 10 times more potent than morphine ● Oral and parenteral available ● Immediate and long-acting available

Methadone ● Synthetic opioid receptor agonist, NMDA receptor blocker, serotonin and norepinephrine reuptake inhibitor ● Long half-life (8-59 hours) ● Opioid withdrawal treatment ● Has effect on neuropathic pain ● Effective for acute pain, but used primarily for chronic cancer and noncancer pain

15 Dosing Methadone: Opioid Naive Patient Gradual Titration Initiation ● 2.5 mg every 8 hours ● Slowly titrate to effect

Faster Titration Initiation ● 2.5 mg every 6-8 hours ● Slowly titrate to effect

● These recommendations represent a conservative approach

Methadone Conversion Table

Daily Oral Morphine Dose Ratio Estimated Methadone

<100 mg 3:1 20-30%

100-300 mg 5:1 10-20%

300-600 mg 10:1 8-12% 600-1,000 mg 12:1 5-10%

>1,000 mg 20:1 5%

16 Methadone Conversion Example 1

● Oral morphine dose: 80 mg daily ● Calculated Methadone dose: 15 mg daily 80*20%=16 mg ● Initial Methadone dose: 5 mg q8h 15 mg/3=5 mg ● Increase by calculated MET dose every 5-7 days PRN

Example 2

● Oral morphine dose: 300 mg daily ● Calculated methadone: 30 mg daily 300*10%=30 mg ● Initiate methadone dose: 10 mg q8h 30 mg/3=10 mg ● Increase by calculated MET dose every 5-7 days PRN

17 Daily Oral Morphine Exceeding 500 mg Example 3

● For morphine doses greater than 500 mg daily; add a third of the calculated methadone dose every 5 days Example: ● Oral morphine dose: 600 mg daily ● Calculated methadone: 42 mg daily 600*7%=42 mg methadone ● 1st 5 days: 5 mg methadone q8h and 400 mg morphine (in divided doses) (⅓)*42=14 mg, next closest dose is 15 mg, 15/3=5 mg q8h, 600 mg*(⅔)=400 mg ● Next 5 days: 10 mg methadone q8h, 200 mg morphine (in divided doses) 42*(⅔)=28, next closest dose is 30 mg, 30/3=10 mg q8h, 600*(⅓)=200 mg ● Then 15 mg methadone q8h, no morphine

Changing Methadone Dosing Interval

● Determine daily dosage for adequate analgesia ● Trial of longer dosing intervals may be attempted ● When patients are stable, divide total daily dose into every 12 hours

18 Buprenorphine Transdermal Patch

● Opioid partial agonist and antagonist ● Ceiling analgesia and respiratory depression ● Drug half-life is 30 hours ● Can displace pure agonist such as morphine and induce withdrawal

Buprenorphine Conversion

● Available as Butrans 5, 7.5, 10, 15, and 20 mcg/hour

Patch Strength Morphine Equivalent

Butrans 5 mcg Oral Morphine less than 30 mg/ 24 hours

Butrans 10 mcg Oral Morphine 30 mg-80 mg/ 24 hours

Butrans may not be Oral Morphine over 80 mg/24 hours appropriate for pain relief, use alternate analgesic

Manufacturer Recommendations

19 Starting Buprenorphine

● Opioid naive: 5 mcg/hr patch, titrate up as necessary ● Previously on opioid: Find equivalent converted dose ● Begin weekly with breakthrough pain meds PRN ● Dose adjustments: recommend after 7 days; not more frequently than 3 days ● Maximum dose: 20 mcg/hr patch ● Doses ≥40 mcg/hr may be associated with QT prolongation

Fentanyl

● Synthetic opioid ● 100 times more potent than morphine ● Transdermal patch for moderate-severe pain ● Transmucosal(lozenge, sublingual) for breakthrough pain

20 Fentanyl Transdermal Patch

● Onset 6-12 hours ● Steady state achieved after 3-6 days ● Change patch every 72 hours

Fentanyl Conversion Methods

FDA Manufacturing Label Breitbart Method ● The manufacturer recommendation is a ● Brietbart recommended ratio of 2:1 very conservative approach and often ● 2 mg oral morphine/24 hr = 1 mcg/hr undertreats pain of transdermal fentanyl ● Example: Patient on 145 mg oral morphine/day would use a 75 mcg/hr fentanyl patch ● Brietbart formula is for experienced practitioners due to its aggressive approach

Fentanyl Package Insert Conversion Chart

21 Fentanyl Points

● Use clinical judgment for conversions ● Do not use FDA chart to convert patch to morphine ● Respiratory depression increased in elderly, hepatic and renally impaired: choose lower dosing end ● When in doubt, go low and slow

Opioid Agonist–Antagonists

Options: pentazocine, butorphanol, nalbuphine ● Ceiling effect on respiratory depression ● Lower abuse potential than morphine Limited use due to: ● Psychotomimetic responses (e.g., and dysphoria with pentazocine) ● Ceiling analgesic effect ● Can cause withdrawal in opioid-dependent patients

22 Opioid Antagonist

Naloxone ● Binds competitively to opioid receptors but does not produce analgesia ● Used to reverse toxic effects of opioids

Approximate Equianalgesic Dosing of Opioid Analgesics in Adults*

Opioid Oral Dose IM, SQ, IV Dose Rectal

Codeine 200 mg 120-130 mg ***

Fentanyl *** 0.1 mg ***

Hydrocodone 30 mg *** ***

Hydromorphone 7.5 mg 1.5 mg 3 mg

Meperidine 300 mg 75 mg ***

Morphine 30 mg 10 mg ***

Oxycodone 20 mg *** ***

Oxymorphone 10 mg 1 mg 10 mg

* Table adapted from Drug Facts and Comparisons *** Not commercially available, compounded product available at Dandurand Drugs

23 Common Side Effects of Opioids ● Sedation ● and ● Constipation ● Dry Mouth ● Pruritis ● Bronchoconstriction ● Toxicity: agitation, hallucinations, confusion, myoclonic jerks

Reference

Pham, Trinh. "Pharmacology and Therapeutics of Pain Medications: Part 1." Drug Topics (2013): 42-54. DrugTopics.com. Drug Topics. Web. 10 Apr. 2015. .

"Pharmacology and Therapeutics of Pain Medications: Part 2." Pharmacology and Therapeutics of Pain Medications: Part 2 (2013): 58-69. Drugtopics.com. Drug Topics. Web. 10 Apr. 2015. .

Borton, Chloe, and Colin Tidy. "Pain Control in Palliative Care." Patient.co.uk. Patient.co.uk, 19 July 2012. Web. 7 Apr. 2015. .

Kubotera, Natsuki, and Jeffrey Fudin. "Pain Management for Pharmacists: Concepts and Definitions." Pain Management for Pharmacists: Concepts and Definitions (2013): 36-45. DrugTopics.com. Drug Topics. Web. 7 Apr. 2015. .

24 Reference Cont.

Lechyd, Byrdd, and Aneurin Bevin. "Opiate Conversion Doses." Health in Wales. NHS Wales, 1 Oct. 2010. Web. 10 Apr. 2015. <http://www.wales.nhs.uk/sites3/Documents/814/OpiateConversionDoses[Final]Nov2010.pdf>.

"Opioid Conversion Guidelines." Gippsland Health Alliance. Gippsland Region Palliative Care Consortium Clinical Practice Group, 1 Feb. 2011. Web. 12 Apr. 2015. <http://www.gha.net.au/Uploadlibrary/406205172GRPCC-CPG002_1.0_2011- Opioid.pdf>.

"Transdermal Buprenorphine Information Leaflet." Hull and East Yorkshire Hospitals. Hull and East Yorkshire Hospitals, 1 Mar. 2014. Web. 12 Apr. 2015. <http://www.hey.nhs.uk/herpc/guidelines/transdermalBuprenorphine.pdf>. Vadaurri, Vince, Topical Treatment of Neuropathic Pain. International J of Pharmaceutical Compounding, 2008; 183-190. Ferrari, Anna, Coccia, C, et al. Methadone-metabolism, and interactions. Elsevier, Pharmacological Research 50 (2004) 551-559. Argoff, Charles, Silverstein, Daniel, A Comparison of Long-and Short-Acting Opioids for the Treatment of Chronic Noncancer Pain: Tailoring Therapy to Meet Patient Needs. Mayo Clin Porc 2009 July; 84(7): 602-612.

Reference Cont.

Ross JR, Rutter D, Welsh K, et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005:5(5):324-336 Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage, 2005;29 (5 Suppl):S2-S9 Nicholson B, Passik SD. Management of chronic noncancer pain in the primary care setting. Southern Med J. 2007;100(10):1028- 1036 Ereshefsky L, Culpepper L, Preskorn S, The Use of Pharmacotherapy for Depression, Clinical Symposia, Vol 59, Number 1, May 2009 Schieir O, Thombs BD, Hudson, Taillefer S, Steele R, Bertrand C, Couture F, Fitzcharles MA, Gagne M, Garfield B, Gutkowski A, Kang H, Kapusta M, Ligier S, Mathieu JP, Menard H, Mercille S, Star M, Stein M, Zummer M, Baron M. ,Symptom of depression predict the trajectory of pain among patients with early inflammatory arthritis: a path analysis approach to assessing change. J Rheumatology. 2009 Feb;36(2) 231-9 Wick J, Zanni G. What’s New in Pain Management. Pharmacy Times. 2006. Retrieved July 18, 2006 from http://www.pharmacytimes.com Nykamp D, Williams S. Low Back Pain: Patient Management. U.S. Pharmacist. 2006; 31(5):79-86.

25 Reference Cont.

Drug Facts and Comparisons. 784-802. American Pain Society, Principle of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview, Ill: American P:ain Society; 2003. Zichterman, Anne, Opioid Pharmacology and Considerations in Pain Management. U.S. Pharmacist. May 2007 Bauer CS, Nieto-Rostro M, RahmanW, Tran-Van-Minh A, Ferron L, Douglas L, Kadurin I, Sri Ranjan Y, Fernandea-Alacid L, Millar NS, Ddicenson AH, Lujan R, Dolphin AC . The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha 2 delta ligand pregabalin. J Neuroscience 2009 Apr1; 29 (13) :4076-88. Bondy B, Baghai TC, Minov C, Schule C, Schwarz MJ, Zwanzger P, Rupprecht R, Moller HJ. Substance P serum levels are increased in major

26 Overview of Beers Criteria

Michael Dandurand PharmD, BCPS, FACA Slides by Quang Ta

Outline

◦ Overview of the Utility of Beers Criteria ◦ List of Potentially Inappropriate Medications Use in Older Adults (Table 2 in guideline) ◦ List of Potentially Inappropriate Medications Use in Older Adults due to Drug‐Disease Interaction (table 3 in guideline) ◦ List of Potentially Inappropriate Medications to be Used With Caution in Older Adults (table 4 in guideline) ◦ List of Potentially Clinically Important Non‐Anti‐infective Drug‐Drug Interactions that Should Be Avoided in Older Adults (table 5 in guideline) ◦ List of Non‐Anti‐Infective Medications that Should Be Adjusted with Varying Levels of Kidney Function (table 6 in guideline)

Main Reference Used: The American Geriatrics Society 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2015;63(11):2227‐46.

1 Overview of Beers Criteria

For use in patients ≥ 65 years old ◦ Not for hospice and palliative care Intention: ◦ Reduce older adults’ exposure to potentially inappropriate medications (PIMs) ◦ Not meant to replace clinical judgement First published in 1991, current version: 2015, previous version: 2012 Summary of notable changes: page 2230 of the original guideline. Complete list of changes/updates can be found in the original guideline (J Am Geriatr Soc. 2015;63(11):2227‐46)

Main Reference Used: The American Geriatrics Society 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2015;63(11):2227‐46.

Potentially Inappropriate Medications Use in Older Adults

Medications Recommendation 1st‐generation Antihistamines (full list in original Beers AVOID ( may be appropriate for acute Criteria documents). Common medications: treatment such as severe allergic reaction) chlorpheniramine, dimenhydrinate, diphenhydramine, () doxylamine, , meclizine, .

Antiparkinson Agents: Benztropine (oral), AVOID (anticholinergic, not recommended for EPS prevention, better alternative available for Parkinson) Antispasmodics: Atropine (excludes ophthalmic), AVOID Belladona alkaloids, clinidinum‐, (anticholinergic, questionable effectiveness) dicyclomine, hyoscyamine, propantheline, scopolamine

Table 7 in original Guideline lists the drugs with anticholinergic property

2 Potentially Inappropriate Antithrombotic and anti‐infective Medications Use in Older Adults

Dipyridamole, oral short‐acting (this does not apply to AVOID the ER combination with aspirin) (orthostatic , better alternative available, IV form OK for cardiac stress testing) Ticlodipine AVOID (safer alternative available) Nitrofurantoin* AVOID for long‐term suppression or when CrCl < 30 mL/min (CrCl < 60 mL/min in old guideline) updated (toxicities such as pulmonary, hepatotoxicity, and peripheral neuropathy)

*See original guideline regarding quality of evidence

Potentially Inappropriate CV Meds (2/2) Medications Use in Older Adults Peripheral Alpha‐1 Blockers (Doxazosin, Prazosin, AVOID use as an antihypertensive Terazosin) ()

Central Alpha Blockers* (, Guanabenz, AVOID clonidine as 1st line antihypertensive Orthostatic , , Reserpine >0.1 mg/d) AVOID the others hypotension, CNS SE Disopyramide* AVOID (anticholinergic, may induce heart failure in the elderly) Dronedarone AVOID in patients with permanent Afib, or patients with severe or decompensated heart failure (worse outcome) Digoxin AVOID as 1st line therapy for Afib or Heart Failure*, if used for Afib or heart failure*: avoid dose > 0.125 mg/d (questionable benefit, decreased renal clearance) Nifedipine IR AVOID (hypotension, risk of myocardial ischemia precipitation) Amiodarone AVOID as 1st line in Afib unless patient has heart failure or substantial left ventricular hypertrophy (toxicities)

See original guideline for changes regarding antiarrhythmic agents *Central Alpha Blockers, Disopyramide, Digoxin in Heart Failure: See original guideline regarding quality of evidence

3 Potentially Inappropriate CNS Meds (1/2) Medications Use in Older Adults

Antidepressant, alone or in combination AVOID (TCAs, paroxetine) (anticholinergic) (1st and 2nd generation) AVOID except for schizophrenia, bipolar disorder, or short‐term use as antiemetic during chemotherapy (↑risk of stroke, cognive decline, mortality) (e.g. , ) AVOID (dependence risk) (short and long‐acting) AVOID. Maybe appropriate for certain conditions such as seizure disorders, REM sleep disorder, withdrawal, ethanol withdrawal, severe GAD, and periprocedural anesthesia (general risks of benzodiazepine, elderly: ↑sensivity, ↓metabolism) AVOID (physical dependence risk, sedation)

Potentially Inappropriate CNS Meds (2/2) Medications Use in Older Adults

Nonbenzodiazepine, Benzodiazepine Receptor Agonist AVOID Hypnotics (, , ) (risks similar to benzodiazepines, ↑ ER visit, hospitalizations, minimal improvement in sleep)

Ergoloid mesylates (dehydrogenated alkaloids) AVOID (lack of efficacy) Isoxsuprine

4 AVOID Mesylates: mechanisms not well established. Possible mechanisms: • Decreases vascular tone and heart rate (by acting centrally) or blocks alpha‐receptors (by acting peripherally) • Affects neuronal cell metabolism, improves oxygen uptake, normalizes neurotransmitter level Has indications for Alzheimer’s disease – dementia and symptomatic treatment of age‐related Dementia

AVOID Isoxuprine: not well understood. Most common explanation: beta‐ stimulation ‐> uterine and vascular smooth muscle relaxation Has indication for Dementia, peripheral vascular disease, Raynaud’s disease

Micromedex Pictures: Wikimedia Commons

Potentially Inappropriate Endocrine meds Medications Use in Older Adults Androgens** (methyltestosterone, AVOID unless indicated for hypogonadism (confirmed, with clinical symptoms) ) (cardiac problem risk) Desiccated thyroid * AVOID (concern for cardiac effects, safer alternative available) Estrogens, with or without AVOID oral and topical patch progestins (cancer risk, lack of efficacy for cognitive and cardioprotection) Vaginal cream or tablets**: acceptable at low‐dose for dyspareunia, lower UTI, and other vaginal symptoms Growth hormone AVOID, except for hormone replacement after pituitary gland removal (SE, small impact on body composition) Insulin (sliding scale) AVOID (risk of hypoglycemia) Sulfonylureas (long‐duration: AVOID (risk of hypoglycemia) chlorpropamide, glyburide) Megestrol AVOID (minimal effect, risk of thrombotic events and possibly death) *See original guideline regarding quality of evidence **See original guideline regarding strength of recommendation

5 Potentially Inappropriate Gastrointestinal meds Medications Use in Older Adults

Metoclopramide AVOID, unless for gastroparesis (EPS risk, including tardive dyskinesia) Mineral oil (oral) AVOID (Aspiration risk, side effects, safer alternatives available) Proton‐pump inhibitors AVOID scheduled use for more than 8 weeks except for new high risk patients (oral corticosteroids, chronic NSAIDs, erosive esophagitis, Barrett’s esophagitis, pathological hypersecretion, or need for maintenance treatment)

(C. difficile risk, bone loss and fracture risk)

Potentially Inappropriate Pain meds, and Genitourinary med Medications Use in Older Adults Meperidine AVOID, especially in patients with CKD (efficacy problem, high risk of neurotoxicity) Non‐COX‐2 selective NSAIDs (and aspirin > 325 mg/d) AVOID chronic use due to commonly known risks of NSAIDs, unless other alternatives not effective and gastroprotective agent can be taken (PPI or misoprostol) Indomethacin, Ketorolac (including parenteral) AVOID (Indomethacin: more SE and CNS SE than other NSAIDs Ketorolac: high risk of GI bleeding, PUD, and AKI) Pentazocine* AVOID (more CNS adverse effects than other opioids) Skeletal Muscle Relaxants (, Chlorzoxazone AVOID , Metaxalone, Methocarbamol, (anticholinergic) )

Desmopressin new AVOID for treatment of nocturia or nocturnal polyuria (hyponatremia risk)

*See original guideline regarding quality of evidence

6 Potentially Inappropriate Medications due to Drug‐Disease Interactions

Heart Failure (these agents can potentially increase fluid retention) • NSAIDs (and COX2 inhibitor, do I need to say or mention this?) • Non‐dihydropyridine CCBs (diltiazem, ) – avoid only in HFrEF • TZD (pioglitazone, rosiglitazone) AVOID • Cilostazol* • Dronadarone (severe or recently decompensated heart failure)

Syncope (these agents can cause orthostatic hypotension or bradycardia) • Acetylcholine esterase inhibitors • Peripheral alpha‐1 blockers** (Doxazosin, Prazosin, Terazosin) • Tertiary TCAs AVOID • • ** • **

*See original guideline regarding quality of evidence **See original guideline regarding strength of recommendation

Potentially Inappropriate Medications due to Drug‐Disease Interactions

Chronic seizures or epilepsy (These agents can lower seizure threshold) • • Chlorpromazine • AVOID*. But may be acceptable in patients with well‐ • controlled seizures + other alternatives for these are not • Olanzapine effective • Thioridazine • Thiothixene •

*See original guideline regarding quality of evidence

7 Potentially Inappropriate Medications due to Drug‐Disease Interactions Delirium Dementia or cognitive impairment History of falls or fractures • • Anticholinergics • Anticholinergics • Antipsychotics new • Antipsychotics, chronic and • Antipsychotics as‐needed use • Benzodiazepines • Benzodiazepines • Benzodiazepines • Chlorpromazine • Corticosteroids • H2‐receptor antagonists (cimetidine, • H2‐receptor antagonists famotidine, nizatidine, ranitidine) new • Meperidine • Opioids • Sedative hypnotics • , new • Nonbenzodiazepine, benzodiazepine receptor agonist benzodiazepine receptor agonist hypnotics (Eszopiclone, hypnotics (Eszopiclone, Zolpidem, Zaleplon) Zolpidem, Zaleplon) • TCAs, SSRIs

AVOID in general, see additional note next slide

Potentially Inappropriate Medications due to Drug‐Disease Interactions

For Delirium, Dementia or Cognitive Impairment: • Antipsychotics: AVOID. They are associated with risk of stroke and mortality in patients with dementia. Avoid them unless nonpharmacological treatment is not effective or patient can potentially cause substantial harm to self or others.

For Delirium • Avoid the medications on previous slide in older patients with or at high risk of delirium

For History of Falls or Fractures: • If one of the medications on previous slide must be use: try to reduce other CNS‐active agents that can increase fall risk, and implement strategies to reduce fall risk.

8 Potentially Inappropriate Medications due to Drug‐Disease Interactions Insomnia • Oral decongestants (pseudoephedrine, phenylephrine) • Stimulants (amphetamine, , methylphenidate, ) AVOID • Theobromines (theophylline, ) Parkinson disease • All antipsychotics (except , , clozapine which are less likely to lead to worsening of Parkinson disease) AVOID • Antiemetics (, prochloperazine, promethazine) History of gastric or duodenal ulcers • Aspirin (more than 325 mg a day) AVOID unless other agents not effective and • Non‐selective NSAIDs (non‐COX‐2 selective NSAIDs) patient can take GI protective agents CKD Stages IV or less (CrCl < 30 mL/min) • NSAIDs (non‐selective and COX‐2 selective) AVOID

Potentially Inappropriate Medications due to Drug‐Disease Interactions

Urinary incontinence (all types) in women • Estrogen oral and transdermal (except intravaginal estrogen) AVOID in women • Peripheral alpha‐1 blockers (doxazosin, prazosin, terazosin)

Lower urinary tract symptoms, BPH (benign prostatic hyperplasia) • Strongly Anticholinergic drugs (except Antimuscarinics for urinary incontinence) AVOID in men

9 Potentially Inappropriate Medications to Be Used with Caution in Older Adults Medications Recommendation Aspirin* – cardiac events primary Use with caution in patients ≥ 80 years old prevention (lack of evidence for benefit vs. risk) Dabigatran Use with caution in patients ≥ 75 years old (increased risk of GI bleed) Use with caution in patients with CrCl < 30 (lack evidence for efficacy and safety) Prasugrel** Use with caution in patients ≥ 75 years old (increased bleeding risk; benefit in highest‐risk older adults with prior MI or diabetes may offset risk) Antipsychotics Use with caution SSRIs, SNRIs, TCAs, (may cause syndrome of inappropriate antidiuretic hormone secretion or , hyponatremia. Monitor Na level closely when initiating or changing dose) Carboplatin, Cisplatin, Vincristine Cyclophosphamide Diuretics Vasodilators** Use with caution (may exacerbate syncope in patients with history of syncope)

*See original guideline regarding quality of evidence **See original guideline regarding strength of recommendation

new List of Potentially Clinically Important Non‐Anti‐infective Drug‐ Drug Interactions that Should Be Avoided in Older Adults

Interacting Medications Risk Recommendation ACE inhibitors and Amiloride or ↑ risk of AVOID. OK to use in patients with hypokalemia Triamterene hyperkalemia while on ACE inhibitors Anticholinergic (multiple agents) ↑ Cognive decline AVOID or minimize # of anticholinergic drugs

Antidepressants, Antipsychotics, ↑ Fall risk AVOID total of more than 3 CNS‐active drugs. Benzodiazepines and ↑ Fracture risk Minimize # , benzodiazepine (benzodiazepines) receptor agonist hypnotics, Opioids Corticosteroids (oral & parenteral) ↑ PUD risk, GI bleed AVOID. Provide GI protection if not possible to risk avoid. Warfarin‐Amiodarone ↑ Bleeding risk AVOID if possible. Otherwise, monitor INR closely. Warfarin‐NSAIDs

10 new List of Potentially Clinically Important Non‐Anti‐infective Drug‐ Drug Interactions that Should Be Avoided in Older Adults

Lithium and ACE inhibitor ↑ Lithium toxicity AVOID. Or monitor concentration of lithium. Lithium and Loop diuretic

Peripheral alpha‐1 blockers and ↑ Urinary inconnence in AVOID in older women. Exception: when the loop diuretics (see note) older women condition warrants both drugs

Theophylline‐Cimetidine ↑ Theophylline toxicity AVOID

Note: Interaction check on Micromedex and Lexicomp doesn’t show an interaction between either doxazosin, prazosin, or terazosin and furosemide, bumetanide or torsemide (last checked March 25, 2018). Mechanistically, it makes sense that the combination can cause increase in urinary incontinence.

Adjustment for Non‐Anti‐Infective Medications new in Adults with Varying Kidney Function

CrCl Level Medication(s) Recommendation CrCl < 25 mL/min Apixaban Avoid Amiloride, Triamterene, Spironolactone Nitrofurantoin (see note) Avoid all of these agents at CrCl < 30 Probenecid, Colchicine mL/min with the exception of CrCl < 30 mL/min Enoxaparin, Fondaparinux, Dabigatran, Rivaroxaban Tramadol (Tramadol IR: Reduce Tramadol (see note) dose, ER: Avoid) Duloxetine

CrCl 30‐50 mL/min Rivaroxaban, Edoxaban Reduce dose

Cimetidine, Famotidine, Ranitidine, Nizatidine CrCl < 50 mL/min Reduce dose

Nitrofurantoin is listed in table 2, not table 6 in the guideline Tramadol: low quality of evidence, strength of recommendation: weak

11 Adjustment for Non‐Anti‐Infective Medications new in Adults with Varying Kidney Function

CrCl < 60 mL/min Gabapentin, Pregabalin Reduce dose

CrCl ≤ 80 mL/min Levetiracetam Reduce dose

CrCl > 95 mL/min Edoxaban Avoid

Adjustment for Non‐Anti‐Infective Medications new in Adults with Varying Kidney Function

Rivaroxaban: ◦ CrCl < 30 mL/min: Avoid ◦ CrCl 30‐50 mL/min: Reduce dose Edoxaban: ◦ CrCl < 30 mL/min: Avoid ◦ CrCl 30‐50 mL/min: Reduce dose ◦ CrCl > 95 mL/min: Avoid

12 References

Ergoloid Mesylates. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed April 27, 2018. Isoxsuprine. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed April 27, 2018 National Guideline Clearinghouse (NGC). Guideline summary: American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. In: National Guideline Clearinghouse (NGC) [Web site]. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2015 Nov 01. Available at https://www.guideline.gov. Accessed March 24, 2018. The 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;60(4):616‐31. Epub 2012 Feb 29. Accessed March 25, 2018 The American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227‐46. Epub 2015 Oct 8. Accessed March 25, 2018 Interaction Check between Furosemide, Torsemide, Bumetanide and Doxazosin, Prazosin and Terazosin was done using Lexicomp and Micromedex (March 25, 2018) Pictures: Anypodetos (Wikimedia Commons contributor). Chemical structure of , , alpha‐dihydroergocryptine, and beta‐dihydroergocryptine, the components of ergoloid (co‐dergocrine, dihydroergotoxine). Available at https://commons.wikimedia.org. Accessed Mar 27, 2018 JaGa (Wikimedia Commons contributor). Skeletal structure of isoxsuprine. Available at https://commons.wikimedia.org. Accessed Mar 27, 2018

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