pharmacologic pain management for the older adult leigh m. boehmer, pharm.d., bcop clinical...

Pharmacologic Pain Management for the Older Adult

Leigh M. Boehmer, Pharm.D., BCOPClinical Pharmacist, Medical OncologyBarnes Jewish HospitalApril 11, 2015

Disclosure

• Leigh M. Boehmer, Pharm.D., has no real or apparent conflicts of interest to report

Objectives

• Review how physiologic changes and altered pharmacology affect management of pain in the elderly

• Describe available tools for medication review for possible therapeutic duplication, inappropriate use, and drug interactions in the elderly

• Discuss special considerations for pharmacologic pain management in specific clinical settings in the elderly

US Elderly: Demographics

• Those >85 yoa are fastest growing segment of US population– 5 million today; 20 million by 2050

• 1:6 Americans >65 yoa by 2020– 54 million elderly, up from 3 million in 1990

• 1.3 billion >65 yoa worldwide in 2040

Available at www.census.gov. Accessed on 2.14.15.

Pain Prevalence in the Elderly

• 1:5 elderly have pain– 3:5 pain lasting for ≥1 year

• 31% of women and 19% of men >75 yoa report pain in ≥3 sites

• Community-dwellers: 25-56%• Nursing home residents: 45-80%

– Pain not detected by treating MDs in 34%

American Geriatrics Society. JAGS. 2002;50: S205-24.

Available at www.chcr.brown.edu/dying/severepain.htm. Accessed on 2.28.15.

Age-Related Pain Changes

• ↓ # and function of peripheral nociceptive neurons

• Thermal and vibratory stimuli sensory threshold increases with age

• 50% ↓ in Pacini’s corpuscles and 10-30% ↓ in Merkle’s disks (pain receptors)

• ↓ endogenous analgesic response via ↓ secretion of endorphins

Cassel C (Ed), et al. Geriatric Medicine: An Evidence-Based Approach. 2003.


• Myelinated nerves:– ↓ density– ↑ abnormal/degenerating fibers– Slower conduction velocity

• Unmyelinated nerves:– ↓ # large fibers– No change in small fibers– Substance P content ↓


Loss of synapsesChanges in firing rate

Slower conduction

velocity

Regression of dendrites

↓ soma size


• Central nervous system– Loss in # of dorsal horn, cortex, midbrain,

and brainstem neurons– ↓ circulating catecholamines, acetylcholine,

GABA, and serotonin – Altered cerebral evoked responses


GABA=gamma-amminobutyric acid

Age-Related Physiologic Changes

• ↓ volume of distribution– ↓ lean body weight

• ↓ serum protein concentrations• ↓ renal function• ↓ liver mass and hepatic blood flow• ↓ activity of drug-metabolizing enzymes• ↓ pulmonary function

Age-Related Pharmacologic Changes

Pharmacologic Concern Changes with Aging Common Disease Effects

Gastrointestinal (GI) absorption or function

• Slowing of GI transit time; may prolong effects of continuous release drugs

• Opioid-related GI dysmotility may be enhanced

• Disorders that alter gastric pH may ↓↑ select drug absorption

• Surgically altered anatomy may ↓ select drug absorption

Transdermal absorption• Few changes in absorption

under most circumstances• Temperature and other

patch technology may affect absorption

Distribution• ↑ fat to lean body weight

ratio may ↑ Vd for fat-soluble drugs

• Aging and obesity may result in ↑ drug half-life

Vd=volume of distribution

American Geriatrics Society. JAGS. 2009;57: 1331-46.

Achlorhydria and Drug Absorption

Which of the following agents has been associated with significantly increased GI absorption in the setting of achlorhydria?

a) morphine

b) oxycodone

c) hydromorphone

d) methadone

http://1.bp.blogspot.com/-g9KEWsJ2Ee8/TontouYQ7fI/AAAAAAAACnw/J0lZZEzylpo/s1600/daily-double.jpg

Achlorhydria and Drug Absorption

Which of the following agents has been associated with significantly increased GI absorption in the setting of achlorhydria?

a) morphine

b) oxycodone

c) hydromorphone

d) methadone

Garnett W. Am J Health-Syst Pharm. 1998;55: 2268-79.


Age-Related Pharmacologic Changes

Pharmacologic Concern

Changes with Aging Common Disease Effects

Liver metabolism

• Oxidation may ↓ resulting in ↑ drug half-life

• Conjugation usually preserved• First-pass effect usually unchanged• Genetic polymorphisms may affect

CYP450 enzymes

• Cirrhosis, hepatitis, or cancer may disrupt oxidation but usually not conjugation

Renal excretion• GFR ↓ with age, which results in ↓

renal drug clearance• CKD may further

predispose to renal toxicity

Active metabolites• ↓ renal clearance will prolong

effects of metabolites• Renal disease may

result in ↑ drug half-life

CYP=cytochrome P, GFR=glomerular filtration rate, CKD=chronic kidney disease


Hepatic Changes in the Elderly

• ↓ liver mass by 1% per year after age 50• 33% ↓ in flow and 21% ↓ in portal blood

velocity over age 65• ↓ serum albumin levels and quality

– ↑ free fraction of protein bound drugs• No significant change in liver function tests• Decline in ability of liver to regenerate

– Capacity, however, remains unchanged

Kaye A, et al. The Ochsner Journal. 2010; 10(3): 179-87.

Hepatic Changes in the Elderly

• 2 CYP enzymes most important to psychotro- pic prescribing ↓ with age (-1A2 and -3A)

• Bioavailability of high first- pass elimination drugs ↑d due to 30-40% ↓ in elimination of liver metabolized agents

Pergolizzi J, et al. World Institute of Pain. 2008;8(4): 287-313.

Effect of Reduced Hepatic Function on Opioid Pharmacokinetics

Opioid T1/2Metabolite [plasma]

Comment RecommendationEvidence

Level

Morphine ↑ ↓ M6G ↓ Dose ↓ IIb

Oxycodone ↑ ↑ Dose ↓ IIb

Hydromorphone ? ? No data Dose ↓ IV

Fentanyl TD ↑ ? Dose ↓ III

Buprenorphine TD

↑ ↓Low activity metabolite

Dose ↓ IIb

Methadone ↑ ? No data No dose change IIb

T1/2=half-life, M6G=morphine-6-β-glucuronide, ?=unknown, TD=transdermal


Renal Changes in the Elderly

• ↓ size by 20-30% by age 70• ↓ in renal blood flow by 10% per decade

after age 20– GFR ↓ 10 mL/min per decade after age 20– Plasma filtration rate ↓ more than GFR

• ↓ free water absorption by 5% per decade after age 50

• ↓ length, #, and thickness of renal tubules• ↑ interstitial tissue and tubular diverticulaKaye A, et al. The Ochsner Journal. 2010; 10(3): 179-87.

Aging Changes in the Kidney

Available at www.scripps.org. Accessed on 2.15.15.

Effect of Impaired Renal Function on Opioid Pharmacokinetics

Opioid T1/2Metabolite [plasma]

CommentRecomm-endation

Evidence Level

Morphine ↑ ↑↑↑ M6G and M3G may lead to ↓ respiratory drive

Dose ↓ IIa

Oxycodone ↑ ↑↓ clearance of parent compound and metabolite

Dose ↓ IIb

Hydromorphone ↑ ↑↑Metabolite accumulation described

Dose ↓ IIb

Fentanyl TD ↑ ↑ ↓ clearance in elderly Dose ↓ IIb

Buprenorphine TD

= =No clinically relevant changes

Adjust ± IIa

Methadone ↑ ↑ Use with caution Dose ↓ IV

T1/2=half-life, M6G=morphine-6-β-glucuronide, M3G=morphine-3-glucuronide, TD=transdermal


Narrowed Therapeutic Window↑

Dru

g C

on

cen

trat

ion

Available at www.neurology.org. Accessed on 2.28.15.

Factors Affecting Pain Perception

• Uncontrolled pain ↓ overall quality of life• Loneliness ↓s pain threshold and is a risk

factor for depression– Lack of intimate relationships, dependency

and loss ↑ loneliness• Depression and anxiety limit patients’

engagement in treatment and ↑ healthcare needs

Deane G and Smith H. Clin Geriatr Med. 2008;24(2): 185-201.

Objectives




Managing Pain in Older Adults

• Thorough pain assessment• Knowledge of underlying condition(s)• Consideration of comorbidities• Past response to therapies• Psychologic and social circumstances• Economic factors• Caregiver and living situation• Patient’s comfort and functional goals• Treatment team’s goals• Polypharmacy concerns• Drug-drug interactions Arnstein P. Pain Management Nursing. 2010;11(2): S11-22.

Pain Assessment Challenges

• Fear of becoming addicted• Myth that pain is a “natural” part of aging• Sensory and cognitive impairments• Under-reporting of pain• Complications of comorbidities• Caregivers’ perception of pain (lack of

congruence with patient)

Stein W. Clinics in Geriatric Medicine. 2001;17(3): 575-94.

Potentially Inappropriate Medication Use

Estimated annual US healthcare costs related to the use of potentially inappropriate medications (PIM) was which of the following?

a) $3 billion

b) $5.5 billion

c) $7.2 billion

d) $9.3 billion


Potentially Inappropriate Medication Use

Estimated annual US healthcare costs related to the use of potentially inappropriate medications (PIM) was which of the following?

a) $3 billion

b) $5.5 billion

c) $7.2 billion

d) $9.3 billionFu A, et al. Med Care. 2007;45: 472-6.


Screening Tool to Alert doctors to the Right Treatment (START)

• “Inappropriate” prescribing:– Acts of commission (giving unsuitable drugs)– Acts of omission (failure to give when

indicated)• N=600 elderly (≥65 yoa) patients admitted

with acute illness to a teaching hospital– START used to assess errors of omission– ≥1 omissions found in 57.9% of patients

Barry P, et a. Age and Ageing. 2007;36: 632-8.

START Criteria (Select Examples)

• Cardiovascular system• Respiratory system• Central nervous system (CNS)

– Antidepressant in the presence of clear-cut symptoms, lasting at least 3 months (N=10)

• GI system• Locomotor system

– Anti-rheumatic drug therapy with known, mod-severe disease lasting >12 weeks (N=13)

• Endocrine system Barry P, et a. Age and Ageing. 2007;36: 632-8.

Likelihood of Omission

• 65-74 yoa: 55.2% (1 med omitted)• 75-84 yoa: 54.8% (1 med omitted)

– OR 1.05, CI 0.71-1.45; P=0.93

• ≥85 yoa: 72.2% (1 med omitted)– OR 2.08, CI 1.24-3.5; P<0.01

• Females vs. males (1 med omitted)– OR 2.29, CI 1.65-3.19; P<0.01

Barry P, et a. Age and Ageing. 2007;36: 632-8.

2012 Updated Beers Criteria: Pain

Therapeutic Class/Drug(s)

Rationale RecommendationQuality of Evidence

Strength of Recommendation

Meperidine- Neurotoxicity- Not effective in doses used

Avoid High Strong

Non-COX selective NSAIDs

- ↑ risk GI bleeding and peptic ulcer dx

Avoid chronic use, unless other options are not available

Moderate Strong

IndomethacinKetorolac

- ↑ risk GI bleeding- Most AEs of all NSAIDs (indomethacin)

AvoidModerate/

HighStrong

2012 Beers Criteria Update Expert Panel. JAGS. 2012;1-16.

2012 Select Updated Beers Criteria

Therapeutic Class/Drug(s)*



Antispasmodics - Belladonna alkaloids - Librax® - Dicyclomine - Hyoscyamine - Scopolamine

- Highly anticholinergic - Uncertain effectiveness

Avoid, except in short term palliative settings (ex., ↓ oral secretions)

Moderate Strong

Tertiary TCAs - Amitriptyline - Clomipramine - Doxepin (>6 mg/day) - Imipramine

- Highly anticholinergic- Sedating- Orthostatic hypotension

Avoid High Strong

2012 Beers Criteria Update Expert Panel. JAGS. 2012;1-16.

*Select examples only; TCA=tricyclic antidepressant

2012 Select Updated Beers Criteria

Therapeutic Class/Drug(s)*



Benzodiazepines - Alprazolam - Lorazepam - Triazolam - Clonazepam - Diazepam

- ↑ sensitivity to class - ↓ drug metabolism- ↑ risk of cognitive impairment

Avoid for treatment of insomnia, agitation, or delirium

High Strong

Skeletal muscle relaxants - Carisoprodol - Flexeril® - Metaxolone - Methocarbamol

- ↑ fracture risk, sedation- Efficacy at tolerable doses questionable

Avoid Moderate Strong

2012 Beers Criteria Update Expert Panel. JAGS. 2012;1-16.*Select examples only

Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP)

Gallagher P and O’Mahony D. Age and Ageing. 2008;37: 673-9.

Study population

715 consecutive admissions to a university teaching hospital in patients ≥65 yoa

DesignSTOPP and Beers criteria applied to prospective review of diagnoses, reason for admission, and concurrent medications

Results

•Primary endpoint: identification of PIM via STOPP and Beers criteria•Secondary endpoint: Proportion of PIM with causal connection to reason for admission

STOPP Results

• STOPP criteria:– 336 PIMs divided amongst 35% (N=247)

• 25% one PIM, 7% two PIMs, 2% three PIMs, 1% four PIMs; 1 patient with five PIMs

– 91% AEs responsible for admission “caught”• Beers criteria:

– 226 PIMs divided amongst 25% (N=177)• 19% one PIM, 5% two PIMs, 3% three PIMs; 1

patient with four PIMs

– 48% AEs responsible for admission “caught”Gallagher P and O’Mahony D. Age and Ageing. 2008;37: 673-9.

STOPP (Select) Criteria

Criterion N PIM AE as a causal factor to admission

Long term, long-acting benzodiazepine

6526 (fall 9; fall + fracture 8; fall + head injury 1; overdose 1; cognitive decline 7)

NSAID with h/o PUD or GI bleeding 3 1 (PUD)

NSAID with h/o mod-severe HTN 20 3 (GI bleed 2; PUD 1)

Long-term NSAID for joint pain 9 1 (PUD)

NSAID with chronic renal failure 9 1 (acute renal failure)

Long-term opiates in those with recurrent falls

1 1 (fall + femur fracture)

Long-term opiates as first-line therapy for mild-mod pain

13 3 (fall + femur fracture)

Long-term opiates in those with dementia, unless mod-severe pain

2 2 (delirium 1; fall + femur fracture 1)

Gallagher P and O’Mahony D. Age and Ageing. 2008;37: 673-9.

h/o=history of, PUD=peptic ulcer disease, HTN=hypertension

Dietary Supplements

• Herbals• Megavitamins• Minerals• Amino acids• Folk remedies• Lifestyle diets

$30 billion market annually

Choi J, et al. Support Care Cancer. 2009; 17: 231-40.

http://images.google.com/imgres?imgurl=http://www.nlm.nih.gov/pubs/factsheets/graphics/brand2.jpg&imgrefurl=http://www.nlm.nih.gov/pubs/factsheets/dietaryfs.html&usg=__7GvymgF4XtB-zPnDdN17LWGswI4=&h=596&w=585&sz=85&hl=en&start=65&tbnid=_Uq3tcuvuaI58M:&tbnh=135&tbnw=133&prev=/images?q=dietary+supplements&gbv=2&ndsp=18&hl=en&sa=N&start=54

Dietary Supplement Health and Education Act of 1994

• Not FDA regulated• No safety or efficacy requirements• Must state product not intended to

diagnose, treat, cure, or prevent disease• General well being and benefit statements

are permitted• FDA may ban if unsafe for human

consumption

Wesa K, et al. Hematol Oncol Clin N Am. 2008; 22: 343-53.

Conditions for which CAM is Most Frequently Used

Back

pain

Head

cold

Neck

pain

Joint

pain

Arthrit

is

Anxiet

y/de

pres

sion

Stom

ach

upse

t

Heada

che

Recur

ring

pain

Inso

mnia

0

5

10

15

20

Pe

rce

nt

CAM=complementary and alternative medicineAdapted from Bruckenthal P. Pain Management Nursing. 2010; 11(2): S23-31.

Let’s Talk…

What drug/supplement interaction database(s) do you use in your practice?

a. Lexi-Comp®

b. MicroMedex®

c. Natural Medicines Comprehensive Database®

d. Other

Spectrum of Clinical Risk

Deng G, et al. Journal of the Society for Integrative Oncology. 2007; 5(2): 65-84.

Opioid Pharmacokinetic Interactions

OpioidPrimary

MetabolismDrug-Drug Interactions Evidence Level

MorphineUGT 2B7UGT 1A3

Ranitidine, rifampin, valspodar IIb

Oxycodone CYP 2D6 Unlikely to cause effects IV

HydromorphoneUGT WB7UGT 1A3

Very little data on effects IV

Fentanyl TD CYP 3A4Potent inhibitors may ↑ fentanyl (ex., ritonavir, ketoconazole)

Ib

Buprenorphine TD CYP 3A4 Only minor effects IV

MethadoneCYP 3A4CYP 2B6CYP 2C19

Inducers and inhibitors of respective CYP enzymes

IV


UGT=UDP-glucuronosyltransferase

Select CYP450 Drug Interactions

CYP3A4 CYP2D6 CYP2C9 CYP2C19

Substrate

AlfentanilHydrocodoneOxycodone

Propoxyphene

CodeineFentanylMorphine

OxycodoneTramadol

CelecoxibIbuprofen

Methadone

CarisoprodolMethadone

InhibitorClarithromycin

DiltiazemVerapamil

AmiodaronePropranololParoxetine

AmiodaroneClopidogrelFluconazole

CimetidineFluoxetine

Omeprazole

InducerRifampin

DexamethasonePhenytoin

Not inducible

AprepitantCarbamazepine

Phenytoin

Phenobarbital

GinkgoPhenytoin

CYP450 Drug Interactions. The Pharmacist’s Letter. 2009 update

Let’s Talk…

AL has been on oxycodone for chronic, severe pain for 4 months. She was recently discharged on rifampin for osteomyelitis and presents to clinic with 9/10 uncontrolled pain. Aware of a potential interaction, you suggest…

a. increasing oxycodone dose

b. rotating to morphine for duration of antibiotics

c. starting diltiazem to balance the interaction

d. adding alfentanil as a second pain agent

Reasons for De-Prescribing in Geriatric Patients

• ↓ potential adverse effects• ↓ associated drug(s) costs• ↓ polypharmacy • Improved quality of life• Improved medication adherence

Lindsay J, et al. Support Care Cancer. 2014;22: 1113-9.Reeve E, et al. Int J Clin Pharm. 2014; 36: 26-9.

Approach to Safe De-Prescribing: A Geriatric Model

Establish Life Expectancy

Identify Treatmen

t & Patient Goals

Assess Time to Benefit

Treatment Targets

Hardy J and Hilmer S. J Pharm Pract Res. 2011; 41(2): 146-51.

Approach to Safe De-Prescribing: A Geriatric Model

AccurateMed List

Assess AdjustFollow Up and

Repeat

Hardy J and Hilmer S. J Pharm Pract Res. 2011; 41(2): 146-51.

Use Caution when De-Prescribing

Drug/Class Adverse withdrawal effect(s) Suggested action

Alpha-blockers Rebound HTN, agitation Wean gradually

Beta-blockersRebound tachycardia, palpitations, angina re-emergence

Wean gradually

Nitrates Angina re-emergence Gradual tapering

Furosemide Re-emergence of heart failure Caution if h/o heart failure

Benzodiazepines Delirium, insomnia, seizures Wean gradually

Anticholinergics Anxiety, nausea, vomiting, dizziness Wean gradually

Steroids HPA suppression if long-term use Wean gradually if long-term

Antipsychotics Dyskinesia, nausea, agitation Wean gradually

Antidepressants Dysphoric mood, agitation Wean gradually

Digoxin Re-emergence of A. fib Caution if h/o rapid A. fib

HTN=hypertension, HPA=hypothalamic-pituitary axis, A. fib=atrial fibrillation Hardy J and Hilmer S. J Pharm Pract Res. 2011; 41(2): 146-51.

Objectives




Chronic-Pain vs. Addicted Patient Characteristics

Chronic-pain patients Addicted patients

Medication use is not out of control Medication use is out of control

Medication use improves quality of life Medication use impairs quality of life

Wants to decrease medication is adverse effects develop

Medication use continues or increases despite adverse effects

Is concerned about the physical problem being treated with the drug

Unaware of or in denial about any problems that develop as a result of treatment

Follows the practitioner-patient agreement for opioid use

Does not follow opioid agreement

May have leftover medication Does not have leftover medication

Loses prescriptions

Always has a story about why more drug is needed

Adapted from Webster LR and Dove B. Avoiding Opioid Abuse While Managing Pain. 2007.

Risk Assessment Tools

Tool Use Administrator Length Availability

Current Opioid Misuse Measure (COMM)

Monitor for misuse by patients currently on long-term opioid therapy

Self-report 17 items www.inflexxion.com/COMM/

Diagnosis, Intractability, Risk, Efficacy (DIRE)

Opioid addiction screening

Clinician 7 items Belgrade MJ, et al. J Pain. 2006;7:671-81.

Opioid Risk Tool (ORT)


Clinician or self-report

5 Y/N questions

www.opioidrisk.com/node/887

Screener and Opioid Assessment for Patients with Pain (SOAPP, -R)


Self-report 24 items www.inflexxion.com/SOAPP/

Chou E, et al. J Pain. 2009;10(2): 113-30.

Acetaminophen (APAP) MOA

• Centrally acting analgesic, increases pain threshold

• MOA not well understood...– Nitric oxide pathway interaction– COX-2 inhibition– Interaction with serotonergic, opioidergic, or

endocannabinoid systems• Antipyretic due to action in hypothalamus

– Vasodilation; ↑ peripheral blood circulation

Jones, V. Journal of Pain & Palliative Care Pharmacotherapy. 2011; 25: 340-9.

Oncology Drug Development

Used as an analgesic and antipyretic, acetaminophen is available in more than ____ pharmaceutical products in the US?

a) 200

b) 400

c) 600

d) 800


Oncology Drug Development

Used as an analgesic and antipyretic, acetaminophen is available in more than ____ pharmaceutical products in the US?

a) 200

b) 400

c) 600

d) 800

Pickens, L et al. Journal of Pediatric Nursing. 2011; 26: 494-7.


APAP Highlights

• Treatment of choice for osteoarthritis• Maximum daily dose usually 4 Gm

– ↓ 50-75% in those with hepatic dysfunction or h/o alcohol abuse

• As of 3/2014, all products with >325 mg per dose have discontinued marketing


IV Acetaminophen (Ofirmev®)

• Approved for mild-to-mod pain and mod-to-severe pain in combination with opioids

• 3 active comparitor studies found no significant difference in efficacy or AEs; 1 showed numerical ↓ in opioid consumption

• 2 meta-analyses showed ~20% reduced morphine requirements on post-op day 1

• Markedly more expensive than alternatives: oral or rectal acetaminophen and IV ketorolac

Remy C, et al. British Journal of Anaesthesia. 2005; 94(4): 505-13.

Elia N, et al. Anesthesiology. 2005; 103: 1296-1304.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• 23.5% of elderly adverse drug event-related hospitalizations due to NSAIDs

• Non-acetylated forms (ex., salsalate) may have lower GI toxicity than aspirin

• COX-2 selective agents (ex., celecoxib) have fewer significant GI adverse events

• Concomitant administration of H2RAs or PPIs may ↓ the risk of GI ulceration

• Eradication of H. pylori ↓ NSAID-associated peptic ulcerationCOX=cyclooxygenase, H2RA=H2 receptor antagonists,

PPI=proton pump inhibitor American Geriatrics Society. JAGS. 2009;57: 1331-46.

NSAID COX-1/-2 Selectivity

Fowler T, et al. J Am Assoc Nurse Pract. 2014;26(8): 414-23.

Select NSAIDs for Persistent Pain in Older Adults

AnalgesicRecommended Starting

DoseComments

Choline magnesium trisalicylate

500-750 mg PO every 8hLong half-life may allow daily or BID dosing; minimal antiplatelet effect

Salsalate 500-750 mg PO every 12hMay need to check salicylate levels; minimal antiplatelet effect

Celecoxib 100 mg PO dailyHigher doses linked to ↑ rates of GI and cardiovascular AEs

Naproxen sodium 220 mg PO twice daily Less cardiovascular AEs

Ibuprofen 200 mg PO TID May inhibit aspirin’s antiplatelet effect

Diclofenac sodium50 mg PO BID or

75 mg ER PO dailyMay see higher cardiovascular risk profile

ER=extended release


Common NSAID Adverse Events

System Adverse Event(s)

GI• Dyspepsia, abdominal pain, gastric ulcers, bleeding, perforation• ↑ risk with non-selective NSAIDs

Cardiovascular• ↑ blood pressure, myocardial infarction, congestive heart failure,

cerebrovascular accident• ↑ risk with COX-2 selective NSAIDs

Hematologic • ↑ risk for bleeding and anemia

Renal• Water and sodium retention, ↓ renal blood flow, electrolyte

imbalances, prerenal azotemia, hyporeninemic hypoaldosteronism

Hepatic • ↑ transaminases, hepatitis

Fowler T, et al. J Am Assoc Nurse Pract. 2014;26(8): 414-23.

Patient Case Question

PD is a 60 yo female with OA of her right knee and a PMH of mod liver dysfunction and controlled HTN. She has been taking ibuprofen (IBU) 600 mg PO TID for 4 weeks with good relief, but her BP today is 187/92 mmHg. The best option for continued treatment of her OA is…?

a) APAP 1 Gm PO QID

b) Continue with current IBU schedule

c) Celecoxib 200 mg PO daily

d) Diclofenac gel 4 Gm TOP QID

Short-Acting Opioid Highlights

• μ-opioid receptor agonism (primary)• No ceiling effect and have been shown to

relieve all types of pain• Every patient should be prescribed a bowel

regimen to prevent constipation• Long-term therapy associated with hormonal

suppression• Scheduled administration before anticipated

pain episode(s) may be appropriate in patients with cognitive impairmentArnstein P. Pain Management Nursing. 2010;11(2); S11-22.

Available at www.practicalpainmanagement.com. Accessed on 2.15.15.

Opioid-Induced Immunosuppression

Opioid Animals Humans Evidence Level

Morphine ++++ ++++ Ia/b

Oxycodone (--) ND IIa

Hydromorphone (--) ND IIa

Fentanyl ++++ ++++ Ib

Buprenorphine (--) ND Ib

Methadone ? ND IIb


++++=high degree of immunosuppression, (--)=not immunosuppressive, ?=data inconclusive, ND= not determined

Select Variables Influencing Analgesic Response

Pharmacokinetics/ Pharmacodynamics Analgesic response

Pharmacogenomics

Pain related:•Kind of pain•Origin of pain•History of pain control

Environmental factors:•Culture•Education•Family•Occupation

Psychological factors:•Depression•Anxiety•Coping strategies•Diagnosis

Severity of:•Trauma•Surgery•Tissue damage

Adapted from Stamer U, et al. Pharmacogenomics. 2010;11(6):843-64.

Pharmacogenomic Targets

Gene Variant Opioids Affected Outcome(s)

CYP2D6Poor;

ultra rapid metabolizers

Codeine, Tramadol, Oxycodone

↓ analgesia; excessive side effects

ABCB1 3435C > T MorphineTT carriers experience

greater pain relief

OPRM1 118A > GMorphine, Alfentanil, Fentanyl, Methadone

↑ dose requirements due to ↓ efficacy

COMT 1947G > A MorphineGG carriers

experience less pain relief

Jannetto P and Bratanow N. Expert Opin Drug Metab Toxicol. 2011; 7(6): 745-52.

Pertinent LA Opioid Prescribing Information for Elderly Patients

Avinza® Morphine sulfate ER: 30-, 45-, 60-, 75-, 90-, and 120 mg capsules

Dosing interval Once a day

Dosing highlights • Titrate using a minimum of 3-day intervals• May open capsule and sprinkle pellets on applesauce; do not

chew; use immediately• Max daily dose: 1600 mg due to renal toxicity risk of fumaric acid

Drug interactions • Alcohol may result in rapid release of a potentially fatal dose• PGP inhibitors may ↑ absorption by about two-fold

Butrans® Buprenorphine TD: 5-, 10- and 20 mcg/hr

Dosing interval One transdermal system every 7 days

Dosing highlights • Initial dose in mild to moderate hepatic dysfunction: 5 mcg/hr• Maximum dose of 20 mcg/hr due to risk of QTc prolongation

Drug interactions • CYP3A4 inhibitors may ↑ levels; CYP3A4 inducers may ↓ levels• Class Ia and III antiarrhythmics may ↑ risk of QTc prolongation

LA= long-acting, PGP=P-glycoproteinLexicomp®: Avinza and Butrans monographs. Accessed on 2.17.15.


Dolophine® Methadone: 5- and 10 mg tablets

Dosing interval Every 8-12 hours

Dosing highlights • High inter-patient variability in absorption and metabolism• Use low doses according to the table in the package insert

Drug interactions • CYP450 inducers may ↑ levels; CYP450 inhibitors may ↓ levels• Potentially arrhythmogenic agents may ↑ risk of QTc prolongation

Duragesic® Fentanyl TD: 12-, 25-, 50-, 75-, and 100 mcg/hr

Dosing interval One transdermal system every 3 days

Dosing highlights • Use 50% of dose in mild or moderate hepatic or renal dysfunction• Avoid use in severe hepatic or renal impairment• Contraindicated in postoperative or mild pain management

Drug interactions • CYP3A4 inhibitors may ↑ fentanyl exposure• CYP3A4 inducers may ↓ fentanyl exposure

Lexicomp®: Dolophine and Duragesic monographs. Accessed on 2.17.15.


Exalgo® Hydromorphone ER: 8-, 12-, and 16 mg tablets

Dosing interval Once a day

Dosing highlights • Moderate hepatic dysfunction: start with 25% of usual dose• Moderate renal dysfunction: start with 50% of usual dose• Must be able to swallow tablets whole

Drug interactions • Do not use in patients with a sulfa allergy (sodium metabisulfite)

Kadian® Morphine sulfate ER: 10-, 20-, 30-, 40-, 50-, 60-, 80-, 100-, 200 mg

Dosing interval Once a day or every 12 hours

Dosing highlights • Titrate using a minimum of 2-day intervals• May open capsule and sprinkle pellets on applesauce; do not

chew; use immediately• May open capsule and mix into ~10 mL of water, then flush

through a 16-French gastrostomy tube

Drug interactions • Alcohol may result in rapid release of a potentially fatal dose• PGP inhibitors may ↑ absorption by about two-fold

Lexicomp®: Exalgo and Kadian monographs. Accessed on 2.17.15.


Nucynta ER® Tapentadol ER: 50-, 100-, 150-, 200-, and 250 mg tablets

Dosing interval Every 12 hours

Dosing highlights • Dose once daily in moderate hepatic dysfunction with 100 mg per day maximum

• Avoid use in severe hepatic and renal dysfunction• Serotonin syndrome has been described

Drug interactions • Alcohol may result in rapid release of a potentially fatal dose• Contraindicated in patients taking MAOIs

Opana ER® Oxymorphone ER: 5-, 7.5-, 10-, 15-, 20-, 30-, and 40 mg tablets


Dosing highlights • Use 5 mg every 12 hours as initial dose in patients with mild hepatic and/or renal dysfunction and patients >65 yoa

• Contraindicated in moderate and severe hepatic dysfunction

Drug interactions • Alcohol may result in rapid release of a potentially fatal dose

Lexicomp®: Nucynta ER and Opana ER monographs. Accessed on 2.17.15.


OxyContin® Oxycodone CR: 10-, 15-, 20-, 30-, 40-, 60-, and 80 mg tablets


Dosing highlights • Hepatic dysfunction: start with 30-50% of usual dose• Renal dysfunction (CrCl <60 mL/min): start with 50% of usual

dose• Consider using other analgesics in patients with GI disorders that

may predispose them to obstruction

Drug interactions • CYP3A4 inhibitors may ↑ oxycodone exposure• CYP3A4 inducers may ↓ oxycodone exposure

Lexicomp®: Oxycodone monograph. Accessed on 2.17.15.CR=controlled release

Healthcare System Opioid Barriers

• Lack of a neighborhood pharmacy• Transportation issues• Absence of high dose opioid at pharmacy• No caregiver to help with drug preparation

and/or administration• Negative attitudes toward patients needing

opioid therapy

Zuccaro S, et al. Clin Drug Investig. 2012;32(1): S11-9.

Select Adjuvant Pain Agents

Agent(s)Recommended Starting

DoseComments

Desipramine, nortriptyline, amitriptyline

10 mg PO at bedtimeSignificant risk of AEs (anticholinergic and cardiovascular) in older patients

Duloxetine 20 mg PO daily Monitor BP, dizziness, and cognitive effects

Milnacipran12.5 mg PO daily; titrate to

50 mg PO BID↓ dose 50% if CrCl <30 mL/min; do not use with narrow angle glaucoma

Gabapentin 100 mg PO at bedtime Monitor sedation, ataxia, edema

Baclofen 5 mg PO up to TIDMonitor urinary function, cognitive effects, sedation; avoid abrupt discontinuation

Tramadol 12.5-25 mg PO every 4-6hMixed opioid, serotonin- and norepinephrine-reuptake inhibitor; monitor opioid AEs, seizures, serotonin syndrome

Tapentadol 50 mg PO every 4-6h Trials suggest ↓ GI AEs relative to opioids


Non-Pharmacologic Management

• Massage: ↓ pain, improves circulation, ↓ anxiety, ↑ joint mobility

• Exercise: moderate intensity, ≥30 min 3-4 times per week

• Chiropractic: rule out spinal cord injury or nerve root involvement prior to start

• Transcutaneous electrical nerve stimulation• Patient education

Norelli L and Harju S. Clin Geriatr Med. 2008;24(2): 335-44.


• Relaxation: repetitive focus on sound, sensation, muscle tension, inattention towards intrusive thoughts; requires individual acceptance and training

• Meditation: guided or self-directed, allows conscious awareness of thoughts, emotions, and sensations without judgment

• Hypnosis: state of inner absorption and focused attention; reduces pain by distraction, altered perception, and ↑ pain threshold



• Cognitive-behavioral therapy: focuses on changing individual cognitive activity to modify associated behavior, thoughts, and emotions; conducted by trained therapist

• Operant behavior therapy: use of negative and positive consequences to modify behavior

• Mind-body conditioning: Yoga, tai chi, qigong


Future of Pain Management

• Non-traditional analgesics– Targeted gene therapy

• Vectors deliver enkephalins to sensory nerves

– Spicamycin derivative• Non-opioid acetylcholinesterase inhibitor

– Tetrodotoxin derivative• Non-peptide, non-opioid neurotoxin

– Cytokine and nerve growth factor inhibitors

Available at www.clinicaltrials.gov. Accessed on 2.28.15.

Parting Pearls

• Identify applicable age-related pharmacologic changes

• Conduct a prospective review for drug-drug/-herbal interactions before a prescription is written

• Remember PIMs to avoid and errors of omission• Prescribe non-opioids, where appropriate• Begin therapy with the lowest possible dose and

increase slowly• Consider the need for preventive, concurrent

medications• Discuss role of non-pharmacologic management

Pharmacologic Pain Management for the Older Adult

Leigh M. Boehmer, Pharm.D., BCOPClinical Pharmacist, Medical OncologyBarnes Jewish HospitalApril 11, 2015

pharmacologic pain management for the older adult leigh m. boehmer, pharm.d., bcop clinical...

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