Maximizing Medications for
Good Outcomes
Lee H. Stringer, Pharm.D., BCPS, FASCP, CPE
Clinical Pharmacist, Certified Pain Educator
Montana Pain Initiative
May 30, 2014
Health Care, Education and Research
www.billingsclinic.com
Conflict of Interest Disclosure
Lee H. Stringer, Pharm.D.
Has no real or apparent
conflicts of interest to report.
Objectives
1. Explore principles of rational polypharmacy
2. Learn mechanisms of action of non-opioid
and adjuvant analgesics
3. Recognize an appropriate analgesic trial
including proper titration
Terminology
• Narcotic
– A substance that causes narcosis
– Heroin, cocaine, methamphetamine
• Opioid
– A substance that binds to the opioid receptor
– Morphine, fentanyl, oxycodone
Analgesic Classes
Non-opioid
Analgesics
Pure Opioid Analgesics
Adjuvants
APAP and NSAIDs
Morphine
Antidepressants and
antiepileptics
Nociceptive pain
Nociceptive and
neuropathic pain
Nociceptive and
neuropathic pain
Potential end-organ
damage
No end-organ damage?
Potential end-organ
damage
Ceiling analgesic effect
No ceiling?
Ceiling dose
American Pain Society. (2008). Principles of analgesic use in the treatment of acute pain and cancer pain (6th ed.). Glenview, IL: American Pain Society.
Key Pharmacotherapeutic
Concepts in Pain Management
• Consider multimodal analgesia
• Polypharmacy is the RULE, rather than the
exception
• Consider the need for dose titration (up/down)
• Minimize side effects through careful medication
selection
• Anticipate and treat side effects
• Always have a contingency plan
Werder SF, Preskorn SH. Managing polypharmacy: walking the line between help and harm. J Fam Prac 2003;2(2)
Gallagher RM. Rational integration of pharmacologic, behavioral, and rehabilitation strategies in the treatment of chronic pain. Am J Phys Med Rehabil
2005;84(3Suppl):S64-76.
Considerations for Rational
Polypharmacy
•
•
•
•
•
Know drug mechanisms of action
Avoid overlapping mechanisms
Know drug toxicities
Avoid overlapping/additive toxicities
Understand drug pharmacokinetics
Werder SF, Preskorn SH. Managing polypharmacy: walking the line between help and harm. J Fam Prac 2003;2(2)
Gallagher RM. Rational integration of pharmacologic, behavioral, and rehabilitation strategies in the treatment of chronic pain. Am J Phys Med Rehabil
2005;84(3Suppl):S64-76.
Considerations for Rational
Polypharmacy, cont’d
• Maximize current regimen
• Ensure an appropriate trial is given
• Have convincing evidence that combination >
monotherapy
• Treat “symptom clusters”
Werder SF, Preskorn SH. Managing polypharmacy: walking the line between help and harm. J Fam Prac 2003;2(2)
Gallagher RM. Rational integration of pharmacologic, behavioral, and rehabilitation strategies in the treatment of chronic pain. Am J Phys Med Rehabil
2005;84(3Suppl):S64-76.
Barriers to Rational Polypharmacy
•
•
•
•
•
Drug-Drug Interactions
Drug-Disease Interactions
Medication misuse
Cost (financial toxicity)
Pill burden
Werder SF, Preskorn SH. Managing polypharmacy: walking the line between help and harm. J Fam Prac 2003;2(2)
Gallagher RM. Rational integration of pharmacologic, behavioral, and rehabilitation strategies in the treatment of chronic pain. Am J Phys Med Rehabil
2005;84(3Suppl):S64-76.
Polypharmacy in Pain Medicine
• Goal: achieve optimal pain/function
improvement with minimal toxicity
– Facilitate use of lower doses of one or more
drugs
– Maintain efficacy
– Synergize effect of two drugs with differing
mechanisms of action
Fishbain DA. Polypharmacy treatment approaches to the psychiatric and somatic comorbidities found in patients with chronic pain. Am J Phys Med Rehabil.
2005;84(Suppl 3):S56-63.
Mechanistic Stratification
Beydoun A, Backonja MM. Mechanistic stratification of antineuralgic agents. J Pain Symptom Manage. 2005:25;S18-30.
Pathophysiologic Stratification
• Transduction: Capsaicin, LA, NSAID/steroid, topical
opioid
• Conduction (Transmission): LA, TCA
• Plasticity (Modulation)
– Ectopic activity: LA, TCA, NSAID
– Synaptic transmission: gabapentinoids, NMDA
antagonists, α-agonists, ziconotide
– Descending modulation: TCA, SNRI, opioids
• Perception: TCA, SNRI, gabapentinoids, systemic
opioid
Mao J et al. Combination drug therapy for chronic pain: a call for more clinical studies. J Pain. 2011;12:157-6.
Non-opioid Analgesics:
Acetaminophen
Benefit of APAP in combinations at
“LOW” doses
Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficiacy; individual patient dtat meta-analysis of single-dose oral tramadol plus
acetaminophen in acute postoperative pain. J Pain Symptom Manage. 2002:23;121-130.
Benefit of APAP in combinations at
“HIGH” doses
Study
Mean
MED
Average
APAP benefit
baseline pain > 70 MED?
No difference
in pain control
Axelsson et al (2003)
70 mg
2
No
43%
Axelsson et al (2008)
90 mg
4
No
68%
Stockler et al (2004)
200 mg
3.1
Yes
26.7%
Israel et al (2010)
225 mg
-
No
68%
Non-opioid Analgesics:
NSAIDs
COX Selectivity
Antman E, DeMets D, Loscalzo. Cyclooxygenase Inhibition and Cardiovasular Risk. Circulation. 2005:112;759-70.
NSAID Chemical Class
•
•
•
•
•
•
•
•
•
Salicylic acid derivatives: ASA, diflunisal, salsalate
Propionic acids: naproxen, ibuprofen, ketoprofen
Indolacetic acids: indomethacin, sulindac, etodolac
Pyrrolacetic acid: ketorolac
Anthranilic acid: mefenamic acid
Phenylacetic acid: diclofenac
Enolic acids: piroxicam, meloxicam
Naphthylaklanone: nabumetone
COX-2 inhibitor: celecoxib
American Pain Society. (2008). Principles of analgesic use in the treatment of acute pain and cancer pain (6th ed.). Glenview, IL: American Pain Society.
NSAIDs and CV Risk
• Danish study 99,187 post-MI patients
Risk of Death Associated with NSAID use after MI
Year Post-MI
No. of Events
Hazard Ratio
1
1086
1.59 [1.49-1.69]
2
712
1.84 [1.69-1.70]
3
546
1.81 [1.66-1.99]
4
468
1.83 [0.66-2.01]
5
377
1.73 [1.56-1.93]
>5
963
1.63 [1.52-1.74]
Olsen AM et al. Curr Opin Cardiol. 2013;28:683-8.
Olsen AM et al. Circulation.2012;126:1955-63.
NSAID Risk Stratification
Risk Category
Therapeutic Recommendation
Low
Age < 65
No CV risk factors
No concurrent aspirin or anticoagulants
Traditional NSAID for shortest duration and
lowest dose
Intermediate
Age > 65
No history of complicated GI ulceration
Low CV risk
Concurrent ASA for primary prophylaxis
Traditional NSAID + cytoprotectant (PPI,
H2RA, misoprostol)
Once daily celecoxib + cytoprotectant
High
Elderly, frail, hypertensive, renal/liver
History of complicated GI ulceration
History of CV disease or on antiplatelet for
secondary prophylaxis
History of heart failure
Substitute with acetaminophen
Avoid chronic NSAID use if possible
Naproxen + cytoprotectant
Once daily celecoxib + cytoprotectant
Consider a topical
Crofford LJ. Use of NSAIDs in treating patients with arthritis. Arthritis Res Ther. 2013;15(Suppl3):S2.
NSAIDs- Issues Often
Overlooked
• Protein binding and drug-drug interactions
– Traditional NSAID 2 hours before ASA
•
•
•
•
Available topically
Available OTC (knowyourdose.org)
Combination with a steroid?
Combination with APAP?
Adjuvant Analgesics
NNT for Neuropathic Pain
Tricyclic Antidepressants
• Secondary amines: Nortriptyline or
desipramine
• Tertiary amines: Amitriptyline et al.
Sedation
Anticholinergic
Hypotension
Cardiac
effects
Weight gain
Seizure risk
Tertiary
+++
+++
+++
+++
++
++
Secondary
+/0
+
+
++
+
+
Selecting a First-line Drug for PN
• Glaucoma, orthostasis, cardiac issues, HTN,
suicidal ideation, weight gain concern: avoid TCAs
• Hepatic insufficiency: avoid duloxetine
• Peripheral edema: avoid pregabalin
• Cost concern: avoid duloxetine, pregabalin
• Erectile dysfunction: use venlafaxine
• Insomnia: sedating TCA
• Depression: SNRI, TCA
Titration
Medication
Starting Dose
Titration
Maximum Dose
Duration of
Adequate Trial
Nortriptyline
Desipramine
10 mg qHS
Increase by 10-15 mg
q3-7 days as tolerated
150 mg/day
6-8 weeks with at
least 2 weeks at
max tolerated
dose
Duloxetine DR
30 mg daily
Increase to 60 mg after
1 week
120 mg/day
4 weeks
Venlafaxine ER
37.5 mg daily
Increase to 75 mg after
1 week
225 mg/day
4-6 weeks
Gabapentin
100-300 mg TID
Increase by 100-300
mg/dose every 1-7
days as tolerated
3600 mg/day
(reduce for renal)
3-8 weeks for
titration with 2
weeks at max
tolerated dose
Pregabalin
50 mg TID or
75 mg BID
Increase to 300 mg/day
after 3-7 days then by
150 mg every 3-7 days
as tolerated
600 mg/day
(reduce for renal)
4 weeks
Lidocaine
pathch 5%
1-3 patches daily
for 12 hours
3 patches/day
3 weeks
Medications in Disguise
Medications in Disguise
Conclusions
1. Opioids as the adjuvant
2. Rational polypharmacy is the rule, not the
exception
3. Understanding mechanisms of action will
facilitate safe and effective polypharmacy
4. Give an appropriate trial and don’t forget to
titrate
QUESTIONS?
Lee H. Stringer, Pharm.D., BCPS, FASCP, CPE
406-238-5590
leehallstringer@paineducator.com