problem solving in persistent pain syndromes: a case-based approach copyright © 2005 thomson...
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Problem Solving in Persistent Pain Syndromes:
a case-based approach
Copyright © 2005 Thomson Professional Postgraduate Services®. All rights reserved.
Chronic Pain Affects All Aspects of Patient’s Life
Social Consequences• Marital/family
relations• Intimacy/sexual activity• Social isolation
Socioeconomic Consequences• Healthcare costs• Disability• Lost workdays
Quality of Life• Physical functioning• Ability to perform
activities of daily living• Work• Recreation
Psychological Morbidity• Depression• Anxiety, anger• Sleep disturbances• Loss of self-esteem
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Mixed Type
Nociceptive vs Neuropathic Pain
NociceptivePain
Neuropathic Pain
Postoperativepain
Mechanicallow back pain
Arthritis
Sports/exerciseinjuries
Postherpeticneuralgia
Neuropathic low back pain
Trigeminalneuralgia
Polyneuropathy (diabetic, HIV)
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Pain, Neural Excitation (“Wind-up”), and the HPA Axis
• Neuropathic pain induces changes in peripheral and central nervous system
• In the dorsal horn this results in dramatic increase in firing of neurons– from 1 every 3 seconds – to up to 30/second
• In the brain, hypothalamic activation by increased nociceptive input causes activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in discharge of peripheral cortisol and activation of vasoactive immune system compounds
Blackburn-Munro G, et al. J Neuroendocrinology. 2001;13:1009-1023.17
Wind-up Pain: Mood Effects
• Activation of serotonergic and noradrenergic centers in brain stem
• Stimulation and dysfunction of limbic system, prefrontal cortex, hypothalamus, dorsal horn of spinal cord
• Depression, anxiety, panic, vegetative signs of depression, suicidal thoughts, and chronic pain
Blackburn-Munro G, et al. J Neuroendocrinology. 2001;13:1009-1023.
Stahl SM. J Clin Psychiatry. 2002;63:382-383.18
DorsalHorn
BRAIN
Pharmacologic Agents Affect Pain Differently
Descending Modulation
PeripheralSensitization
Central Sensitization
PNS
Local Anesthetics
Topical Analgesics
Anticonvulsants
Tricyclic Antidepressants
Opioids
Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Tricyclic/SNRI Antidepressants
Anticonvulsants
Opioids
Tricyclic/SNRI Antidepressants
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SPINALCORDCNS
Mechanisms of Action: Analgesic Agents
• Anticonvulsants– sodium-channel blockade (oxcarbazepine)– calcium-channel blockade (gabapentin)
• Antidepressants– inhibit reuptake of norepinephrine and serotonin into presynaptic
neurons (duloxetine)• Opioids
– block neurotransmitter-release by nociceptive fibers, thus decreasing transmission of pain-producing signals (oxycodone)
• Topical Analgesics– sodium-channel blockade (lidocaine patch 5%)– vanilloid receptor (capsaicin)
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FDA-Approved Treatments for Neuropathic Pain
• Carbamazepine– trigeminal neuralgia
• Duloxetine– peripheral diabetic neuropathy
• Gabapentin– postherpetic neuralgia
• Lidocaine Patch 5%– postherpetic neuralgia
• Pregabalin– peripheral diabetic neuropathy– postherpetic neuralgia
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Antidepressants in Neuropathic Pain Disorders*
• Multiple proposed sites and mechanisms of action – central and peripheral nervous system
– anticholinergic, serotonergic, noradrenergic
• RCTs show benefit (especially amitriptyline, nortriptyline, desipramine)
• Improvements in insomnia, anxiety, depression
*Not approved by FDA for this use.
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Amitryptyline – Sites of Action
Descending Modulation
PeripheralSensitization
Amitriptyline(anticholinergic,
Inhibits 5-HT and NE
reuptake)
Tricyclic antidepressants are thought to affect pain transmission primarily in the CNS by inhibiting the reuptake of norepinephrine and serotonin, both of which influence descending pain pathways.
Maizels M, McCarberg B. Am Fam Phys. 2005;71:483-490.
Na channel
blocker
DorsalHorn
BRAIN
PNS
SPINALCORD
CNS
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Tricyclic Antidepressants: Adverse Effects
• Commonly reported AEs (generally anticholinergic):– blurred vision– cognitive changes– constipation– dry mouth– orthostatic hypotension– sedation– sexual dysfunction– tachycardia– urinary retention
• Desipramine
• Nortriptyline
• Imipramine
• Doxepin
• Amitriptyline
FewestAEs
Most AEsAEs = adverse effects.
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Tricyclic Antidepressantsfor Neuropathic Pain Disorders*
• Consider preprescription cardiac evaluation• Intolerable side effects more frequent with amitriptyline
– not recommended in patients 601
• Use drug with fewer side effects • Can split dose to reduce side effects• Start at 10 to 25 mg at bedtime
– increase every week as tolerated to a target dose of 25 to 150 mg– expect individual variability in treatment response
• Expect partial effect– use multiple agents (other classes and mechanism)
• Not being used simultaneously to treat depression
*Not approved by FDA for this use.1. AGS Panel on Persistent Pain in Older Persons. JAGS. 2002;50:S205-S224.31
Topical Agents Act Locally
• Aspirin Preparations– eg, aspirin in chloroform or ethyl ether
• Capsaicin– extracted from chili peppers
• EMLA (eutectic mixture of local anesthetics)• Lidocaine patch 5%
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Lidocaine Patch 5% Works Locally Through Sodium Channels
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Descending Modulation
DorsalHorn
BRAIN
PNS
SPINALCORD
CNS
CentralSensitization
PeripheralSensitization
Lidocaine Patch 5%
Na channel
blocker
Lidocaine Patch 5% for Diabetic Neuropathy*
Barbano RL et al. Arch Neurol. 2004;61:914-918.
BPI=Brief Pain Inventory.
*Not approved by FDA for this use.†P0.001 at Week 3 versus baseline.
BPI: Daily Pain Diary Ratings and Pain Relief Scores
6.3
3.6
0123456789
10
Baseline Week 3
Me
an
da
ily p
ain
rat
ing
Me
an
pa
in r
elie
f s
core
(%
)
28.6
63.4
0102030405060708090
100
Baseline Week 3
N=53
†
†
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Gabapentin Works Centrally Through Calcium Channels
Anticonvulsants act at several sites that may be relevant to pain, but the precise mechanism of analgesic effect remains unclear. They are thought to limit neuronal excitation and enhance inhibition at various ion channels, especially the calcium channels.
Maizels M, McCarberg B. Am Fam Phys. 2005;71:483-490.40
DorsalHorn
BRAIN
PNS
SPINALCORD
CNS
PeripheralSensitization
Gabapentin
Descending Modulation
Gabapentin
Central Sensitization
Lidocaine Patch 5% With Gabapentin
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DorsalHorn
BRAIN
PNS
SPINALCORD
CNSDescending Modulation
Central Sensitization
PeripheralSensitization
Lidocaine Patch 5%
Gabapentin
Gabapentin
Gabapentin in Neuropathic Pain Disorders*
• FDA approved for PHN
• Anticonvulsant: alpha2delta calcium channel antagonist
• Limited intestinal absorption• Usually well tolerated; serious adverse effects rare
– dizziness and sedation can occur
• No significant drug interactions• Peak time: 2 to 3 h; elimination half-life: 5 to 7 h• Usual dosage range for neuropathic pain up to
3,600 mg/d (tid–qid)*
*Not approved by FDA for this use.
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0
2
4
6
8
10
Screening 1 2 3 4 5 6 7 8
Week
Me
an
pa
in s
co
re
*Not approved by FDA for this use.† P<0.01. ‡ P<0.05.
Gabapentin in the Treatment of Painful Diabetic Neuropathy*
PlaceboGabapentin
Adapted from Backonja M et al. JAMA. 1998;280:1831-1836.
N=165
†
†
‡†
‡ ‡ ‡
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Anticonvulsant Drugs for Neuropathic Pain Disorders
• Postherpetic neuralgia– gabapentin*– pregabalin*
• Diabetic neuropathy– carbamazepine– gabapentin– lamotrigine– phenytoin– pregabalin*
• HIV-associated neuropathy – lamotrigine
• Trigeminal neuralgia– carbamazepine*– lamotrigine– oxcarbazepine
• Central poststroke pain– lamotrigine
*Approved by FDA for this use.HIV = human immunodeficiency virus.
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Serotonin and Norepinephrine Reuptake Inhibitors
Randomized clinical trials show benefit from dual action neurotransmitter reuptake inhibitors• Duloxetine
– FDA approved for peripheral diabetic neuropathy
• Venlafaxine
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DorsalHorn
BRAIN
PNS
SPINALCORD
CNS
Duloxetine Works Centrally in Descending Pathways and Spinal Cord
Descending Modulation
PeripheralSensitization
Central Sensitization
Duloxetine is a dual reuptake inhibitor that enhances the levels of the neurotransmitters serotonin and norepinephrine.
Duloxetine
Duloxetine
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NE, 5-HT
Duloxetine Is Effective for Diabetic Neuropathic Pain
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
1 2 3 4 5 6 7 8 9 10 11 120
Week
Me
an
ch
an
ge
in 2
4-h
ou
r av
era
ge
p
ain
se
ve
rity
sco
re
Placebo (n=108)Duloxetine 60 mg qd (n=114)Duloxetine 60 mg bid (n=112)
** *
* * * * * * * *
** * * * * * * * * *
*
*P<0.001 vs placebo.
Wernicke J et al. J Pain. 2004;5(suppl 1):S48.
*
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Duloxetine
• Approved 9-7-2004 for management of pain association with diabetic neuropathy
• Once-daily dosing available in 20, 30, and 60 mg strengths
• Contraindicated in patients with uncontrolled narrow-angle glaucoma and patients taking monoamine oxidase inhibitors (MAOIs)
• Common sides effects include nausea, diarrhea, constipation, dizziness, drowsiness, anxiety, nervousness, insomnia
Short- and Long-acting Opioids
• Morphine sulfate
• Codeine
• Hydrocodone
• Oxycodone
• Hydromorphone
• Oxymorphone
• Fentanyl
• Methadone • Sustained-release
morphine • Sustained-release
oxycodone• Transdermal fentanyl• Levorphanol
Short-acting Opioids Long-acting Opioids
Opioid Efficacy Studies in Neuropathic Pain Disorders
• Diabetic neuropathy– tramadol– oxycodone
• Nonmalignant neuropathic pain disorders– IV fentanyl
• Postherpetic neuralgia– IV morphine– controlled-release oxycodone
• Phantom limb pain– oral morphine
IV = intravenous.55
0
10
20
30
40
50
60
70
80
90
Mean daily pain Steady pain Brief pain Skin pain
Placebo (benztropine 0.25 mg)
CR oxycodone (10 mg)
CR Oxycodonefor Diabetic Neuropathy*
†† †
†
*Not approved by FDA for this use.†P=0.0001.
VA
S (
mm
)
Adapted from Watson CP et al. Pain. 2003;105:71-78.
N=36
56
Efficacy of Tramadol in Painful Polyneuropathy
Adapted from Sindrup SH et al. Pain. 1999;83:85-90.
Placebo
Me
dia
n r
ati
ng
(0–1
0 p
oin
t sc
ale
)
0
2
4
6
8
10
Pain Paresthesia Touch-evoked pain
6
4
6
4
5
3
Tramadol
P=0.001 P=0.001
P<0.001
N=45
57
Summary
• Customize therapy due to variance in response, individual clinical/social circumstances, and toxicity
• Rational polypharmacy – mechanisms, drug synergy, additive effects, or complementary effects
• Consider consultation for complex cases or patients who are refractory to first- or second-line therapies
• Never lose focus on managing the whole patient
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