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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
Quality of Life
• Physical functioning
• Ability to perform
activities of daily living
• Work
• Recreation
Social Consequences
• Marital/family
relations
• Intimacy/sexual
activity
• Social isolation
6
Psychological Morbidity
• Depression
• Anxiety, anger
• Sleep disturbances
• Loss of self-esteem
Socioeconomic
Consequences
• Healthcare costs
• Disability
• Lost workdays
Nociceptive vs Neuropathic Pain
Nociceptive
Mixed Type
Pain
Postoperative
pain
Mechanical
low back pain
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Postherpetic
neuralgia
Arthritis
Sports/exercise
injuries
Neuropathic
Pain
Trigeminal
neuralgia
Neuropathic
low back pain
Polyneuropathy
(diabetic, HIV)
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 hypothalamicpituitary-adrenal (HPA) axis, resulting in discharge of
peripheral cortisol and activation of vasoactive immune
system compounds
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Blackburn-Munro G, et al. J Neuroendocrinology. 2001;13:1009-1023.
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.
18
Stahl SM. J Clin Psychiatry. 2002;63:382-383.
Pharmacologic Agents
Affect Pain Differently
BRAIN
CNS
SPINAL
CORD
Descending Modulation
Anticonvulsants
Opioids
Tricyclic/SNRI Antidepressants
Central Sensitization
PNS
Peripheral
Sensitization
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Dorsal
Horn
Local Anesthetics
Topical Analgesics
Anticonvulsants
Tricyclic Antidepressants
Opioids
Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Tricyclic/SNRI Antidepressants
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)
21
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
25
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
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.
PNS
Na channel
blocker
29
BRAIN
Descending Modulation
CNS
SPINAL
CORD
Dorsal
Horn
Amitriptyline
(anticholinergic,
Inhibits 5-HT and NE
reuptake)
Peripheral
Sensitization
Maizels M, McCarberg B. Am Fam Phys. 2005;71:483-490.
Tricyclic Antidepressants:
Adverse Effects
• Commonly reported AEs
(generally anticholinergic):
– blurred vision
– cognitive changes
– constipation
– dry mouth
– orthostatic hypotension
– sedation
– sexual dysfunction
– tachycardia
– urinary retention
AEs = adverse effects.
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Fewest
AEs
• Desipramine
• Nortriptyline
• Imipramine
• Doxepin
Most
AEs
• Amitriptyline
Tricyclic Antidepressants
for 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.
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1. AGS Panel on Persistent Pain in Older Persons. JAGS. 2002;50:S205-S224.
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%
34
Lidocaine Patch 5% Works Locally
Through Sodium Channels
BRAIN
Descending
Modulation
CNS
PNS
Na
channel
blocker
36
SPINAL
CORD
Dorsal
Horn
Peripheral
Sensitization
Lidocaine Patch 5%
Central
Sensitization
Lidocaine Patch 5% for
Diabetic Neuropathy*
10
9
8
7
6
5
4
3
2
1
0
N=53
6.3
†
3.6
Baseline
Week 3
BPI=Brief Pain Inventory.
*Not approved by FDA for this use.
†
37 P0.001 at Week 3 versus baseline.
Mean pain relief score (%)
Mean daily pain rating
BPI: Daily Pain Diary Ratings and Pain Relief Scores
100
90
80
70
60
50
40
30
20
10
0
63.4
†
28.6
Baseline
Week 3
Barbano RL et al. Arch Neurol. 2004;61:914-918.
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 CNS
enhance inhibition at various
ion channels, especially the
calcium channels.
PNS
BRAIN
SPINAL
CORD
Dorsal
Horn
Gabapentin
Descending
Modulation
Central Sensitization
Gabapentin
Peripheral
Sensitization
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Maizels M, McCarberg B. Am Fam Phys. 2005;71:483-490.
Lidocaine Patch 5%
With Gabapentin
BRAIN
CNS
PNS
SPINAL
CORD
Dorsal
Horn
Peripheral
Sensitization
Lidocaine Patch 5%
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Gabapentin
Descending
Modulation
Central Sensitization
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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Gabapentin in the Treatment
of Painful Diabetic Neuropathy*
Mean pain score
10
Placebo
Gabapentin
8
N=165
6
4
†
†
‡
†
‡
‡
‡
4
5
6
7
8
2
0
Screening 1
2
3
*Not approved by FDA for this use.
Week
† P<0.01.
‡ P<0.05.
Adapted from Backonja M et al. JAMA. 1998;280:1831-1836.
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Anticonvulsant Drugs for
Neuropathic Pain Disorders
• Postherpetic neuralgia
– gabapentin*
– pregabalin*
• Diabetic neuropathy
–
–
–
–
–
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carbamazepine
gabapentin
lamotrigine
phenytoin
pregabalin*
*Approved by FDA for this use.
HIV = human immunodeficiency virus.
• HIV-associated neuropathy
– lamotrigine
• Trigeminal neuralgia
– carbamazepine*
– lamotrigine
– oxcarbazepine
• Central poststroke pain
– lamotrigine
Serotonin and Norepinephrine
Reuptake Inhibitors
Randomized clinical trials show benefit from dual
action neurotransmitter reuptake inhibitors
• Duloxetine
– FDA approved for peripheral diabetic neuropathy
• Venlafaxine
49
Duloxetine Works Centrally in
Descending Pathways and Spinal Cord
Duloxetine is a dual
reuptake inhibitor
that enhances the
levels of the
neurotransmitters
serotonin and
norepinephrine.
PNS
BRAIN
CNS
SPINAL
CORD
Duloxetine
Central Sensitization
Dorsal
Horn
NE, 5-HT
Peripheral
Sensitization
50
Descending Modulation
Duloxetine
Mean change in 24-hour average
pain severity score
Duloxetine Is Effective for Diabetic
Neuropathic Pain
Placebo (n=108)
Duloxetine 60 mg qd (n=114)
Duloxetine 60 mg bid (n=112)
0
-0.5
-1
*
-1.5
*
-2
*
-2.5
*
*
-3
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
5
6
7
8
9
10
11
12
*
-3.5
0
*P<0.001 vs placebo.
51
*
1
2
3
4
Week
Wernicke J et al. J Pain. 2004;5(suppl 1):S48.
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
Short-acting Opioids
•
•
•
•
•
•
•
Morphine sulfate
Codeine
Hydrocodone
Oxycodone
Hydromorphone
Oxymorphone
Fentanyl
Long-acting Opioids
• Methadone
• Sustained-release
morphine
• Sustained-release
oxycodone
• Transdermal fentanyl
• Levorphanol
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
CR Oxycodone
for Diabetic Neuropathy*
Placebo (benztropine 0.25 mg)
CR oxycodone (10 mg)
N=36
90
80
VAS (mm)
70
60
50
†
†
†
†
40
30
20
10
0
56
Mean daily pain
Steady pain
Brief pain
Skin pain
*Not approved by FDA for this use.
†P=0.0001.
Adapted from Watson CP et al. Pain. 2003;105:71-78.
Efficacy of Tramadol
in Painful Polyneuropathy
Placebo
Tramadol
10
N=45
8
6
6
6
4
P=0.001
P=0.001
4
4
5
P<0.001
3
2
0
Pain
57
Paresthesia
Touch-evoked pain
Adapted from Sindrup SH et al. Pain. 1999;83:85-90.
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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