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

†

†

37

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

41

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.

46

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

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.

*

51

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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