Neuropathic Pain: New Strategies to Improve Clinical Outcome catjan2006... · Neuropathic Pain: New Strategies to Improve Clinical Outcome Chronic Pain: ... Neuropathic Pain Questionnaire

1NATIONAL INITIATIVE ON PAIN CONTROL™

Neuropathic Pain: New Strategies to Improve Clinical Outcome

Chronic Pain:New Strategies to Improve

Clinical Outcome

1

Mark S. Wallace, MD

Associate Professor, Clinical Anesthesiology

University of California, San Diego

Educational Objectives

• Select appropriate therapies based upon an understanding of the multiple pathophysiologies involved in chronic pain

• Describe the clinical assessments that will make it possible to optimize treatment for patients with neuropathic pain

• Discuss the latest approaches to reduce pain and improve patient quality of life

3

“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”

IASP Definition of Pain

4

Acute vs Chronic Pain

Characteristic Acute Pain Chronic Pain

Cause Generally known Often unknown

Duration of pain Short, Persists afterwell-characterized healing, ≥3 months

Treatment Underlying disease Underlying approach and pain disorder disease

5

Physical Functioning• Ability to perform

activities of daily living• Sleep disturbances

Social Consequences• Relationships with family

and friends• Intimacy/sexual activity• Social isolation

Effects of Chronic Pain on the Patient

Psychological Morbidity• Depression• Anxiety• Anger• Loss of self-esteem

Societal Consequences• Healthcare costs• Disability• Lost workdays

6

What Are the Goals of Clinical Assessment?

• Identify underlying causes of neuropathy• Identify comorbid conditions• Evaluate psychosocial factors• Evaluate functional status (activity levels) • Set goals • Develop a targeted treatment plan• Determine when to refer to specialist or multidisciplinary

team (pain clinic)• Achieve diagnosis of pain

23



Pain Specialist

Physical Therapist

Primary Care Physician Coordination of the Multidisciplinary Team

Psychiatrist

Neurologist

Social Worker

Speech Therapist

Physiatrist

Psychologist

Nurses

Neurosurgeon

Occupational Therapist

Pharmacist

Physician Assistant

Integrated Coordinated Interdisciplinary

31

Primary CarePhysician

Assessing the Patient Who Has Pain

• Onset and duration• Location/distribution• Quality• Intensity• Aggravating/relieving factors• Associated features or secondary signs/symptoms• Associated factors

– mood/emotional distress– functional activities

• Treatment response

25

Pain Assessment Scales

No Mild Moderate Severe Very Worstpain pain pain pain severe possible

pain pain

Verbal Pain Intensity Scale1

Nopain

Visual Analog Scale1

“Faces” Scale3

0 1 2 3 4 5

0–10 Numeric Pain Intensity Scale2

No Moderate Worstpain pain possible pain

0 1 2 3 4 5 6 7 8 9 10

1. Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. 1996:8-10.2. McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16.

3. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing 5th ed. 1997:1215-1216.

Worstpossible

pain

26

Neuropathic Pain Questionnaire Short Form

Quantitative and discriminative

Numbness

Tingling pain

Increased pain due to touch

I---------------------------------------------I0 100

none worst imaginable

sensitivity of 64.5% specificity of 78.6% total predictive accuracy of 73.0%

Backonja MM, Krause SJ. Clin J Pain. 2003;19:315-316.35

Activities Impaired by Increasing Pain Severity*

Cleeland CS, Ryan KM. Ann Acad Med Singapore. 1994;23:129-138.

>>>>>>>>> >>>>>>>>> >>> Worst Pain Rating >>> >>>>>>>>> >>>>>>>>>

Enjoy3

EnjoyWork

4

WorkEnjoy

ActiveMood

5

SleepActiveMoodWorkEnjoy

6

WalkSleepActiveMoodWorkEnjoy

7

RelateWalkSleepActiveMoodWorkEnjoy

8

11* Assessed in cancer pain patients

Clinical Assessment:Neurologic History

• Symptoms• Onset• Etiologic factors

– diabetes mellitus (undiagnosed)– alcohol– vitamin deficiencies (B12, thiamine, etc)– hereditary– neurotoxicity (environmental, iatrogenic)– trauma/structural lesions (herniated nucleus pulposus, carpal tunnel

syndrome)

28



Clinical Assessment:Psychosocial History

• Current psychiatric symptoms• History of addictive disease• Change in social function

– work– family and relationships– recreation

• Medical-legal status

29

Clinical Assessment:Neurologic Examination

• Sensory examination– helps confirm neuropathic pain and distribution

• Sensory elements– sensory deficits: eg, touch, pin, temperature, vibration– allodynia: light touch– hyperalgesia: single or multiple pinpricks

30

Clinical Assessment:Neurologic Examination (cont)

• Motor– muscle bulk/tone (atrophy/flaccidity)– muscle strength– coordination– gait

• Autonomic– limb temperature– sweating– hair and nail growth– skin color changes

31

Diagnostic Studies and Limitations

Studies• Blood studies• X-ray, CT, MRI• Electromyography (EMG)• Nerve conduction velocity

(NCV) • Quantitative sensory testing

(QST)• Epidermal skin biopsy

Limitations of EMG/NCV• Insensitive in acute injury• Normal result does not rule out

neuropathic pain• Cannot assess function of

small-fiber nerves involved in most neuropathic pain

Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. McGraw-Hill Companies; 2000.32

Functional Magnetic Resonance Imaging (fMRI) and the Neuropathic Pain Process

• What is fMRI?– rapid succession of MRI images shows changes

in brain chemical composition or fluid flow• example: hemoglobin shows up better than

deoxyhemoglobin– displays areas of increased blood flow

(neural activity)– determines areas activated by physical sensation– does not require radioactive isotope injections

• Recent fMRI data suggest:– midbrain reticular formation involvement in neuropathic pain– cortical activation during experimental allodynia– altering pain medication impacts neurophysiologic response to pain

intensity

Cohen MS et al. Trends Neurosci. 1994;17:268-277; Zambreanu L et al. J Pain. 2004;5(suppl 1):1;Maihofner C et al. Eur J Neurosci. 2004;19:3211-3218; Schweinhardt P et al. J Pain. 2004;5(suppl 1):39.43

Massachusetts General Hospital.

Mixed TypeCaused by a

combination of both primary injury and secondary effects

Nociceptive vs Neuropathic Pain

NociceptivePain

Caused by activity in neural pathways in

response to potentially tissue-damaging stimuli

Neuropathic Pain

Initiated or caused by primary lesion or dysfunction in the nervous system

Postoperativepain

Mechanicallow back pain

Sickle cellcrisis

ArthritisPostherpetic

neuralgia

Neuropathic low back pain

CRPS*

Sports/exerciseinjuries

*Complex regional pain syndrome.

Central post-stroke pain

Trigeminalneuralgia

Distalpolyneuropathy (eg, diabetic, HIV)

7



PAIN MECHANISMS

CRPS/ PHN/ Neuropathy

Chung/ Bennet/ Selzer

NEUROPATHIC

PostoperativeCapsaicin

FormalinFACILITATED

Thermal/ Mechanical Pain

HP/TF/PPACUTEHUMANANIMALMECHANISM

ACUTE PAIN

Peripheral Activation

VR1

External

Stimuli

Adapted from Woolf CJ, Salter MW. Science. 2000;288:1765-68.

•Heat

•Chemical

•Mechanical

Voltage gated sodium

channels

Action potentials

Ca2+ FACILITATED PAIN

Peripheral Modulation

VR1

BK recept

or

HEAT

External Stimulus

Sensitizing Stimulus

PGE2

Bradykinin

PKA

PKCε

EP recept

or SNS/PN3SNS/PN3TTXTTX--resistantresistant

sodium sodium channelchannel

Adapted from Woolf CJ, Salter MW. Science. 2000;288:1765-68.

Activation of Central Neurons

Dorsal Horn NeuronDorsal Horn Neuron

CC--fiber terminalfiber terminal

AMPA

NMDA

Ca++

GlutamateGlutamate

PKCPKC

P

P

(+)(+)

(-)

Woolf CJ, Salter MW. Science. 2000;288:1765-68.Schwartzman RJ, et al. Arch Neurol. 2001;58:1547-

50.

Substance P



Sensitization

Gottschalk A, Smith DS. Am Fam Physician. 2001;1979-84.

InjuryInjury

Pain

Inte

nsity

10

8

6

4

2

0

Stimulus Intensity

NormalPain

Response

Allodynia

Hyperalgesia

Hyperalgesia –heightened sense of pain to noxious stimuli

Allodynia – pain resulting from normally painless stimuli

Modulation of Central Neurons



AMPA

NMDA

Ca++

Substance P

GlutamateGlutamate GABAGlycine

PKCPKC

P

P

(+)(+)

(-)

Woolf CJ, Salter MW. Science. 2000;288:1765-68.Schwartzman RJ, et al. Arch Neurol. 2001;58:1547-50.Terman GW, Bonica JJ. In: Bonica’s Management of Pain.

2001:73-152.

COX-2–Specific InhibitorsClinical Profile

• At least as effective as traditional NSAIDs in– acute pain (surgical pain, dysmenorrhea)– chronic pain (OA, RA)

• Favorable safety profile vs traditional NSAIDs

Morrison et al. JADA. 2000;131:1729-37. Malstrom et al. Clin Ther. 1999;21:1653-63. Data on file, Pharmacia Corp. Emery et al. Lancet. 1999;354:2106-11. Day et al. Arch Intern Med.2000;160:1781-87. McKenna et al. Scand J Rheumatol. 2001;30:11-8. Chang et al. ClinTher. 2001;23:1446-55. Gimbel et al. Clin Ther. 2001;23:228-41. Bombardier et al. N Engl J Med. 2000;343:1520-28. Silverstein et al. JAMA. 2000;284:1247-55. Leese et al. J ClinPharmacol. 2000;40:124-32.

NEUROPATHIC PAIN

Neuropathic Pain: Issues and Challenges

• Common type of pain– 25% to 50% of all pain clinic visits

• Underassessment and undertreatment• Interpatient variability in response to treatment• Complex pathophysiology• Patient not believed

9

Nerve Injury Spontaneous Afferent ActivityMechanical sensitivity

Origin:NeuromaDorsal Root Ganglia

Mechanism:Na+ ChannelReceptors

Transmitters (amines)Cytokines (TNFa)Enzymes (trypsin)



Nerve Injury•Cross talk between large-small afferents•Cross talk between sympatheticand afferent fibers

•Activation of large myelinated fiberevokes activity in small afferent fiber (allodynia)•Activation of sympatheticefferent evokes activity in small afferents

Nerve Injury Sympathetic Sprouting in peripheralterminals and DRG

Nerve Injury Loss of inhibitory InterneuronsDecreased GABA and Glycine Tactile Allodynia



AMPA

NMDA

Ca++

Substance P

GlutamateGlutamate GABAGlycine

PKCPKC

P

P

(+)(+)

(-)

Woolf CJ, Salter MW. Science. 2000;288:1765-68.Schwartzman RJ, et al. Arch Neurol. 2001;58:1547-50.Terman GW, Bonica JJ. In: Bonica’s Management of Pain.

2001:73-152.

Nerve Injury Dorsal Horn Sprouting

After nerve injury, C-fiber terminals atrophy and A-fiber terminals sprout

into the superficial dorsal horn

Normal terminations of primary afferents in the dorsal horn

Adapted from Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-1964.

Nerve Injury Spinal Glutamate Release

•Increased spontaneous activity of primary afferent•Loss of inhibitory neurons•Activation of immediate early genes•Phosphorylation of channels and receptors

LONG TERM/PERSISTENT CHANGES IN FUNCTION

Nerve Injury Activation of non neuronal cells(astrocytes, spinal microglia)

•Increased spinal expression of COX, NOS, glutamatetransporters, proteinases

LONG TERM/PERSISTENT CHANGES IN FUNCTION



Multiple Pathophysiologies May BeInvolved in Neuropathic Pain

• More than one mechanism of action likely involved

• Neuropathic pain may result from abnormal peripheral nerve function and neural processing of impulses due to abnormal neuronal receptor and mediator activity

• Combination of medications may be needed to manage pain: topicals, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioids

• In the future, ability to determine the relationship between thepathophysiology and symptoms/signs may help target therapy

19

Estimated Prevalence ofNeuropathic Pain in the United States*

Painful diabetic neuropathy 600,000Postherpetic neuralgia 500,000Cancer-associated 200,000Spinal cord injury 120,000Causalgia and reflex

sympathetic dystrophy 100,000HIV-associated 100,0001

Multiple sclerosis 50,000Phantom pain 50,000Poststroke 30,000Trigeminal neuralgia (tic douloureux) 15,000Low back pain–associated 2,100,000

Total (excluding back pain) 1,765,000Total (including back pain) 3,865,000

Condition Number of Cases

Adapted from Bennett GJ. Hosp Pract. 1998;33:95-114.1. Schifitto G et al. Neurology. 2002;58:1764-1768.

*Based on population of 270 million.

16

Human Models for Neuropathic Pain

• Diabetic neuropathy (DN) and postherpetic neuralgia (PHN) are the most prevalent neuropathic pain disorders

• Majority of randomized controlled trials datais in PHN/DN

• PHN has been the most commonly used model for treating neuropathic pain in clinical trials

26

Herpes Zoster (Thoracic Dermatome)

27

Reactivation of Varicella Zoster Virus

From HopeFrom Hope--SimpsonSimpson. . Proc R Soc Med.Proc R Soc Med. 19651965;58:9;58:9--2020..

Percentage of 421 Herpes Zoster Patients With Pain After 1, 3, and 12 Months

0

10

20

30

40

50

60

0-49 50-59 60-69 70+

Pain after 1 month Pain after 3 monthsPain after 12 months

HelgasonHelgason et al. et al. BMJ.BMJ. 20002000;321:794;321:794--796796. .

Pain was characterized as mild to moderate.Pain was characterized as mild to moderate.

Age (Years)Age (Years)

Per

cent

of

Perc

ent o

f Pat

ient

sP

atie

nts



Proposed Postherpetic Neuralgia Subtypes

Adapted from Fields HL et al. Neurobiol Dis. 1998;5:209-227.

Irritable Deafferentation DeafferentationNociceptor With Allodynia Without Allodynia

Thermal +/- +++ +++sensory deficit

Allodynia +++ +++ None

Local anesthetic Marked relief Absent or minimal Absent or minimalskin infiltration

Mechanism Functionally abnormal Deafferentation Deafferentationnociceptors and with abnormal with central

central sensitization central connections hyperactivity

29

“Undertreatment of acute and chronic pain persists despite decades of efforts to provide clinicians with information about analgesics.”

Treatment of Neuropathic Pain

41

Neuropathic Pain:Approach to Treatment

Reduce psychological

distress

Improve physical

functioning

Improve overall quality of life

Adapted from Turk DC. Clin J Pain. 2000;16:279-280.

Reduce pain

Diagnosis

Treat underlying condition/symptomatic treatment

Prevention (if applicable)

42

Comprehensive Pain Management Plan Components

• Biological Approaches– pharmacologic and/or

nonpharmacologictherapies

• Psychological Intervention– mood disturbances– coping skills– sleep disturbance

• Social/Rehabilitative Issues– family/social relations– work issues– physical rehabilitation

• physical/occupational therapy

• home exercise program

46

Pain Treatment ContinuumLeast

invasiveMost

invasive

Psychological/physical approaches

Topical medications

*Consider referral if previous treatments were unsuccessful.

Systemic medications*

Interventional techniques*

Continuum not related to efficacy

46

Nonpharmacologic Options

• Biofeedback • Relaxation therapy• Physical and occupational therapy• Cognitive/behavioral strategies

– meditation; guided imagery• Acupuncture• Transcutaneous electrical nerve stimulation

47



Pharmacotherapeutic Considerations:Setting Priorities

• Efficacy– clinical trial data– clinical experience

• Safety/tolerability• Ease of use

– dosing– titration– drug-drug interactions– patient acceptability

• Cost

48

FDA-Approved Treatments for Neuropathic Pain

• Pregabalin– Peripheral diabetic neuropathy– Postherpetic neuralgia

• Duloxetine– peripheral diabetic neuropathy

• Lidocaine Patch 5%– postherpetic neuralgia

• Gabapentin– postherpetic neuralgia

• Carbamazepine– trigeminal neuralgia

53

SPINALCORD

BRAIN

Pharmacotherapeutics and the Nervous System

CN

S

Descending Modulation

PeripheralSensitization

Central Sensitization

PNS

Local AnestheticsTopical AnalgesicsAnticonvulsantsTricyclic AntidepressantsOpioids

AnticonvulsantsOpioidsNMDA-Receptor AntagonistsTricyclic/SNRI Antidepressants

AnticonvulsantsOpioidsTricyclic/SNRI Antidepressants

52

Lidocaine Patch 5%• Lidocaine 5% in pliable patch• Up to 3 patches applied once daily directly over

painful site– 12 h on, 12 h off (FDA-approved label)– recently published data indicate 4 patches (18–24 h) safe

• Efficacy demonstrated in 3 randomized controlled trials on postherpetic neuralgia

• Drug interactions and systemic side effects unlikely– most common side effect: application-site sensitivity

• Clinically insignificant serum lidocaine levels• Mechanical barrier decreases allodynia

57

*

Efficacy of Lidocaine Patch 5%in Postherpetic Neuralgia

Observational only

Vehicle

Active

Postapplication time (h)0.5 2 4 6 9 12

-15

-10

-5

0

5

* **

N=35.*P=0.0001 to P=0.021 active vs observational only.†P=0.016 and P=0.041 vehicle vs observational only.‡P<0.001 to P=0.038 active vs vehicle from 4–12 h.

††

* * *

‡ ‡‡

‡

Adapted from Rowbotham MC et al. Pain. 1996;65:39-44.

Cha

nge

in V

AS

(mm

)

58

Lidocaine Patch 5% Works Through Sodium Channels

*Galer et al. Pain. 1999;80:533–538.59

% o

f pat

ient

s

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Days to exit

0

20

40

60

80Therapy for PHN *

Lidocaine Patch 5%

Placebo



Gabapentin in Neuropathic Pain Disorders

• FDA approved for postherpetic neuralgia• Anticonvulsant: uncertain mechanism• 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.

64

Gabapentin in the Treatment of Postherpetic Neuralgia

12.1 7.8

59.5

8.6

43.2

17.4

2.8

22.9

0

20

40

60

80

100

Moderately ormuch

improved

Minimallyimproved

No change Worse

% o

f pat

ient

s

Adapted from Rowbotham M et al. JAMA. 1998;280:1837-1842.

Placebo (n=116)Gabapentin (n=109)

P<0.001

65

0

2

4

6

8

10

Screening 1 2 3 4 5 6 7 8

Week

Mea

n pa

in s

core

*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

†

†‡†

‡ ‡ ‡

67

Pregabalin Overview• FDA-approved for treatment of 2 of the most common

neuropathic pain conditions• Newly elucidated mechanism of action

− Modulates voltage-gated Ca2+ channels via α2-δ subunit• Robust efficacy confirmed in 6 positive trials

− Reduction in pain within 1 week in some patients− High responder rates

• Favorable safety and tolerability profile− Most common adverse events: dizziness and somnolence

• Linear pharmacokinetics, high bioavailability− Predictable, consistent absorption

α2δ

Pregabalin Effect on Mean Weekly Pain Scores in Painful DPN

**Least squares means calculated from the model.Least squares means calculated from the model.††PP≤≤.001.001

Lesser et al. Lesser et al. NeurologyNeurology. 2004. 2004;63:2104;63:2104--21102110. .

†

†

†

†

†

†

†

†

†

†

†

†

0123456789

10

0 1 2 3 4 5 End Point(LOCF)WeeksWeeks

Mea

n Pa

in S

core

*M

ean

Pai

n S

core

*

Placebo (n=97)Pregabalin 75 mg/d (n=77)Pregabalin 300 mg/d (n=81)Pregabalin 600 mg/d (n=82)

The most common adverse events occurring during all controlled cThe most common adverse events occurring during all controlled clinical trials for patients taking pregabalin linical trials for patients taking pregabalin vs those taking a placebo were dizziness, somnolence, dry mouth,vs those taking a placebo were dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attenthinking abnormal (primarily difficulty with concentration/attention).tion).

Pregabalin Effect on Mean Weekly Pain Scores in PHN

**Least squares means calculated from the model. Least squares means calculated from the model. ††PP≤≤.01. .01. ‡‡Dose adjusted to 300 mg/d in cases of renal insufficiency.Dose adjusted to 300 mg/d in cases of renal insufficiency.

Van Van SeventerSeventer et al. Presented at: et al. Presented at: 23rd Annual Scientific Meeting of the American Pain Society; 20023rd Annual Scientific Meeting of the American Pain Society; 20044..

Mea

n P

ain

Sco

re*

Mea

n Pa

in S

core

*

†

††

†

††

†

††

†

††

†

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†

††

†

††

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†

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†

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†

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†

††

†

††

†

††

WeeksWeeks

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 EndPoint

(LOCF)

Placebo (n=93)Pregabalin 150 mg/d (n=87)Pregabalin 300 mg/d (n=98)Pregabalin 600 mg/d‡ (n=90)

Patients taking pregabalin should be counseled that dizziness anPatients taking pregabalin should be counseled that dizziness and somnolence may impair their ability d somnolence may impair their ability to perform potentially hazardous tasks such as driving or operatto perform potentially hazardous tasks such as driving or operating complex machinery until they have ing complex machinery until they have sufficient experience with pregabalin to determine its effect onsufficient experience with pregabalin to determine its effect on cognitive and motor function.cognitive and motor function.



Painful DPN and PHN Treatment-Refractory Study: Distribution of Pain Severity at Baseline and 15 Months

None/MildModerateSevere

Per

cent

of

Per

cent

of P

atie

nts

Patie

nts

BaselineBaseline 15 Months15 Months

DD’’UrsoUrso De Cruz et al. Presented at: American Diabetes Association 64thDe Cruz et al. Presented at: American Diabetes Association 64th Scientific Sessions.Scientific Sessions.June 10June 10--14, 2005.14, 2005.

No/Mild pain: 0No/Mild pain: 0--39; moderate pain: 4039; moderate pain: 40--69; severe pain: 69; severe pain: ≥≥70 on Short Form70 on Short Form--McGill Pain Questionnaire McGill Pain Questionnaire pain visual analog scale pain visual analog scale 1515--month analysis (LOCF). month analysis (LOCF).

0

1020

30

40

50

60

70

80

90

100

Effective at 1800 mg/d• No additional benefit at higher doses

Effective at 150 mg/d• Dose range from 150 mg/d to 600 mg/d*

Dose potency for PHN

9 or more days • Titrate to effective dose of 1800 mg/d

1 day • Effective starting dose of 150 mg/d

Time to effective dose (PHN)

TIDBID or TIDDosing (PHN)

60% 900 mg47% 1200 mg34% 2400 mg33% 3600 mg

≥90% all dosesOral bioavailability

Nonlinear • Plasma concentration increases

disproportionately to dose

Linear • Plasma concentration is dose

proportionate

Pharmacokinetic profile

α2-δ ligand• Selectively binds to the α2-δ site

in CNS tissues

α2-δ ligand• Selectively binds to the α2-δ site

in CNS tissues

Mechanism of action

Postherpetic neuralgiaNeuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia

FDA-approved pain indication

GabapentinPregabalin

Pregabalin and Gabapentin Pharmacology Facts

CO2HNH2

*Some patients with PHN may benefit from up to 600 mg/d given af*Some patients with PHN may benefit from up to 600 mg/d given after 2 to 4 weeks of treatment with 300 mg/d. ter 2 to 4 weeks of treatment with 300 mg/d. Adverse events may increase with dose. CNS = central nervous sysAdverse events may increase with dose. CNS = central nervous system.tem.

CH2CO2HCH2NH2

LyricaLyrica®® (pregabalin) Capsules(pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; NeurontinCV [package insert]. New York, NY: Pfizer Inc; 2005; Neurontin®®

(gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.(gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.

α2δα2δ α2δ

α2δ

Pregabalin: Predictable Response Versus Gabapentin

High BioavailabilityHigh BioavailabilityHigh BioavailabilityLinear PK ProfileLinear PK ProfileLinear PK Profile

Pregabalin Gabapentin

All doses

≥90%

900 mg, 60%

1200 mg, 47%

2400 mg, 34%

3600 mg, 33%

1800 mg Recommended

dose

LyricaLyrica®® (pregabalin) Capsules CV [package(pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005insert]. New York, NY: Pfizer Inc; 2005; Neurontin; Neurontin®® (gabapentin) (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004; [package insert]. New York, NY: Pfizer Inc; 2004; WescheWesche, , BockbraderBockbrader. . Presented at: 24th Annual Scientific Presented at: 24th Annual Scientific Meeting of the American Pain Society; 2005.Meeting of the American Pain Society; 2005.

Dose (mg/d)Dose (mg/d)

0 600 1200 1800 2400 3000 3600 4200 48000

2

4

6

8

10

12

14

16

18

PregabalinGabapentinS

tead

y S

tate

CS

tead

y S

tate

Cm

axm

ax(( µµ

g/m

L)g/

mL)

Pregabalin: Drug Abuse and Dependence

Yes<IVSchedule VYes<IIISchedule IVYes<I and IISchedule IIIYesHighSchedule IINoHigh Schedule I

Medical UseAbuse Potential

• Schedule V controlled substance− Examples of other schedule V drugs include Robitussin A-C®

and Lomotil®− Examples of schedule IV drugs include Ambien®

21 USC 21 USC §§812. Available at: 812. Available at: http://straylight.law.cornell.edu/uscode. Accessed June 8http://straylight.law.cornell.edu/uscode. Accessed June 8, 2005;, 2005; United States United States Department of Justice. Available at: Department of Justice. Available at: http://www.deadiversion.usdoj.govhttp://www.deadiversion.usdoj.gov. Accessed June 23, 2005.. Accessed June 23, 2005.Robitussin ARobitussin A--C is a registered trademark of Wyeth. Ambien is a registered traC is a registered trademark of Wyeth. Ambien is a registered trademark of demark of SanofiSanofi--Aventis.Aventis.

• Studied in an at-risk population− Recreational sedative/hypnotic “nondependent” users (n=15)− Subjective ratings: “good drug effect,” “high,” “liking”− Pregabalin (450 mg single dose) received these ratings

to a degree similar to diazepam (30 mg single dose) • Reports of euphoria

• Adverse events following abrupt/rapid discontinuation

Selected Data Considered by FDA and DEA for Pregabalin Schedule V Designation

Percent of Patients

0.30.8Epilepsy0.00.9PHN0.01.8Painful DPN0.53.7All pregabalin

PlaceboPregabalin

Percent of Patients

1.01.4Diarrhea1.11.8Nausea1.52.1Headache0.72.4Insomnia

PlaceboPregabalin

LyricaLyrica®® (pregabalin) Capsules CV [package(pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; insert]. New York, NY: Pfizer Inc; 2005; Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY.

Antidepressants in Neuropathic Pain Disorders*

• Multiple mechanisms of action• Randomized controlled trials and meta-analyses

demonstrate benefit of tricyclic antidepressants (especially amitriptyline, nortriptyline, desipramine) for postherpetic neuralgia and diabetic neuropathy

• Selective serotonin reuptake inhibitors (SSRIs): inconsistent in diabetic neuropathy

• Onset of analgesia variable– analgesic effects independent of antidepressant activity

• Improvements in insomnia, anxiety, depression• Desipramine and nortriptyline have fewer adverse effects


68



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 AEs

69

AEs = adverse effects.

Nortriptyline vs Amitriptyline

• No differences seen in efficacy– relief of steady, brief, or skin pain– mood, disability, or satisfaction– patient preference for either drug

• Randomized, double-blind crossover trial of safety and efficacy of nortriptyline vs amitriptyline in postherpetic neuralgia*

• Intolerable side effects more frequent with amitriptyline– not recommended in patients ≥ 651

• Use drug with fewer side effects


70 1. AGS Panel on Persistent Pain in Older Persons. JAGS. 2002;50:S205-S224.

Duloxetine 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

Mea

n C

hang

e in

24-

Hou

r Ave

rage

Pa

in S

ever

ity S

core

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):48.

*

74

Venlafaxine#: Efficacy in Diabetic Peripheral Neuropathy

*P < .01 venlafaxine extended release (ER) 150-225 mg vs placebo.†P < .05 venlafaxine ER 150-225 mg vs venlafaxine ER 75 mg.Adapted with permission from Rowbotham MC et al. Pain. 2004:110;697-706.

0

10

20

30

40

50

60

70

1 2 3 4 5 6

Placebo (n = 81)Venlafaxine 75 mg (n = 82)Venlafaxine 150-225 mg (n = 82)

Treatment Week

*†

Percent of Patients With ≥50% Reduction in Pain IntensityR

espo

nse

Rat

e (%

)

# not approved by the FDA for this use

Principles of Opioid Therapy for Neuropathic Pain

• Opioids should be titrated for therapeutic efficacy versus AEs

• Fixed-dose regimens generally preferred over prnregimens

• Document treatment plan and outcomes• Consider use of opioid written care agreement• Opioids can be effective in neuropathic pain• Most opioid AEs controlled with appropriate specific

management (eg, prophylactic bowel regimen, use of stimulants)

• Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction

72

Distinguishing Dependence, Tolerance, and Addiction

• Physical dependence: withdrawal syndrome arises if drug discontinued, dose substantially reduced, or antagonist administered

• Tolerance: greater amount of drug needed to maintain therapeutic effect, or loss of effect over time

• Pseudoaddiction: behavior suggestive of addiction; caused by undertreatment of pain

• Addiction (psychological dependence): psychiatric disorder characterized by continued compulsive use of substance despite harm

73



Opioid Efficacy Studies in Neuropathic Pain Disorders

• Nonmalignant neuropathic pain disorders– IV fentanyl

• Postherpetic neuralgia– IV morphine– controlled-release oxycodone

• Phantom limb pain– oral morphine

• Diabetic neuropathy– tramadol– oxycodone

74 IV = intravenous.

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