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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
2NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
3NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
4NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
5NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
Dorsal Horn NeuronDorsal Horn Neuron
CC--fiber terminalfiber terminal
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)
6NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
Dorsal Horn NeuronDorsal Horn Neuron
CC--fiber terminalfiber terminal
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
7NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
8NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
9NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
10NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
*
†
††
†
††
†
††
†
††
†
††
†
††
†
††
†
††
†
††
†
††
†
††
†
††
†
††
†
††
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.
11NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
*Not approved by FDA for this use.
68
12NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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
*Not approved by FDA for this use.
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
13NATIONAL INITIATIVE ON PAIN CONTROL™
Neuropathic Pain: New Strategies to Improve Clinical Outcome
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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