1

Update on Fibromyalgiaand Postherpetic Neuralgia

Steven Stanos, DO

Update on Fibromyalgiaand Postherpetic Neuralgia

Steven Stanos, DO

1

2

2

FibromyalgiaPathophysiologyFibromyalgiaPathophysiology

Abeles AM, et al. Ann Intern Med. 2007;146:726-734.

Mechanism Description

Central sensitizationAmplification of pain in the spinal cord via spontaneous nerve activity, expanded receptive fields, and augmented stimulus responses

Abnormalities of descending inhibitorypain pathways

Dysfunction in brain centers (or the pathways from these centers) that normally downregulate pain signaling in the spinal cord

Neurotransmitter abnormalities

Decreased serotonin in the central nervous system may lead to aberrant pain signaling, which may be due to serotonin transporterpolymorphismDecreased dopamine transmission in the brain may lead to chronic pain through unclear mechanisms

Neurohumoral abnormalities

Dysfunction in the hypothalamic—pituitary—adrenal axis, including blunted cortisol responses and lack of cortisol diurnal variation, is associated with (but is not specific for) fibromyalgia

Psychiatric comorbid conditions

Patients with fibromyalgia have increased rates of psychiatric comorbid conditions, including depression, anxiety, posttraumatic stress, and somatization; these may predispose to the development of fibromyalgia

3

3

FibromyalgiaPossible Spinal and Supraspinal EffectsFibromyalgiaPossible Spinal and Supraspinal Effects

Descending Modulation

Facilitation Substance P Glutamate and

EAAs NGF

Inhibition Descending

anti-nociceptive pathways Norepinephrine

and serotonin (5HT1a,b)

Opioidsa

Ascendingpathways

Descendingmodulatory pathways

a Recent evidence suggests reduced µ-opioid receptor availability in patients with fibromyalgia; the arrows refer to the pathologic state.Harris RE, et al. J Neurosci. 2007;27:10000-10006; Millan MJ, et al. Prog Neurobiol. 2002;66:355-474.

4

4

Fibromyalgia PathophysiologyHPA Axis and Psychological Stress ConnectionFibromyalgia PathophysiologyHPA Axis and Psychological Stress Connection

McBeth J, et al. Arthritis Rheum. 2007;56:360-371.

“TRIGGER EVENT”Psychological

Distress

Geneticfactors

Genetics↓

Serotonin

↑

Substance PPain

Fibromyalgia

↓CRH ↓ACTH ↓Cortisol

ALTERED HPA AXIS FUNCTION

5

5

CFS, chronic fatigue syndrome; GAD, generalized anxiety disorder; LBP, low back pain; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; PTSD, post-traumatic stress disorder; TMD, temporomandibular disorders.Clauw DJ, et al. Neuroimmunomodulation. 1997;4:134-153.

FibromyalgiaFibromyalgia 2%-4% of population; defined by widespread pain and tenderness

CFSCFS 1% of population; fatigue and 4 of 8 “minor criteria”

Somatoform Somatoform disordersdisorders4% of population; multiple unexplained symptoms,no “organic” findings

Regional pain Regional pain syndromessyndromes (eg, tension headache,TMD, idiopathic LBP)

Psychiatric Psychiatric disordersdisorders MDD, OCD, bipolar, PTSD, GAD, panic attack

FibromyalgiaOverlap With Related SyndromesFibromyalgiaOverlap With Related Syndromes

Pain and/or sensory

amplification

6

6

• Strong genetic predisposition and similar comorbidity

• Coaggregation in families

• Cognitive disturbances

• Dysfunction of the HPA axis

• Chronic stress-induced cytokine expression in the brain

• Central monoaminergic neurotransmission

FibromyalgiaShared Features With Depression FibromyalgiaShared Features With Depression

http://www.medscape.com/viewprogram/17278_pnt. FPO

7

7

FibromyalgiaRecommended Diagnostic Work-upFibromyalgiaRecommended Diagnostic Work-up

ESR=erythrocyte sedimentation rate.Adapted from: Burckhardt CS, et al. Guideline for the Management of Fibromyalgia SyndromePain in Adults and Children; 2005http://www.medscape.com/viewprogram/17278_pnt. FPO

History of chronic,widespread pain for ≥ 3 months

Confirm diagnosis of fibromyalgia

Rule out other conditions that may present with chronic widespread pain (very much “operator dependent”)

General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests, avoid screening

serologic tests) Sleep and mood evaluation

Confirm presence of tender points(Need 11of 18)

8

8

FibromyalgiaDifferential DiagnosisFibromyalgiaDifferential Diagnosis

• Rheumatic illness– Systemic CTD (RA, myositis, SLE, PMR)

• False + ANA “pitfalls”• Seronegative spondyloarthropathies

• Other chronic pain disorder (OA, spinal stenosis, neuropathy)

• Infectious disease– Lyme disease– Viral (hepatitis C, HIV, “EBV”)

• Hypothyroidism

• Consider concurrent systemic illness and primary sleep and mood disorders

CTD=connective tissue disease. RA=rheumatoid arthritis. SLE=systemic lupus erythematosus; PMR=polymyalgia rheumatica; ANA=antinuclear antibodies; HIV=human immunodeficiency virus; EBV=Epstein-Barr virus.http://www.medscape.com/viewprogram/17278_pnt. FPO

9

9

FibromyalgiaStepwise Treatment Algorithm FibromyalgiaStepwise Treatment Algorithm

Arnold LM. Arthritis Res Ther. 2006;8:212.

Step 1. Confirm diagnosis of fibromyalgiaa. Identify important symptom domains, their severity, and level of patient function

b. Evaluate for comorbid medical and psychiatric disorders(eg, sleep apnea, OA, anxiety disorder)

c. Assess psychosocial stressors, level of fitness, and barriers to treatmentd. Provide education about fibromyalgia

e. Review treatment options

Step 2. Recommend treatment based on the individual evaluationa. As a first-line approach for patient with moderate to severe pain, trail with evidence-based

medications, such as SSNRI (not for patients with bipolar disorder), α2δ ligand (especially for patients with prominent sleep disturbance and anxiety),

or, if these do not work, SSRI or TCAb. Evaluate for comorbid medical and psychiatric disorders

(eg, sleep apnea, OA, anxiety disorder)

Step 3. If not responding to medication alone, considerCBT or group education

a. Encourage exercise according to fitness level (eg, goal of 30 to 60 minutes of low-moderate intensity aerobic exercise [e.g., walking, pool exercises, stationary bike]

at least 2 to 3 times a week)b. Encourage participation in supervised or group exercise

10

10

FibromyalgiaPossible Two TypesFibromyalgiaPossible Two Types

de Souza JB, et al. Rheumatol Int. 2008 Sep 27. [Epub ahead of print].

Heterogeneity is largely due to differences in depressive and anxiety symptoms

Pain Fatigue Stiffness Morning

Tiredness Anxiety Depression0

2

4

6

8

10

Vis

ual

An

alo

g S

cale

Fibromyalgia-Type I (n=27)

Fibromyalgia-Type I (n=34)

11

11

FibromyalgiaGenetic InfluencesFibromyalgiaGenetic Influences

0

10

20

30

40

50

60

Long/Long Long/Short Short/Short

Healthy controls (n=110)

Patients with fibromyalgia (n=62)

a P=0.046.SNP, single nucleotide polymorphism.Bondy B, et al. Neurobiol Dis. 1999;6:433-439; Cohen H, et al. Arthritis Rheum. 2002;46:845-847; Hoefgen B, et al. Biol Psychiatry. 2005;57:247-251; Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488; Yeo A, et al. Gut. 2004;53:1452-1458.

Genotype at a SNP in the regulatory promoter region of the serotonin transporter gene (5-HTT)

Gen

e F

req

ue

ncy

, %

a

• Short/Short subgroup showed higher mean levels of depression and psychological distress

• Polymorphism also associated with anxiety-related personality traits, diarrhea-predominant IBS, and MDD

• Additional linkage between fibromyalgia and a SNP in the serotonin 2A receptor gene (5-HT2A)

Serotonin-Related Genes

12

12

FibromyalgiaGenetic Influences (cont’d)

FibromyalgiaGenetic Influences (cont’d)

• Dopamine D4-receptor exon III repeat polymorphism– Decreased frequency of 7-repeat allele in fibromyalgia – Also associated with low novelty-seeking personality

• Altered dopamine D2-receptor function in fibromyalgia

• Catechol-O-methyltransferase (COMT)– 1 of several enzymes that degrade catecholamines

• Dopamine, epinephrine, norepinephrine

– 1 variant associated with diminished µ-opioid system responses, higher sensory and affective ratings of pain, and more negative affective state

Buskila D, et al. Mol Psychiatry. 2004;9:730-731; Gürsoy S, et al. Rheumatol Int. 2003;23:104-107; Malt EA, et al. J Affect Disord. 2003;75:77-82; Zubieta JK, et al. Science. 2003;299:1240-1243.

Dopamine- and Catecholamine-Related Genes

13

13

FibromyalgiaFamily StudyFibromyalgiaFamily Study

• OR of fibromyalgia in a relative of fibromyalgia proband vs fibromyalgia in a relative of RA proband was 8.5a – Primarily due to the effect of female relatives

• Relatives of fibromyalgia probands showed increased tender point scores and decreased myalgic scores compared with relatives of RA probandsb

a 95% confidence interval 2.8–26; P=0.0002.b P<0.0001 for both comparisons.OR, odds ratio.Arnold LM, et al. Arthritis Rheum. 2004;50:944-952.

DisorderRelatives of

Fibromyalgia Probands, %

n=533

Relatives of RA Probands, %

n=272

Fibromyalgia 6.4 1.1

Major mood disorders

MDD 29.5 18.3

Bipolar I disorder 1.3 0.4

Bipolar II disorder 1.3 0.4

14

14

Fibromyalgia Enhanced Pain ProcessingFibromyalgia Enhanced Pain Processing

• Lower mechanical and thermal pain thresholds (allodynia)

• High pain ratings for noxious stimuli (hyperalgesia)

• Altered temporal summation of painful stimuli (wind-up)

3sec, interstimulus intervals of 3 sec; 5sec, interstimulus intervals of 5 sec; FM, fibromyalgia patient;NC, normal control; T, tap stimulus.Geisser ME, et al. Pain. 2003;102:247-254; Petzke F, et al. Pain. 2003;105:403-413;Staud R. Arthritis Res Ther. 2006;8:208-214; Staud R, et al. Pain. 2001;91:165-175.

Pai

n R

atin

gs,

0-1

00

T1 T5 T10 T15

0

10

20

30

40

50

60

70NC-3sec NC-5sec

FM-3sec FM-5sec

15

15

FibromyalgiafMRI FindingsFibromyalgiafMRI Findings

fMRI, functional magnetic resonance imaging.N=16 patients with fibromyalgia and 16 matched controls.Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.

14

12

10

8

6

4

2

04.51.5 2.5 3.5

Stimulus Intensity, kg/cm2

Pai

n I

nte

nsi

ty

Fibromyalgia

Subjective pain control

Stimulus pressure control

Similar pressure produced significantly greater activation at 13 regions in the patient group and 1 region in the control group

16

16

• 54-year-old financial consultant• Presents to PCP for evaluation of pain that started 4

months ago in her shoulders and spread recently toher hips, arms, and back

–Pain levels vary, 5-8/10–She can’t work as efficiently as before

• History of symptoms consistent with IBS for the last 3 years, and recent depression, poor sleep andchronic fatigue

• PCP suspects SLE, RA, or fibromyalgia

Case StudyIntroducing KatherineCase StudyIntroducing Katherine

• What formal diagnostic, laboratory, and imaging tests may be helpful when diagnosing Katherine?

– Does she have any fibromyalgia predisposing factors?

IBS, irritable bowel syndrome; PCP, primary care physician; RA rheumatoid arthritis; SLE, systemic lupus erythematosus.

17

17

FibromyalgiaComprehensive AssessmentFibromyalgiaComprehensive Assessment

ACR, American College of Rheumatology; ESR, erythrocyte sedimentation rate; QoL, quality of life.Burckhardt CS, et al. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children. Glenville, Ill: American Pain Society; 2005.

Patient with probable

fibromyalgia

Detailed history focusing on illness that may mimic,

complicate, or occur concurrently with fibromyalgia

Clinical diagnosis of fibromyalgia based

on 1990 ACR criteria

Evaluate the severity of other fibromyalgia symptoms: fatigue, sleep disturbance,

mood/cognitive disturbance

Assess functional status at initial and subsequent visits

Characterize pain type,location, source, intensity, duration, effects on QoL

Analyze complete blood count, ESR, muscle enzymes,

liver function, thyroid function

18

18

FibromyalgiaACR Diagnostic CriteriaFibromyalgiaACR Diagnostic Criteria

• History (≥3 months) of widespread pain– Above and below the waist– Bilateral– In the axial skeleton

• Manual tenderpoint examination– Pain in ≥11 of 18 specific

fibromyalgia tender points on digital palpation

– ~ palpation force: 4 kg/1.4 cm2

Okifuji A, et al. J Rheumatol. 1997;24:377-383.Wolfe F, et al. Arthritis Rheum. 1990;33:160-172.http://www.fibromyalgia-symptoms.org/fibromyalgia_diagnosis.html. Accessed August 1, 2008.

19

19

Key Fibromyalgia DomainsPatient PerspectivesKey Fibromyalgia DomainsPatient Perspectives

Arnold LM, et al. Patient Educ Couns. 2008;73:114-120.

• Physical– Pain – Fatigue– Disturbed sleep

• Emotional/cognitive– Depression, anxiety– Cognitive impairment (decreased concentration, disorganization – Memory problems

• Social– Disrupted family relationships– Social isolation– Disrupted relationships with friends

• Work/activity– Reduced activities of daily living– Reduced leisure activities/avoidance of physical activity– Loss of career/inability to advance in career or education

20

20

• Based on normal laboratory results and comprehensive examination, PCP rules out RA,PMR, and SLE

• Digital palpation reveals pain at 14 of the 18 tender points

• She reports having trouble concentrating • PCP diagnoses fibromyalgia, recommends a support

group, and provides educational material to help Katherine understand the disease

Would your treatment plan differ if Katherine reported 9 of 18 tender points?Are cognitive deficits common in patients with fibromyalgia?

KatherineDiagnosisKatherineDiagnosis

PMR, polymyalgia rheumatica.

21

21

a P<0.05 compared with age-matched controls; b P=0.055 compared with age-matched controls.d’, a measure of how effectively a subject can discriminate an item as new or previously studied.N=23 fibromyalgia patients, 23 age-matched controls, and 22 education-matched controls who were 20 years older.Park DC, et al. Arthritis Rheum. 2001;44:2125-2133.

FibromyalgiaCognitive DysfunctionFibromyalgiaCognitive Dysfunction

Co

rre

ct

Re

sp

on

se

s

10

20

30

Working MemoryCapacity

Su

mm

ed

Sc

ore

Fro

m S

pe

ed

Ta

sk

s

40

80

120

160

Information-ProcessingSpeed

Co

rre

ct

An

sw

ers

20

40

60

80

Verbal Knowledge

Nu

mb

er

of

Wo

rds

Pro

du

ce

d

20

40

60

80

Verbal Fluency

d’

1

2

3

4

Recognition MemoryR

ec

all

ed

Wo

rds

10

20

30

Free Recall

a aa

a

Age-matched controls Fibromyalgia patientsOlder subjects

b

22

22

Pharmacologic therapies to improve symptoms

Clauw DJ, et al. Best Pract Res Clin Rheumatol. 2003;17:685-701(B).

Nonpharmacologic therapies to address dysfunction

FibromyalgiaDually Focused TreatmentFibromyalgiaDually Focused Treatment

Symptoms of pain, fatigue, etc

• Nociceptive processes

• Neuroendocrine and sleep dysfunction

• Disordered sensory processing

Functional consequences of symptoms

• Increased distress

• Decreased activity

• Isolation

• Poor sleep

• Maladaptive illness behaviors

23

23

CAM, complementary and alternative medicine; SNRI, serotonin–norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.Burckhardt CS, et al. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children. Glenville, Ill: American Pain Society; 2005.

FibromyalgiaInterventionsFibromyalgiaInterventions

CAMCognitive-

behavioral, alternative therapies

PsychologicalSupport

Psychotherapy, support groups

Multimodal TherapeuticStrategies for Fibromyalgia

Patient EducationExplain what the condition is

and what it is not

Physical TherapyExercise programs

PharmacotherapySNRIs, TCAs,

anticonvulsants, tramadol

Address ComorbiditiesSleep dysfunction, depression, anxiety

24

24

Fibromyalgia Nonpharmacologic TherapiesFibromyalgia Nonpharmacologic Therapies

• Strong evidence– Education– Aerobic exercise– Cognitive-behavioral

therapy

• Modest evidence– Strength training– Hypnotherapy,

biofeedback, balneotherapy

• Weak evidence– Acupuncture– Chiropractic, manual,

and massage therapy– Electrotherapy– Ultrasound

• No evidence– Tender point injections– Flexibility exercise

Burckhardt CS, et al. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children. Glenville, Ill: American Pain Society; 2005; Goldenberg DL, et al. JAMA. 2004;292:2388-2395.

25

25

FibromyalgiaAerobic ExerciseFibromyalgiaAerobic Exercise

a P<0.001; meta-analysis of 4 independent studies.Busch AJ, et al. Cochrane Database Syst Rev. 2002, Issue 2. Art. No. CD003786. doi:10.1002/14651858.CD003786.McCain GA, et al. Arthritis Rheum. 1988;31:1135-1141.

• Benefits first reported 30 years ago– Nearly universally beneficial

• Tolerance, compliance, and adherence are biggest hurdles

• Programs should be individualized– Begin several months after

pharmacologic therapy– Begin with low-impact

exercises

a

a

Mea

n C

han

ge

in P

aram

eter

, %

-10

-5

0

5

10

15

20

25

30

AerobicPerformance

Mean TenderPoint PainThreshold

Pain Intensity

Exercise Control

26

26

FibromyalgiaCognitive-Behavioral TherapyFibromyalgiaCognitive-Behavioral Therapy

Goldenberg DL, et al. JAMA. 2004;292:2388-2395.Hadhazy V, et al. J Rheumatol. 2000;27:2911-2918.Williams DA. Best Pract Res Clin Rheumatol. 2003;17:649-665.

PhysicalResponse

Feelings

Thoughts

Behavior

• Longitudinal trials show reduced pain severity and improved function

• Systematic reviews demonstrate reduced pain and fatigue, improved mood and function

• Improvements also seen with meditation, relaxation, stress management

• Effects depend heavily on therapist and program

27

27

FibromyalgiaCBT vs Routine CareFibromyalgiaCBT vs Routine Care

*Statistically significant.OR=odds ratio.Williams DA, et al J Rheumatol. 2002; 29(6):1280-1286.http://www.medscape.com/viewprogram/17278_pnt. FPO

% o

f P

atie

nt

Res

po

nse

s

Physical Functioning or

2.9, p<0.05Sensory Pain Affective Pain

0

5

10

15

20

30

25

CBT (n=62)

Routine (n=60)

28

28

Fibromyalgia Pharmacologic TherapiesFibromyalgia Pharmacologic Therapies

• Strong evidence– Dual-reuptake inhibitors

• Tricyclic compounds• SNRIs

– Anticonvulsants

• Modest evidence– Dopamine agonists– Gamma hydroxybutyrate– Tramadol– SSRIs

• Weak evidence– Growth hormone– 5-hydroxytryptamine– Tropisetron– SAMe

• No evidence– Opioids– Corticosteroids– NSAIDs– Benzodiazepine and

nonbenzodiazepine hypnotics

NSAID, nonsteroidal anti-inflammatory drug; SAMe, S-adenosyl-L-methionine; SSRI, selective serotonin reuptake inhibitor. Modified from: Burckhardt CS, et al. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children. Glenville, Ill: American Pain Society; 2005; Goldenberg DL, et al. JAMA. 2004;292:2388-2395.

29

29

Te

nd

ern

es

s

FibromyalgiaDual-Uptake Inhibitors: TCAsFibromyalgiaDual-Uptake Inhibitors: TCAs

AE, adverse event.Box plot of effect size in 9 controlled studies of TCA treatment of fibromyalgia. Observations lying beyond the 5th and 95th percentiles.Arnold LM, et al. Psychosomatics. 2000;41:104-113.

• TCAs associated with effect sizes substantially larger than 0 for all measurements

• Largest improvements in sleep quality

• Most modest improvements in stiffness, tenderness

• Common AEs include sedation, anticholinergic side effects, weight gain

Outcome Measure

Eff

ect

Siz

e, S

tan

da

rd D

evia

tio

n

1.5

1.0

0.5

0.0

-0.5

M.D

. G

lob

al

As

se

ss

me

nt

Pa

tie

nt

Glo

ba

l A

ss

es

sm

en

t

Pa

in

Fa

tig

ue

Sle

ep

Sti

ffn

es

s

30

30

FibromyalgiaDual-Uptake Inhibitors: CyclobenzaprineFibromyalgiaDual-Uptake Inhibitors: Cyclobenzaprine

• Often classified as muscle relaxant, but actually structurally a tricyclic compound

• Moderate improvements noted for sleep after 4, 8, and 12 weeks of treatment – Modest improvement

in pain levels observed only at 4 weeks

• Common AEs include sedation, anticholinergic side effects, and weight gain

Favors Placebo Favors Treatment

0 1 25

Bennett (1988)

Carette (1994)

Quimby (1989)

Overall (95% Cl) 3.0 (95% CI: 1.6-5.7)

CI, confidence interval.Tofferi JK, et al. Arthritis Rheum. 2004;51:9-13.

Effect Size on Dichotomous Outcomes of Improvement

31

31

FibromyalgiaDual-Uptake Inhibitors: SNRIsFibromyalgiaDual-Uptake Inhibitors: SNRIs

• Do not interact with adrenergic, cholinergic, or histaminergic receptors, or sodium channels– Duloxetine

• FDA approved for fibromyalgia, GAD, MDD, and pain associated with DPN

– Venlafaxine• FDA approved for GAD, social anxiety disorder,

MDD, and panic disorder• Ineffective in an RCT for fibromyalgia

– Milnaciprana

a New Drug Application submitted to the FDA for fibromyalgia.Burckhardt CS, et al. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children. Glenville, Ill: American Pain Society; 2005.

Duloxetine

Venlafaxine

Milnacipran

32

32

FibromyalgiaSNRIs: Proposed MOAFibromyalgiaSNRIs: Proposed MOA

Perception

Ascendingpathways

Descendingmodulatory pathways

Modulation

Transmission

Transduction

Inhibition• Augmented descending inhibition via amplification of norepinephrine and serotonin signaling

MOA, mechanism of action.

33

33

FibromyalgiaDuloxetine in Randomized TrialsFibromyalgiaDuloxetine in Randomized Trials

Sultan A. BMC Neurology. 2008;8:29.

Mean DifferenceIV, Fixed, 95% CI

Favours placebo Favors duloxetine 60 mg

-2 -1 0 1 20

Arnold (2005)

Russell (2008)

Overall (95% Cl) 0.89 (0.49, 1.30)

Mean DifferenceIV, Fixed, 95% CI

Favours placebo Favors duloxetine 120 mg

-2 -1 0 1 2

1.07 (0.66, 1.47)

34

34

Fibromyalgia Anticonvulsants: 2 LigandsFibromyalgia Anticonvulsants: 2 Ligands

• Drugs that diminish neuronal excitability

• Bind to 2 subunit of voltage-gated calcium channels– Reduce calcium influx, thereby

inhibiting neurotransmitter release

• FDA indications– Fibromyalgia (pregabalin) – Neuropathic pain associated with

DPN (pregabalin)– PHN (gabapentin, pregabalin)– Adjunctive therapy for partial-onset

seizures in adults (pregabalin) or adults and children (gabapentin)

Arnold LM, et al. Arthritis Rheum. 2007;56:1336-1344; Crofford LJ, et al. Arthritis Rheum. 2005;52:1264-1273;Van Petegem F, Minor DL. Biochem Soc Trans. 2006;34:887-893.

α2

α1

N

δγ

c

c

N

c

35

35

Fibromyalgia Anticonvulsants: PregabalinFibromyalgia Anticonvulsants: Pregabalin

• Significant improvements seen in MOS-sleep problem index, total SF-MPQ score, MAF global fatigue index, 4 SF-36 domains

• Common AEs (>10%) in the 450 mg-per-day group: dizziness, somnolence, headache, dry mouth, and peripheral edema

>30

% r

esp

on

der

s, %

Pregabalin Dose, mg/dPregabalin Dose, mg/d

27.131.3

37.9

48.4

0

10

20

30

40

50

60

Placebo 150 300 450

aa

a P=0.003 compared with placebo after 8 weeks of treatment using 0-10 pain scores (N=529).MAF, multidimensional assessment of fatigue; MOS, medical outcomes study; SF-MPQ, McGill Pain Questionnaire-Short Form.Crofford LJ, et al. Arthritis Rheum. 2005;52:1264-1273.

36

36

Fehrenbacher JC, et al. Pain. 2003;105:133-141; Maneuf YP, et al. Pain. 2001;93:191-196.

FibromyalgiaPregabalin/Gabapentin: Proposed MOAFibromyalgiaPregabalin/Gabapentin: Proposed MOA

Perception

Ascendingpathways

Descendingmodulatory pathways

Modulation

Transmission

Transduction

Facilitation• Decrease substance P release in inflammatory states• Inhibit substance P–induced glutamate release

37

37

• Pain has increased in the 2 weeks since last visit to PCP

• Stopped working• Rarely leaves the house because of depression • Despite spending much of the day in bed,

Katherine reports feeling tired and run-down

• Based on Katherine’s presentation, how would you proceed with her treatment?• In addition to treatment of pain, should Katherine be prescribed medication for

any other condition?• What would constitute “successful” treatment?

KatherineFollow-UpKatherineFollow-Up

38

38

FibromyalgiaInterdisciplinary Pain ManagementFibromyalgiaInterdisciplinary Pain Management

Occupational Therapist

Integrated and Coordinated

Nurses

Spine Surgeon

Pharmacist

Social Worker

Anesthesiologist

Physician Assistant

Physical Therapist

Psychologist

Physiatrist

Neurologist

Psychiatrist

Pain Specialist

Primary Clinician

39

39

FibromyalgiaConclusionsFibromyalgiaConclusions

• Wide range of data support the notion that fibromyalgia is a chronic pain disorder characterized by augmented central pain processing

• Diagnosis should be based on ACR criteria, comprehensive assessment, exclusion of other potential disorders associated with widespread pain, and evaluation of the range of symptomology

• Due to its complexity, it is best understood from amultidisciplinary perspective– To address pain and relevant comorbidities, treatment should

include both pharmacologic and nonpharmacologic modalities

40

40Case: Ms. KaribeanCase: Ms. Karibean

• 82 year old female. Chronic left abdominal pain. Rash from “insect bite” she suffered while on a cruise healed 4 months ago. Increase pain and sensitivity to light touch from clothing in same area. Pain worse at night, difficulty falling asleep and frequent awakenings due to pain.

• Ibuprofen, Tylenol #3 not working.

41

41

Primary Infection, Latency, and Recurrence of Varicella Zoster VirusPrimary Infection, Latency, and Recurrence of Varicella Zoster Virus

5. Herpes zoster (shingles)

Straus SE, et al. In: Fitzpatrick's Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill Professional; 2003:2070-2080.

1. Entry

4. Latency (sensory ganglion)

2. Spread

3. Varicella infection

(chickenpox)

42

42

43

43

The Spectrum of Pain in Herpes ZosterThe Spectrum of Pain in Herpes Zoster

Prodrome Onset

Typically ≤1 wk 2-4 wk Can Be Years

Acute pain Postherpetic neuralgia (PHN)

Rash Onset

Rash Healed

Pain Cessation

1 mo 3 mo 6 mo

Irving GA, Wallace MS. In: Pain Management for the Practicing Physician. New York, NY: Churchill Livingstone; 1997:141-147.

Bowsher D. J Pain Symptom Manage.1996;12:290-299.

44

44Pain Distribution in PHNPain Distribution in PHN

• Thoracic dermatomes are affected in the majority of patients (>50%)

• Other dermatomes are affected less often– Trigeminal dermatome

– Lumbar dermatome

– Cervical dermatome

Straus SE, et al Fitzpatrick's Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill Professional; 2003.

45

45

46

46

Considerations for Comprehensive ManagementConsiderations for Comprehensive Management• Biologic intervention

– Pharmacologic and/or nonpharmacologic approaches

• Psychological intervention– Address mood and

sleep disturbances– Enhance coping skills

• Social/rehabilitative intervention– Family/social support– Address work issues– Physical rehabilitation

• Physical/occupational therapy

• Home exercise program

47

47

Patient Factors1,2

• Comorbidities

• Mental status

• Risks of drug misuse/ abuse

• Risks of unintentionaloverdose

• Adherence

• Prior therapies

edication costs

Drug Factors1,2

• Efficacy

• Safety

• Potential for AEs

• Tolerability

• Drug interactions

• Monotherapy vs.combination therapy

• Treatment costs

Some Treatment Considerations in Neuropathic Pain of PHNSome Treatment Considerations in Neuropathic Pain of PHN

AEs=adverse events.1. Dworkin RH, et al. Pain. 2007;132:237-251. 2. Gilron I, et al. CMAJ. 2006;175:265-275.

48

48

Evidence-Based Medications for Neuropathic Pain of PHNEvidence-Based Medications for Neuropathic Pain of PHN

Medication Beginning Dose Titration Maximum Dose

TCAs 25 mg QHS Increase by 25 mg every 3–7 days

150 mg/d, keep <100 ng/mL

Duloxetine 30 mg QD Increase to 60 mg QD after 1 week 60 mg BID

Venlafaxine 37.5 mg QD or BID Increase by 75 mg each week 225 mg daily

Gabapentin* 100–300 mg QHS or TID

Increase by 100–300 mg TID every 1–7 days 3600 mg/d

Pregabalin* 50 mg TID or 75 mg BID

Increase to 300 mg daily after 3–7 days, then by 150 mg/d every 3–7 days

600 mg/d

Lidocaine patch 5%* Max. 3 patches daily for max. 12 hours None needed Max. 3 patches,

12 hours

Opioids 10–15 mg morphine equivalents q4h or prn

After 1–2 weeks, convert total daily dose to long acting

None

Tramadol HCl 50 mg QD or BID Increase by 50–100 mg/d in divided doses every 3–7days 300–400 mg/d

Dworkin RH, et al. Pain. 2007;132:237-251.

*Only lidocaine patch 5%, gabapentin, and pregabalin have indications specific for the treatment of PHN pain.

49

49

Lidocaine Patch 5%: Blood Levels Various ApplicationsLidocaine Patch 5%: Blood Levels Various Applications

5

4

3

2

1

0Lidocaine* patch 5%

2 mg/minInfusion

2 g of 5%Cream to Burns

µg

/mL

ArthroscopicKnee Surgery

AntiarrhythmicLevel

Toxic Level

*In normal, healthy volunteers