1 Update on Fibromyalgia and Postherpetic Neuralgia Steven

1 Update on Fibromyalgia and Postherpetic Neuralgia Steven Stanos, DO 1

Fibromyalgia Pathophysiology 2 Mechanism Description Central sensitization Amplification of pain in the spinal cord via spontaneous nerve activity, expanded receptive fields, and augmented stimulus responses Abnormalities of descending inhibitory pain 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 transporter polymorphism Decreased 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 Patients with fibromyalgia have increased rates of psychiatric Psychiatric comorbid conditions, including depression, anxiety, posttraumatic stress, and somatization; these may predispose to the conditions development of fibromyalgia Abeles AM, et al. Ann Intern Med. 2007; 146: 726 -734. 2

Fibromyalgia Possible Spinal and Supraspinal Effects 3 Descending Modulation Facilitation Substance P Glutamate and EAAs NGF Descending modulatory pathways Inhibition Descending anti-nociceptive pathways Norepinephrine and serotonin (5 HT 1 a, b) Opioidsa Ascending pathways 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. a 3

Fibromyalgia Pathophysiology HPA Axis and Psychological Stress Connection 4 “TRIGGER EVENT” Psychological Distress ALTERED HPA AXIS FUNCTION Genetic factors Genetics ↓CRH ↓ACTH ↓Cortisol ↓ Serotonin ↑ Substance P Mc. Beth J, et al. Arthritis Rheum. 2007; 56: 360 -371. Fibromyalgia Pain 4

Fibromyalgia Overlap With Related Syndromes CFS Fibromyalgia 1% of population; fatigue and 4 of 8 “minor criteria” 2%-4% of population; defined by widespread pain and tenderness Pain and/or sensory amplification Regional pain syndromes (eg, tension headache, TMD, idiopathic LBP) 5 Psychiatric disorders MDD, OCD, bipolar, PTSD, GAD, panic attack Somatoform disorders 4% of population; multiple unexplained symptoms, no “organic” findings 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. 5

Fibromyalgia Shared Features With Depression • • • 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 http: //www. medscape. com/viewprogram/17278_pnt. FPO 6

Fibromyalgia Recommended Diagnostic Work-up 7 History of chronic, widespread pain for ≥ 3 months 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 11 of 18) Confirm diagnosis of fibromyalgia ESR=erythrocyte sedimentation rate. Adapted from: Burckhardt CS, et al. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children; 2005 http: //www. medscape. com/viewprogram/17278_pnt. FPO 7

Fibromyalgia Differential Diagnosis 8 • 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 8

Fibromyalgia Stepwise Treatment Algorithm 9 Step 1. Confirm diagnosis of fibromyalgia a. 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 treatment d. Provide education about fibromyalgia e. Review treatment options Step 2. Recommend treatment based on the individual evaluation a. 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), α 2δ ligand (especially for patients with prominent sleep disturbance and anxiety), or, if these do not work, SSRI or TCA b. Evaluate for comorbid medical and psychiatric disorders (eg, sleep apnea, OA, anxiety disorder) Step 3. If not responding to medication alone, consider CBT 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 Arnold LM. Arthritis Res Ther. 2006; 8: 212. 9

Fibromyalgia Possible Two Types 10 Heterogeneity is largely due to differences in depressive and anxiety symptoms 10 Visual Analog Scale 8 6 4 Fibromyalgia-Type I (n=27) 2 Fibromyalgia-Type I (n=34) 0 Pain Fatigue Stiffness Morning Tiredness Anxiety Depression de Souza JB, et al. Rheumatol Int. 2008 Sep 27. [Epub ahead of print]. 10

Fibromyalgia Genetic Influences 11 Gene Frequency, % Serotonin-Related Genes • Short/Short subgroup showed higher mean levels of depression and psychological distress a Genotype at a SNP in the regulatory promoter region of the serotonin transporter gene (5 -HTT) • Polymorphism also associated with anxiety-related personality traits, diarrhea-predominant IBS, and MDD • Additional linkage between fibromyalgia and a SNP in the serotonin 2 A receptor gene (5 -HT 2 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. a 11

Fibromyalgia Genetic Influences (cont’d) 12 Dopamine- and Catecholamine-Related Genes • Dopamine D 4 -receptor exon III repeat polymorphism – Decreased frequency of 7 -repeat allele in fibromyalgia – Also associated with low novelty-seeking personality • Altered dopamine D 2 -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. 12

Fibromyalgia Family Study 13 Relatives of Fibromyalgia Probands, % Relatives of RA Probands, % n=533 n=272 6. 4 1. 1 MDD 29. 5 18. 3 Bipolar I disorder 1. 3 0. 4 Bipolar II disorder 1. 3 0. 4 Disorder Fibromyalgia Major mood disorders • OR of fibromyalgia in a relative of fibromyalgia proband vs fibromyalgia in a relative of RA proband was 8. 5 a – 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 95% confidence interval 2. 8– 26; P=0. 0002. P<0. 0001 for both comparisons. OR, odds ratio. Arnold LM, et al. Arthritis Rheum. 2004; 50: 944 -952. a b 13

Fibromyalgia Enhanced Pain Processing NC-3 sec • Lower mechanical and thermal pain thresholds (allodynia) NC-5 sec FM-3 sec 70 FM-5 sec 60 Pain Ratings, 0 -100 14 50 • High pain ratings for noxious stimuli (hyperalgesia) 40 30 • Altered temporal summation of painful stimuli (wind-up) 20 10 0 T 1 T 5 T 10 T 15 3 sec, interstimulus intervals of 3 sec; 5 sec, 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. 14

Fibromyalgia f. MRI Findings 15 14 Pain Intensity 12 10 8 6 Fibromyalgia 4 Subjective pain control 2 Stimulus pressure control 0 1. 5 2. 5 3. 5 4. 5 Stimulus Intensity, kg/cm 2 Similar pressure produced significantly greater activation at 13 regions in the patient group and 1 region in the control group f. MRI, functional magnetic resonance imaging. N=16 patients with fibromyalgia and 16 matched controls. Gracely RH, et al. Arthritis Rheum. 2002; 46: 1333 -1343. 15

Case Study Introducing Katherine 16 • 54 -year-old financial consultant • Presents to PCP for evaluation of pain that started 4 months ago in her shoulders and spread recently to her 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 and chronic fatigue • PCP suspects SLE, RA, or fibromyalgia • 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. 16

Fibromyalgia Comprehensive Assessment 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 Patient with probable fibromyalgia Characterize pain type, location, source, intensity, duration, effects on Qo. L 17 Assess functional status at initial and subsequent visits Analyze complete blood count, ESR, muscle enzymes, liver function, thyroid function ACR, American College of Rheumatology; ESR, erythrocyte sedimentation rate; Qo. L, 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. 17

Fibromyalgia ACR Diagnostic Criteria 18 • History (≥ 3 months) of widespread pain – Above and below the waist – Bilateral – In the axial skeleton • Manual tender point examination – Pain in ≥ 11 of 18 specific fibromyalgia tender points on digital palpation – ~ palpation force: 4 kg/1. 4 cm 2 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. 18

Key Fibromyalgia Domains Patient Perspectives 19 • 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 Arnold LM, et al. Patient Educ Couns. 2008; 73: 114 -120. 19

Katherine Diagnosis 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? PMR, polymyalgia rheumatica. 20

Fibromyalgia 10 80 60 40 20 Verbal Fluency Age-matched controls a 3 d’ 20 10 2 1 Free Recall Working Memory Capacity b 4 80 60 a 40 20 Verbal Knowledge Older subjects Recognition Memory Summed Score From Speed Tasks 20 21 a 30 Recalled Words 30 a Correct Answers Number of Words Produced Correct Responses Cognitive Dysfunction 160 120 80 40 Information-Processing Speed Fibromyalgia patients 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. a 21

Fibromyalgia Dually 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 Clauw DJ, et al. Best Pract Res Clin Rheumatol. 2003; 17: 685 -701(B). 22 Pharmacologic therapies to improve symptoms Nonpharmacologic therapies to address dysfunction 22

Fibromyalgia Interventions 23 Patient Education Explain what the condition is and what it is not CAM Cognitivebehavioral, alternative therapies Physical Therapy Exercise programs Multimodal Therapeutic Strategies for Fibromyalgia Pharmacotherapy SNRIs, TCAs, anticonvulsants, tramadol Psychological Support Psychotherapy, support groups Address Comorbidities Sleep dysfunction, depression, anxiety 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. 23

Fibromyalgia Nonpharmacologic Therapies • Strong evidence – Education – Aerobic exercise – Cognitive-behavioral therapy • Modest evidence – Strength training – Hypnotherapy, biofeedback, balneotherapy 24 • 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. 24

Fibromyalgia Aerobic Exercise 25 Control – Nearly universally beneficial a 30 • Tolerance, compliance, and adherence are biggest hurdles • Programs should be individualized Mean Change in Parameter, % 25 20 a 15 10 – Begin several months after pharmacologic therapy – Begin with low-impact exercises 5 0 -5 -10 • Benefits first reported 30 years ago Aerobic Performance Mean Tender Point Pain Threshold Pain Intensity P<0. 001; meta-analysis of 4 independent studies. Busch AJ, et al. Cochrane Database Syst Rev. 2002, Issue 2. Art. No. CD 003786. doi: 10. 1002/14651858. CD 003786. Mc. Cain GA, et al. Arthritis Rheum. 1988; 31: 1135 -1141. a 25

Fibromyalgia Cognitive-Behavioral Therapy • Longitudinal trials show reduced pain severity and improved function Thoughts Physical Response 26 Feelings • Systematic reviews demonstrate reduced pain and fatigue, improved mood and function • Improvements also seen with meditation, relaxation, stress management Behavior 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. • Effects depend heavily on therapist and program 26

Fibromyalgia CBT vs Routine Care 27 % of Patient Responses 30 CBT (n=62) Routine (n=60) 25 20 15 10 5 0 Physical Functioning or 2. 9, p<0. 05 Sensory Pain *Statistically significant. OR=odds ratio. Williams DA, et al J Rheumatol. 2002; 29(6): 1280 -1286. http: //www. medscape. com/viewprogram/17278_pnt. FPO Affective Pain 27

Fibromyalgia Pharmacologic Therapies • Strong evidence – Dual-reuptake inhibitors • Tricyclic compounds • SNRIs – Anticonvulsants • Modest evidence – – Dopamine agonists Gamma hydroxybutyrate Tramadol SSRIs 28 • 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. 28

Fibromyalgia Dual-Uptake Inhibitors: TCAs Outcome Measure 1. 0 0. 5 Stiffness Tenderness Sleep Fatigue Pain -0. 5 M. D. Global Assessment 0. 0 Patient Global Assessment Effect Size, Standard Deviation 1. 5 29 • 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 AE, adverse event. Box plot of effect size in 9 controlled studies of TCA treatment of fibromyalgia. Observations lying beyond the 5 th and 95 th percentiles. Arnold LM, et al. Psychosomatics. 2000; 41: 104 -113. 29

Fibromyalgia Dual-Uptake Inhibitors: Cyclobenzaprine Favors Placebo Favors Treatment Bennett (1988) • Often classified as muscle relaxant, but actually structurally a tricyclic compound • Moderate improvements noted for sleep after 4, 8, and 12 weeks of treatment Carette (1994) Quimby (1989) Overall (95% Cl) 0 30 3. 0 (95% CI: 1. 6 -5. 7) 1 25 Effect Size on Dichotomous Outcomes of Improvement CI, confidence interval. Tofferi JK, et al. Arthritis Rheum. 2004; 51: 9 -13. – Modest improvement in pain levels observed only at 4 weeks • Common AEs include sedation, anticholinergic side effects, and weight gain 30

Fibromyalgia Dual-Uptake Inhibitors: SNRIs 31 • Do not interact with adrenergic, cholinergic, or histaminergic receptors, or sodium channels – Duloxetine • FDA approved for fibromyalgia, GAD, MDD, and pain associated with DPN Duloxetine – Venlafaxine • FDA approved for GAD, social anxiety disorder, MDD, and panic disorder • Ineffective in an RCT for fibromyalgia – Milnaciprana Venlafaxine Milnacipran 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. a 31

Fibromyalgia SNRIs: Proposed MOA Perception 32 Inhibition • Augmented descending inhibition via amplification of norepinephrine and serotonin signaling Modulation Ascending pathways Descending modulatory pathways Transduction Transmission MOA, mechanism of action. 32

Fibromyalgia Duloxetine in Randomized Trials Mean Difference IV, Fixed, 95% CI 33 Mean Difference IV, Fixed, 95% CI Arnold (2005) Russell (2008) Overall (95% Cl) -2 -1 Favours placebo 1. 07 (0. 66, 1. 47) 0. 89 (0. 49, 1. 30) 0 1 2 Favors duloxetine 60 mg Sultan A. BMC Neurology. 2008; 8: 29. -2 -1 Favours placebo 0 1 2 Favors duloxetine 120 mg 33

Fibromyalgia Anticonvulsants: 2 Ligands • Drugs that diminish neuronal excitability α 2 N 34 • Bind to 2 subunit of voltage-gated calcium channels γ δ – Reduce calcium influx, thereby inhibiting neurotransmitter release α 1 • FDA indications N c c c – 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. 34

Fibromyalgia Anticonvulsants: Pregabalin 35 >30% responders, % a • 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 Pregabalin Dose, mg/d 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, Mc. Gill Pain Questionnaire-Short Form. Crofford LJ, et al. Arthritis Rheum. 2005; 52: 1264 -1273. a 35

Fibromyalgia Pregabalin/Gabapentin: Proposed MOA Perception 36 Facilitation • Decrease substance P release in inflammatory states • Inhibit substance P–induced glutamate release Modulation Ascending pathways Descending modulatory pathways Transduction Transmission Fehrenbacher JC, et al. Pain. 2003; 105: 133 -141; Maneuf YP, et al. Pain. 2001; 93: 191 -196. 36

Katherine Follow-Up 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? 37

Fibromyalgia Interdisciplinary Pain Management 38 Integrated and Coordinated Pain Specialist Nurses Psychiatrist Spine Surgeon Primary Clinician Neurologist Pharmacist Physiatrist Social Worker Psychologist Anesthesiologist Occupational Therapist Physician Assistant Physical Therapist 38

Fibromyalgia Conclusions 39 • 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 a multidisciplinary perspective – To address pain and relevant comorbidities, treatment should include both pharmacologic and nonpharmacologic modalities 39

Case: Ms. Karibean 40 • 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. 40

Primary Infection, Latency, and Recurrence of Varicella Zoster Virus 41 1. Entry 4. Latency (sensory ganglion) 5. Herpes zoster (shingles) 2. Spread 3. Varicella infection (chickenpox) Straus SE, et al. In: Fitzpatrick's Dermatology in General Medicine. 6 th ed. New York, NY: Mc. Graw-Hill Professional; 2003: 20702080. 41

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The Spectrum of Pain in Herpes Zoster 43 Rash Onset Prodrome Onset Typically ≤ 1 wk Pain Cessation Rash Healed 2 -4 wk Acute pain Can Be Years Postherpetic neuralgia (PHN) 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. 43

Pain Distribution in PHN 44 • 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. 6 th ed. New York, NY: Mc. Graw-Hill Professional; 2003. 44

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Considerations for Comprehensive Management • Biologic intervention – Pharmacologic and/or nonpharmacologic approaches • Psychological intervention – Address mood and sleep disturbances – Enhance coping skills • Social/rehabilitative intervention 46 – Family/social support – Address work issues – Physical rehabilitation • Physical/occupational therapy • Home exercise program 46

Some Treatment Considerations in Neuropathic Pain of PHN Drug Factors 1, 2 Patient Factors 1, 2 • Efficacy • Safety • Potential for AEs • Tolerability • Drug interactions • Monotherapy vs. combination therapy • Treatment costs 47 • Comorbidities • Mental status • Risks of drug misuse/ abuse • Risks of unintentional overdose • Adherence • Prior therapies edication costs AEs=adverse events. 1. Dworkin RH, et al. Pain. 2007; 132: 237 -251. 2. Gilron I, et al. CMAJ. 2006; 175: 265 -275. 47

Evidence-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/m. L 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 q 4 h or prn After 1– 2 weeks, convert total None daily dose to long acting Tramadol HCl 50 mg QD or BID Increase by 50– 100 mg/d in divided doses every 3– 7 days 48 300– 400 mg/d *Only lidocaine patch 5%, gabapentin, and pregabalin have indications specific for the treatment of PHN pain. Dworkin RH, et al. Pain. 2007; 132: 237 -251. 48

Lidocaine Patch 5%: Blood Levels Various Applications 49 5 µg/m. L 4 3 2 1 0 Lidocaine* patch 5% 2 mg/min Infusion Arthroscopic Knee Surgery *In normal, healthy volunteers 2 g of 5% Cream to Burns Antiarrhythmic Level Toxic Level 49