1. Key Strategies for Managing Neuropathic Pain Copyright © 2005 Thomson Professional Postgraduate Services ®. All rights reserved.

2. 2 IASP Definition of Pain “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”

3. 3 Acute vs Chronic Pain CharacteristicAcute PainChronic Pain CauseGenerally knownOften unknown Duration of painShort, well-characterized Persists after healing,  3 months Treatment approach Resolution of underlying cause, usually self-limited Underlying cause and pain disorder; outcome is often pain control, not cure

4. 4 Domains of Chronic Pain Social Consequences Marital/family relations Intimacy/sexual activity Social isolation Socioeconomic Consequences Healthcare costs Disability Lost workdays Quality of Life Physical functioning Ability to perform activities of daily living Work Recreation Psychological Morbidity Depression Anxiety, anger Sleep disturbances Loss of self-esteem

5. 5 Mixed Type Caused by a combination of both primary injury and secondary effects Nociceptive vs Neuropathic Pain Nociceptive Pain 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 Postoperative pain Mechanical low back pain Sickle cell crisis Arthritis Postherpetic neuralgia Neuropathic low back pain CRPS* Sports/exercise injuries *Complex regional pain syndrome Central post- stroke pain Trigeminal neuralgia Distal polyneuropathy (eg, diabetic, HIV)

6. 6 Possible Descriptions of Neuropathic Pain Sensations –numbness –tingling –burning –paresthetic –paroxysmal –lancinating –electriclike –raw skin –shooting –deep, dull, bonelike ache Signs/Symptoms –allodynia: pain from a stimulus that does not normally evoke pain thermal mechanical –hyperalgesia: exaggerated response to a normally painful stimulus

7. Physiology of Pain Perception Transduction Transmission Modulation Perception Interpretation Behavior Injury Descending Pathway Peripheral Nerve Dorsal Root Ganglion C-Fiber A-beta Fiber A-delta Fiber Ascending Pathways Dorsal Horn Brain Spinal Cord Adapted with permission from WebMD Scientific American ® Medicine. 7

8. 8 Pathophysiology of Neuropathic Pain Chemical excitation of nonnociceptors Recruitment of nerves outside of site of injury Excitotoxicity Sodium channels Ectopic discharge Deafferentation Central sensitization –maintained by peripheral input Sympathetic involvement Antidromic neurogenic inflammation

9. 9 Multiple Pathophysiologies May Be Involved 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 the pathophysiology and symptoms/signs may help target therapy

10. 10 Percentages of Herpes Zoster Patients With Persistent Pain 0 10 20 30 40 50 60 70 80 0192939495969  70 Age (y)  1 month  1 year % of patients Adapted from DeMorgas JM, Kierland RR. Arch Dermatol. 1957;75:193-196.

11. 11 What Are the Goals of Clinical Assessment? Achieve diagnosis of pain Identify underlying causes of neuropathy Identify comorbid conditions Evaluate psychosocial factors Evaluate functional status (activity levels) Set goals Develop targeted treatment plan Determine when to refer to specialist or multidisciplinary team (pain clinic)

12. 12 Assessing the Patient With 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

13. 13 Pain Treatment Continuum Least invasive Most invasive Psychological/physical approaches Topical medications *Consider referral if previous treatments were unsuccessful. Systemic medications* Interventional techniques* Continuum not related to efficacy

14. 14 Nonpharmacologic Options Biofeedback Relaxation therapy Physical and occupational therapy Cognitive/behavioral strategies –meditation; guided imagery Acupuncture Transcutaneous electrical nerve stimulation

15. 15 Pharmacologic Treatment Options Classes of agents with efficacy demonstrated in multiple, randomized, controlled trials for neuropathic pain –topical analgesics (capsaicin, lidocaine patch 5%) –anticonvulsants (gabapentin, lamotrigine, pregabalin) –antidepressants (nortriptyline, desipramine) –opioids (oxycodone, tramadol) Consider safety and tolerability when initiating treatment

16. 16 FDA-Approved Treatments for Neuropathic Pain Carbamazepine –trigeminal neuralgia Duloxetine –peripheral diabetic neuropathy Gabapentin –postherpetic neuralgia Lidocaine Patch 5% –postherpetic neuralgia Pregabalin* –peripheral diabetic neuropathy –postherpetic neuralgia *Availability pending based upon controlled substance scheduling by the DEA.

17. 17 BRAIN Pharmacologic Agents Affect Pain Differently Descending Modulation Central Sensitization PNS Local Anesthetics Topical Analgesics Anticonvulsants Tricyclic Antidepressants Opioids Anticonvulsants Opioids NMDA-Receptor Antagonists Tricyclic/SNRI Antidepressants Anticonvulsants Opioids Tricyclic/SNRI Antidepressants CNS Spinal Cord Peripheral Sensitization Dorsal Horn

18. 18 Topical vs Transdermal Drug Delivery Systems Systemic activity Applied away from painful site Serum levels necessary Systemic side effects Peripheral tissue activity Applied directly over painful site Insignificant serum levels Systemic side effects unlikely Topical (lidocaine patch 5%) Transdermal (fentanyl patch)

19. 19 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

20. 20 Anticonvulsant Drugs for Neuropathic Pain Disorders Postherpetic neuralgia –gabapentin* –pregabalin * Diabetic neuropathy –carbamazepine –phenytoin –gabapentin –lamotrigine –pregabalin * HIV-associated neuropathy –lamotrigine Trigeminal neuralgia –carbamazepine* –lamotrigine –oxcarbazepine Central poststroke pain –lamotrigine *Approved by FDA for this use. HIV = human immunodeficiency virus.

21. 21 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.

22. 22 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 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.

23. 23 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 Fewest AEs Most AEs AEs = adverse effects.

24. 24 Principles of Opioid Therapy for Neuropathic Pain Opioids should be titrated for therapeutic efficacy versus AEs Fixed-dose regimens generally preferred over prn regimens 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

25. 25 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

26. 26 Interventional Treatments for Neuropathic Pain Neural blockade –sympathetic blocks for CRPS-I and II (reflex sympathetic dystrophy and causalgia) Neurolytic techniques –alcohol or phenol neurolysis –pulse radio frequency Stimulatory techniques –spinal cord stimulation –peripheral nerve stimulation Medication pumps CRPS = complex regional pain syndrome.

27. 27 Summary of Advances in Treatments for Neuropathic Pain* Botulinum toxin: low back pain Lidocaine patch 5%: low back pain, osteoarthritis, diabetic and HIV-related neuropathy, with gabapentin CR oxycodone: diabetic neuropathy Gabapentin: HIV-related neuropathy, diabetic peripheral neuropathy, others Levetiracetam: neuropathic pain and migraine Oxcarbazepine: neuropathic pain; diabetic neuropathy Bupropion: neuropathic pain Transdermal fentanyl: low back pain *Applications not approved by FDA.

28. 28 Summary Chronic neuropathic pain is a disease, not a symptom “Rational” polypharmacy is often necessary –combining peripheral and central nervous system agents enhances pain relief Treatment goals include: –balancing efficacy, safety, and tolerability –reducing baseline pain and pain exacerbations –improving function and QOL New agents and new uses for existing agents offer additional treatment options