1. Problem Solving in Persistent Pain Syndromes: a case-based approach Copyright © 2005 Thomson Professional Postgraduate Services ®. All rights reserved.

2. Chronic Pain Affects All Aspects of Patient’s Life 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 6

3. Mixed Type Nociceptive vs Neuropathic Pain Nociceptive Pain Neuropathic Pain Postoperative pain Mechanical low back pain Arthritis Sports/exercise injuries Postherpetic neuralgia Neuropathic low back pain Trigeminal neuralgia Polyneuropathy (diabetic, HIV) 10

4. Pain, Neural Excitation (“Wind-up”), and the HPA Axis Neuropathic pain induces changes in peripheral and central nervous system In the dorsal horn this results in dramatic increase in firing of neurons –from 1 every 3 seconds –to up to 30/second In the brain, hypothalamic activation by increased nociceptive input causes activation of the hypothalamic- pituitary-adrenal (HPA) axis, resulting in discharge of peripheral cortisol and activation of vasoactive immune system compounds Blackburn-Munro G, et al. J Neuroendocrinology. 2001;13:1009-1023. 17

5. Wind-up Pain: Mood Effects Activation of serotonergic and noradrenergic centers in brain stem Stimulation and dysfunction of limbic system, prefrontal cortex, hypothalamus, dorsal horn of spinal cord Depression, anxiety, panic, vegetative signs of depression, suicidal thoughts, and chronic pain Blackburn-Munro G, et al. J Neuroendocrinology. 2001;13:1009-1023. Stahl SM. J Clin Psychiatry. 2002;63:382-383. 18

6. Dorsal Horn BRAIN Pharmacologic Agents Affect Pain Differently Descending Modulation Peripheral Sensitization Central Sensitization PNS Local Anesthetics Topical Analgesics Anticonvulsants Tricyclic Antidepressants Opioids Anticonvulsants Opioids NMDA-Receptor Antagonists Tricyclic/SNRI Antidepressants Anticonvulsants Opioids Tricyclic/SNRI Antidepressants 20 SPINAL CORD CNS

7. Mechanisms of Action: Analgesic Agents Anticonvulsants –sodium-channel blockade (oxcarbazepine) –calcium-channel blockade (gabapentin) Antidepressants –inhibit reuptake of norepinephrine and serotonin into presynaptic neurons (duloxetine) Opioids –block neurotransmitter-release by nociceptive fibers, thus decreasing transmission of pain-producing signals (oxycodone) Topical Analgesics –sodium-channel blockade (lidocaine patch 5%) –vanilloid receptor (capsaicin) 21

8. 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 25

9. Antidepressants in Neuropathic Pain Disorders* Multiple proposed sites and mechanisms of action –central and peripheral nervous system –anticholinergic, serotonergic, noradrenergic RCTs show benefit (especially amitriptyline, nortriptyline, desipramine) Improvements in insomnia, anxiety, depression *Not approved by FDA for this use. 28

10. Amitryptyline – Sites of Action Descending Modulation Peripheral Sensitization Amitriptyline (anticholinergic, Inhibits 5-HT and NE reuptake) Tricyclic antidepressants are thought to affect pain transmission primarily in the CNS by inhibiting the reuptake of norepinephrine and serotonin, both of which influence descending pain pathways. Maizels M, McCarberg B. Am Fam Phys. 2005;71:483-490. Na channel blocker Dorsal Horn BRAIN PNS SPINAL CORD CNS 29

11. 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. 30

12. Tricyclic Antidepressants for Neuropathic Pain Disorders* Consider preprescription cardiac evaluation Intolerable side effects more frequent with amitriptyline –not recommended in patients  60 1 Use drug with fewer side effects Can split dose to reduce side effects Start at 10 to 25 mg at bedtime –increase every week as tolerated to a target dose of 25 to 150 mg –expect individual variability in treatment response Expect partial effect –use multiple agents (other classes and mechanism) Not being used simultaneously to treat depression *Not approved by FDA for this use. 1. AGS Panel on Persistent Pain in Older Persons. JAGS. 2002;50:S205-S224. 31

13. Topical Agents Act Locally Aspirin Preparations –eg, aspirin in chloroform or ethyl ether Capsaicin –extracted from chili peppers EMLA (eutectic mixture of local anesthetics) Lidocaine patch 5% 34

14. Lidocaine Patch 5% Works Locally Through Sodium Channels 36 Descending Modulation Dorsal Horn BRAIN PNS SPINAL CORD CNS Central Sensitization Peripheral Sensitization Lidocaine Patch 5% Na channel blocker

15. Lidocaine Patch 5% for Diabetic Neuropathy* Barbano RL et al. Arch Neurol. 2004;61:914-918. BPI=Brief Pain Inventory. *Not approved by FDA for this use. † P  0.001 at Week 3 versus baseline. BPI: Daily Pain Diary Ratings and Pain Relief Scores Mean daily pain rating Mean pain relief score (%) N=53 † † 37

16. Gabapentin Works Centrally Through Calcium Channels Anticonvulsants act at several sites that may be relevant to pain, but the precise mechanism of analgesic effect remains unclear. They are thought to limit neuronal excitation and enhance inhibition at various ion channels, especially the calcium channels. Maizels M, McCarberg B. Am Fam Phys. 2005;71:483-490. 40 Dorsal Horn BRAIN PNS SPINAL CORD CNS Peripheral Sensitization Gabapentin Descending Modulation Gabapentin Central Sensitization

17. Lidocaine Patch 5% With Gabapentin 41 Dorsal Horn BRAIN PNS SPINAL CORD CNS Descending Modulation Central Sensitization Peripheral Sensitization Lidocaine Patch 5% Gabapentin

18. Gabapentin in Neuropathic Pain Disorders* FDA approved for PHN Anticonvulsant: alpha 2 delta calcium channel antagonist 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. 42

19. 0 2 4 6 8 10 Screening12345678 Week Mean pain score *Not approved by FDA for this use. † P<0.01. ‡ P<0.05. Gabapentin in the Treatment of Painful Diabetic Neuropathy* Placebo Gabapentin Adapted from Backonja M et al. JAMA. 1998;280:1831-1836. N=165 † † ‡ † ‡‡ ‡ 43

20. Anticonvulsant Drugs for Neuropathic Pain Disorders Postherpetic neuralgia –gabapentin* –pregabalin* Diabetic neuropathy –carbamazepine –gabapentin –lamotrigine –phenytoin –pregabalin* HIV-associated neuropathy –lamotrigine Trigeminal neuralgia –carbamazepine* –lamotrigine –oxcarbazepine Central poststroke pain –lamotrigine *Approved by FDA for this use. HIV = human immunodeficiency virus. 46

21. Serotonin and Norepinephrine Reuptake Inhibitors Randomized clinical trials show benefit from dual action neurotransmitter reuptake inhibitors Duloxetine –FDA approved for peripheral diabetic neuropathy Venlafaxine 49

22. Dorsal Horn BRAIN PNS SPINAL CORD CNS Duloxetine Works Centrally in Descending Pathways and Spinal Cord Descending Modulation Peripheral Sensitization Central Sensitization Duloxetine is a dual reuptake inhibitor that enhances the levels of the neurotransmitters serotonin and norepinephrine. Duloxetine 50 NE, 5-HT

23. Duloxetine Is Effective for Diabetic Neuropathic Pain -3.5 -3 -2.5 -2 -1.5 -0.5 0 1234567891011120 Week Mean change in 24-hour average pain severity score 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):S48. * 51

24. Duloxetine Approved 9-7-2004 for management of pain association with diabetic neuropathy Once-daily dosing available in 20, 30, and 60 mg strengths Contraindicated in patients with uncontrolled narrow-angle glaucoma and patients taking monoamine oxidase inhibitors (MAOIs) Common sides effects include nausea, diarrhea, constipation, dizziness, drowsiness, anxiety, nervousness, insomnia

25. Short- and Long-acting Opioids Morphine sulfate Codeine Hydrocodone Oxycodone Hydromorphone Oxymorphone Fentanyl Methadone Sustained-release morphine Sustained-release oxycodone Transdermal fentanyl Levorphanol Short-acting Opioids Long-acting Opioids

26. Opioid Efficacy Studies in Neuropathic Pain Disorders Diabetic neuropathy –tramadol –oxycodone Nonmalignant neuropathic pain disorders –IV fentanyl Postherpetic neuralgia –IV morphine –controlled-release oxycodone Phantom limb pain –oral morphine IV = intravenous. 55

27. 0 10 20 30 40 50 60 70 80 90 Mean daily painSteady painBrief painSkin pain Placebo (benztropine 0.25 mg) CR oxycodone (10 mg) CR Oxycodone for Diabetic Neuropathy* † † † † *Not approved by FDA for this use. † P=0.0001. VAS (mm) Adapted from Watson CP et al. Pain. 2003;105:71-78. N=36 56

28. Efficacy of Tramadol in Painful Polyneuropathy Adapted from Sindrup SH et al. Pain. 1999;83:85-90. Placebo Median rating (0–10 point scale) 0 2 4 6 8 10 PainParesthesiaTouch-evoked pain 6 4 6 4 5 3 Tramadol P=0.001 P<0.001 N=45 57

29. Summary Customize therapy due to variance in response, individual clinical/social circumstances, and toxicity Rational polypharmacy – mechanisms, drug synergy, additive effects, or complementary effects Consider consultation for complex cases or patients who are refractory to first- or second-line therapies Never lose focus on managing the whole patient 60