Pharmacotherapeutic Options in Pain Management

1. Pharmacotherapeutic Options in Pain Management Charles E. Argoff, M.D. Director, Cohn Pain Management Center North Shore University Hospital Assistant Professor of Neurology New York University School of Medicine

2. Characteristic Acute Pain Chronic Pain Cause Generally knownOften unknown Duration of pain Short, Persists after well-characterized healing, 3 mo Treatment Underlying disease Underlying disease approach and pain disorder Acute vs Chronic Pain

3. Nociceptive vs Neuropathic Pain Nociceptive Pain Caused by activity in neural pathways in response to potentially tissue-damaging stimuli MixedType Caused by a combination of both primary injury or secondary effects Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system CRPS* Postherpeticneuralgia Postoperativepain Trigeminalneuralgia Arthritis Sickle cellcrisis Neuropathic low back pain Mechanicallow back pain Central post-stroke pain Distalpolyneuropathy (eg, diabetic, HIV) Sports/exerciseinjuries *Complex regional pain syndrome

4. Sensations burning paresthesia paroxysmal lancinating electriclike raw skin shooting deep, dull, bonelike ache Cardinal signs/symptoms allodynia: pain from a stimulus that does not normally evoke pain thermal mechanical hyperalgesia: exaggerated response to a normally painful stimulus Potential Descriptions of Chronic Pain

5. Pathophysiology of Chronic 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

6. Pathophysiology:Peripheral Sensitization Nociceptor Nociceptor Na+channels Innocuousstimulus Painsensation • Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.

7. Pathophysiology:Central Sensitization Normal sensory function Ab fibermechanoreceptor Weaksynapse Nonpainfulsensation Innocuousstimulus Na+channel Na+channel Increased nociceptor drive leads to central sensitization of dorsal horn neurons Increasedsynapsisstrength Painfulsensation Innocuousstimulus Na+channel Na+channel • Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.

8. Pathophysiology:Peripheral and Central Sensitization

10. “Discouraging data on the antidepressant.”

11. Assessment of Pain Intensity Visual Analog Scale Verbal Pain Intensity Scale No Mild Moderate Severe Very Worst pain pain pain pain severe possible pain pain Worstpossiblepain No pain 0–10 Numeric Pain Intensity Scale Faces Scale 0 1 2 3 4 5 6 7 8 9 10 No Moderate Worst pain pain possible pain 0 1 2 3 4 5 Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. FA Davis; 1996:8-10. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing. 5th ed. Mosby, Inc.; 1997:1215-1216. McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16. 21

12. Assessment of Pain Intensity Visual Analog Scale Verbal Pain Intensity Scale No Mild Moderate Severe Very Worst pain pain pain pain severe possible pain pain Worstpossiblepain No pain 0–10 Numeric Pain Intensity Scale Faces Scale 0 1 2 3 4 5 6 7 8 9 10 No Moderate Worst pain pain possible pain 0 1 2 3 4 5 Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. FA Davis; 1996:8-10. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing. 5th ed. Mosby, Inc.; 1997:1215-1216. McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16. 21

13. Multidisciplinary Treatment of Chronic Pain • Pharmacotherapy and other medical/surgical care with appropriate medicine reorganization • Restorative care including active physical and occupational therapy • Psychological counseling utilizing cognitive-behavioral pain management strategies

14. Aim for Monotherapy Titrate only one drug at a time

15. PharmacotherapyGuidelines • Medication must result in: • Significant pain relief • Tolerable side effects function

16. Pharmacotherapy Guidelines • Both physician & patient must realize significant individual variability

17. Pharmacotherapy Guidelines • Slow titration until either: • Significant pain relief • Intolerable side effects • “Toxic serum level”

18. Pharmacotherapy Guidelines • Educate the patient

19. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

20. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

21. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

22. Antidepressants*

23. Review of Antidepressant Analgesia

24. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

25. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

26. Carbamazepine* Divalproex sodium* Gabapentin Clonazepam Phenytoin *Has FDA indication for pain/headache Lamotrigine Topiramate Zonisamide Oxcarbazepine Levatriacetam Tiagabine Anticonvulsants

27. Postherpetic neuralgia gabapentin Diabetic neuropathy carbamazepine phenytoin gabapentin lamotrigine HIV-associated neuropathy lamotrigine Trigeminal neuralgia carbamazepine lamotrigine oxcarbazepine Central poststroke pain lamotrigine Anticonvulsant Drugs and Neuropathic Pain Disorders* *Not approved by FDA for this use. 43

28. Gabapentin in the Treatment of Painful Diabetic Neuropathy* 10 Placebo Gabapentin 8 N=165 6 Mean pain score 4 † † ‡ † ‡ ‡ ‡ 2 †P<0.01; ‡P<0.05. 0 Screening 1 2 3 4 5 6 7 8 Week *Not approved by FDA for this use. Adapted from Backonja M et al. JAMA. 1998;280:1831-1836. 46

29. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

30. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

31. Currently Available Alpha-Adrenergic Agonists • Clonidine • Tizanidine

32. Possible Effective Uses of Tizanidine • Trigeminal neuralgia (Fromm 1993) • Chronic low back pain(Berry 1988) • Cluster headache (D’alessandro 1996) • Chronic tension-type headache (Nakashima 1994) • Spasmodic torticollis (Houten 1984) • Neuropathic pain • Chronic headache(2002)

33. Efficacy of Tizanidine in Neuropathic Pain: An Open-Label StudyMarilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MDUniversity of Arizona, Neurology Clinic • Trial Design: • Open-label (N=22) • 14 peripheral neuropathy, 1 diabetic neuropathy, 3 reflex sympathetic dystrophy, 1 radiculopathy, 2 nerve damage, 1 trigeminal neuralgia • 8 week treatment duration • Zanaflex initiated at dose of 4 mg qd hs for 7 days and increased by 2 mg – 8 mg weekly and taken in divided doses up to three time a day • The dose was escalated to the patient’s effective or maximum tolerated dose or a maximum of 36 mg/day

34. Efficacy of Tizanidine in Neuropathic Pain: An Open-Label StudyMarilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MDUniversity of Arizona, Neurology Clinic • Outcome Measures: • Mean average weekly pain rating from patient diary (VAS) • Biweekly patient global assessment of pain relief • Mean biweekly scores of Neuropathic Pain Scale • Mean biweekly scores on the Wisconsin Brief Pain Inventory

35. Efficacy of Tizanidine in Neuropathic Pain: An Open-Label StudyMarilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MDUniversity of Arizona, Neurology Clinic • Results: • Zanaflex may be an effective treatment of neuropathic pain in many patients and is generally well tolerated, offering an alternative for patients unable to tolerate other medication • The mean effective or maximum tolerated dose was 23 mg/day, the median dose was 24 mg/day and the dose range was 6 – 36 mg/day • Inhibition of the synaptic transmission of nociceptive stimuli in the spinal pathways may mediate this effect

36. Efficacy of Tizanidine in Neuropathic Pain: An Open-Label StudyMarilyn R. Semenchuk, PharmD, BCPP; Scott Sherman, MDUniversity of Arizona, Neurology Clinic

37. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

38. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

39. Nerve Injury Mu-Opioid-RActivation NMDA-R PKC Inhibitors  Excitability Neurotoxicity  Mu-Efficacy Hyperalgesia Mu-Opioid Tolerance Advances in Opioid Analgesia

40. Drugs with Potential NMDA-R Antagonist Properties • Dextromethorphan • Ketamine • d-Methadone • Amantadine • Memantine • Amitriptyline

41. DEXTROMETHORPHANPostherpetic Neuralgia & Painful diabetic neuropathy • 2 RCTs Crossover: 6 weeks • Dextromethorphan alone vs placebo • DN: • mean daily dose = 381 mg/day • Pain decreased ( p=0.01) • PHN: • mean daily dose = 439 mg/day • Did not significantly reduce pain (Nelson 1997)

42. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

43. Muscle Relaxants • Cyclobenzaprine (Flexeril®) • Carisoprodol (Soma®) • Methocarbamol (Robaxin®) • Metaxalone (Skelaxin®) • Orphenadrine citrate (Norflex®)

44. Cyclobenzaprine • Structurally similar to tricyclics • Centrally acting • Nocturnal muscle spasm effects • Side effects: • Drowsiness - Cardiac dysrhythmias • Anticholinergic • Dry mouth • Blurred vision • Urine retention • Constipation • Increased intraocular pressure

45. Carisoprodol • Precursor of meprobamate • Centrally active • Reduction of muscle spasm • Side effects: • Sedation, drowsiness, dependence • Withdrawal symptoms • Agitation • Anorexia • N/V • Hallucination • Seizures

46. Methocarbamol • Investigative usage: MS • Daily dosage: 1000 mg qid • Side effect: drowsiness • Mechanism of action: • Centrally active • Inhibits polysynaptic reflexes • Clinical effects: • Reduction of muscle spasms

47. Metaxalone • Daily dosage: 400-800 mg tid • Clinical effects: • Reduction in muscle spasm • Side effects: • Nausea • Drowsiness • Dizziness

48. Orphenadrine Citrate • Investigative usage: SCI • Daily dosage: 100 mg bid • Analog of diphenhydramine • Given IV for antispasticity trials • Side effects: • Anticholinergic • Rare aplastic anemia

49. Non-Opiate Pharmacotherapy • NSAIDs/Cox-2 • Acetaminophen • Antidepressants • Anticonvulsants • Oral local anesthetics • Alpha adrenergic agents • Neuroleptics • NMDA receptor antagonists • Muscle relaxants • Topical analgesics • Emerging Agents

50. Topical Analgesics: Key Facts • Topical agents are active within the skin, soft tissues and peripheral nerves. • In contrast to transdermal, oral or parenteral medications, use of a topical agent does not result in clinically significant serum drug levels. • Other benefits include lack of systemic side effects and drug-drug interactions. • The mechanism of action of a topical analgesic is unique to the specific agent considered.