The Use Of Adjuvants In Pain Management

1. The Use Of Adjuvants In Pain Management Stewart W. Stein, M.D. Medical Director, Good Shepherd Hospice

2. Objectives • Understand basic principles of pain transmission • Understand the role of adjuvants in the management of pain • Understand advantages and disadvantages of various agents in the management of chronic pain • Understand the use of other modalities in pain management.

3. Ascending Pathways • A-delta fibers are myelinated (insulated with a myelin sheath). The pain is fast and well localized, like the initial prick or stinging sensation following an injury. • C fibers are nonmyelinated and smaller than A-delta fibers. They transmit pain much slower. The pain is more lasting, generalized and described as a dull ache.

4. Ascending Pathways • After afferent A-delta (myelinated and fast) and C-fibers (unmyelinated and slow) synapse with the interneurons. • These cross over to the contralateral side and ascend primarily via the spinothalamic tracts to the thalmus and cortex.

5. Ascending Pathways

6. Pathophysiology • Nociceptor activation / Types of receptors: • Mechanical • Thermal • Chemical • Respond to stimuli that approach or exceed harmful intensity by undergoing conformational, electrical and biochemical changes

7. WHO Pain Ladder

8. Adjuvant Analgesics

9. Adjuvant Analgesics • “Non-opioids with analgesic efficacy” • Primarily used to treat neuropathic pain syndromes although also effective in management of nociceptive pain when used as adjuvants to other medications

10. Adjuvant AnalgesicsStep 1 Agents on the WHO ladder • Non-steroidal anti-inflammatories (NSAIDS) • Antidepressants (TCA’s) • Anticonvulsants / Antiepileptics (AED’s) • Cortisteroids • Bisphosphonates • Anesthetics • N-Methyl D-aspartate antagonists (NMDA)

11. Acetaminophen / Paracetamol • Mechanism of action unclear but may inhibit cyclooxygenase in the CNS • Acetaminophen can cause liver damage if dose exceeds 4 grams a day • Risk of hepatic injury is increased in patients having pre-existing liver damage (alcoholism, hepatitis) • Acetaminophen has also been shown to cause renal damage.

12. NSAIDS • Mechanism of action is the inhibition of cyclooxygenase to decrease prostaglandin synthesis • May have central action at the spinal cord level • They do have a ceiling effect • Tolerance and physical dependence is NOT seen! • Can be associated with end-organ toxicity

13. Neuropathic Pain Syndromes • Trigeminal neuralgia • Post-herpetic neuralgia • Diabetic neuropathy • Chemotherapy-induced neuropathy • Plexopathies • Phantom limb pain • Complex regional pain syndrome • Central post-stroke (damage to thalamus, cortical or subcortical structures) • Syringomyelia • Sympathetically maintained pain syndrome (RSD)

14. Adjuvant Analgesics • Tricyclic Anti-depressants • Inhibit reuptake of norepinephrine and serotonin in nerve endings in the spinal cord and in the brain • NMDA antagonism

15. Antidepressants • Tricyclic Antidepressants • Tertiary amines: • amitriptyline • doxepin • imipramine • clomipramine • Secondary amines: • desipramine • nortriptyline

16. Antidepressants • Serotoninergic agents • Fluoxetine • Paroxetine • Sertraline • Citalopram • Escitalopram

17. Antidepressants • SNRI’s (serotonin / norepinephrine reuptake inhibitors) • Venlafaxine • Desvenlafaxine • Duloxetine

18. Antidepressants • Used for: • Analgesia • Depression • Insomnia • (even pruritis)

19. Antidepressants: • Mechanism of action is inhibition of reuptake of neurotransmitters (serotonin, norepinephrine and dopamine) • Only tricyclic antidepressants have analgesic properties independent of their antidepressant activity

20. Antidepressants:Side Effects • Nausea • Sedation • Confusion • Xerostomia • Tachycardia • Drug interactions • (Anticholinergic )

21. Side Effects of TCA’s ?MI • Long term use of TCA’s is associated with a 2.2 relative risk of myocardial infarction and a 1.7fold increase in mortality vs. placebo or SSRI’s. (screen elderly with EKG?) • American Journal of Medicine (2000) Jan;108(1):2-8 • European Heart Journal (2004) 25 (1): 3-9

22. AED’s (Antiepileptic Drugs)

23. Mechanism of action of AED’s: • Slow recovery of voltage gated Na channels from depolarization (carbamazepine, phenytoin) • Indirect or direct enhancement of inhibitory Gama-aminobutyric acid neurotransmission (Valproic acid, Tiagabine) • Inhibition of excitatory glutamatergic neurotransmission (lamotrigine)

24. Mechanism of action of AED’s • Block voltage dependent Ca++ channel (Gabapentin and Pregabalin) • Carbonic anhydrase inhibition (Topiramate, Zonisamide)

25. Mechanism of action of AED’s:

26. New AED’s (Anti-Epileptic Drugs) • Gabapentin • Topiramate • Levitiracetam • Tiagabine • Oxcarbazepine • Lamotrigine • Felbamate • Pregabalin

27. Use of AED’s: • Start with a low evening dose • Increase GRADUALLY over 4-6 weeks depending on response. (Typically effective at higher doses)

28. New AED’sSide Effects • Drowsiness • Unsteadiness • Aplastic anemia (CB) • Dizziness • Confusion • Rash (VPA) • Ataxia • Nausea and vomiting

29. Gabapentin • Established efficacy in treatment of post herpetic neuralgia • Most common mistake is failure to titrate to effective doses (900mg ineffective in managing PDN in one series)

30. Gabapentin • Titration Schedule: • Day 1: 300mg po at HS • Day 2: 300mg po bid • Day 3: 300mg po tid • Titrate 100-300mg per day over next 2 weeks to target dose of 1800mg. Continue titration over 2 more weeks to 3600mg if indicated for effect. Higher doses have also been successfully used.

31. Pregabalin • Advantages include predictable absorption across the GI tract. Not metabolized or protein-bound. Minimal drug-drug interactions. • Multiple studies demonstrate effective pain relief and decreased sleep interference in PHN and PDN

32. Pregabalin • Dosing schedule • Days 1-3: 50mg po tid • Days 4-7: 100mg po tid • Thereafter 200mg po tid. • Taper dose over 7 days to discontinue

33. Lamotrigine • Demonstrated efficacy in trigeminal neuralgia. • Utility in vascular HA’s and PDN suggested by open label studies

34. Lamotrigine • Dosing: • Start at 25-50mg po daily • Increase by 50mg per day per week until effective or an arbitrary maximum is reached (usually around 900mg daily in 2-3 divided doses)

35. Topiramate • Studies demonstrate utility in management of cluster headache and diabetic neuropathy • Effective dose range is 200-400mg daily in divided (2) doses • Associated with weight loss • Side effects may include abnormal thinking, delusional and psychotic thinking, kidney stones.

36. Carbamazepine • Used in trigeminal neuralgia since the 1960’s! • Starting dose is 200mg po bid. Effective dose is usually 400-1000mg per day. • Induces P450 system so potential for drug-drug interactions. • Aplastic anemia occurs in 1:200,000. More commonly, a reversible leukopenia or thrombocytopenia may occur.

37. Oxcarbazepine • An analog of carbamazepine that retains many therapeutic properties of the drug while avoiding toxicities. (No bone marrow suppression or induction of P450 system) • Start with 300mg at HS. Increase weekly by 300-600mg until effective up to a maximum of 1200-2400mg per day.

38. Phenytoin • Mixed results in trials (1970’s) for PDN. • Usual dose 200-400mg po daily • Side effects include nausea, diplopia, dizziness, confusion, gingival hyperplasia and rarely Stevens-Johnson syndrome. • Induces P450 cytochrome system

39. Valproic acid • Demonstrated efficacy in migraine HA’s. • Side effects include nausea, vomiting, sedation, rash, ataxia and appetite stimulation • 40% develop increased transaminases. • 1:50,000 will develop HEPATIC FAILURE

40. Also part of the equation …. • NNT: The number of patients that need to be treated with a particular drug in order for one patient to experience a 50% reduction in pain • NNH: The number of patients that need to be treated with a particular drug in order for one patient to drop out due to adverse effects

41. TCA (amitriptyline) • NNT = 2-3 • NNH = 14.7

42. AED (gabapentin) • NNT = 5.1 (Includes all doses, high and low) • NNH = 26.1

43. Opioids • Morphine NNT = 2.5 • Oxycodone NNT = 2.6 • Tramadol NNT = 3.9 • NNH for tramadol = 9.0 • NNH morphine and oxycodone = not significant

44. Bisphosphonates • Pamidronate and Zolendronic acid • Localize to bone and inhibit osteoclastic activity • Widely studied in treatment of metastatic bone pain • Risk of osteonecrosis of the mandible.

45. Corticosteroids • Inhibit arachodonic acid (prostaglandin synthesis) resulting in anti-infalmmatory action • Also a membrane stabilizer (blocking c-fiber transmission)

46. NMDA Receptors • Located mostly in the dorsal horn of the spinal cord • Activated by chronic, painful stimulus leading to allodynia, hyperalgesia, and neuropathic pain. • Also responsible for opioid tolerance.

47. Therefore: • Blocking NMDA results not only in improved pain control but also reverses opioid tolerance to varying degrees.

48. NMDA receptor antagonists: • Methadone • Ketamine • Dextromethorphan

49. Ketamine • Useful in refractory neuropathic pain states • Useful to “reset” opioid sensitivity in an opioid-tolerant patient • Also very useful for procedures such as painful wound care

50. Neuropathic pain:How do we proceed? • If we were to look only at pain relief, the order would be: • TCA • opioids • tramadol • gabapentin / pregabalin (recall NNT)