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. 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. 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. 7 WHO Pain Ladder

8. Adjuvant Analgesics

9. “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 Analgesics Step 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. 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’s Side 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)

51. BUT…. If criteria are to be both relief of pain AND quality of life, the order would be:  Gabapentin / pregabalin  Tramadol  Opioids  TCA’s

52. Nerve Blocks: Celiac Plexus Block Used with upper abdominal malignancies Variable benefit (alcohol neurolysis most common)

53. Nerve Blocks: Mandibular / Maxillary / Gasserian ganglion block Used in head and neck cancer pain. Phenol / alcohol used for neurolysis Radiofrequency ablation also used Post neurolytic dysesthesia can occur

54. Axial therapy Both presynaptic and post synaptic opioid receptors within the dorsal horns of the spinal matter inhibit synaptic transmission from the peripheral afferent nociceptor to the second order spinal neuron.

55. Axial Therapy Intrathecal subarachnoid Epidural requires 10 times the intrathecal volume to spread medication over several dermatomal segments

56. Axial Therapy Advantages: Effective Markedly reduced side effects. Disadvantages: Surgical procedure Infection CSF leak

57. Axial vs. Oral Opiate Dosing Oral morphine = 300mg IV morphine = 100mg Epidural = 10mg morphine Intrathecal = 1mg morphine

58. Other Modalities Vertebroplasty Cement (polymethyl methacrylate) is injected into the damaged vertebra and acts as an internal splint. Useful in osteoporosis and cancer-associated fractures

59. Other Modalities TENS Stimulates large “A” fibers that then close the gate for pain coming in from “C” fibers. Used in acute and chronic pain syndromes. Low intensity: not reversed by naloxone High intensity: reversed by naloxone

60. Other Modalities Acupuncture: Possibly acts on reward center (dopamine and serotonin) May increase muscle blood flow May reduce gastric acid and correct gastric arrhythmia, thereby reducing nausea and vomiting.

61. Questions & Comments