Adjuvant Analgesics In Palliative And End-Of-Life Care

1. Adjuvant Analgesics In Palliative And End-Of-Life Care Mike Harlos MD, CCFP, FCFP Professor and Section Head, Palliative Medicine, University of Manitoba Medical Director, WRHA Palliative Care Medical Director, Pediatric Symptom Management Service

2. Case Presentation • 55 yo man • Metastatic CA lung, large L apical tumour • Chemotherapy completed, no response • Metastatic disease to bone, liver • Presents with worsening L arm pain and numbness, allodynia, tingling and burning • Motor exam normal

3. Case PresentationCurrent Medications • Morphine 100 mg po q4h • Ibuprofen over the counter • Sennosides, docusate

4. Adjuvant Analgesics • first developed for non-analgesic indications • subsequently found to have analgesic activity in specific pain scenarios • Common uses: • pain poorly-responsive to opioids (eg. neuropathic pain), or • with intentions of lowering the total opioid dose and thereby mitigate opioid side effects.

5. Adjuvants Used In Palliative Care • General / Not specific • corticosteroids • cannabinoids (very uncommonly used) • Neuropathic Pain • gabapentin • antidepressants • topiramate • ketamine • clonidine • Bone Pain • bisphosphonates • (calcitonin)

6. CORTICOSTEROIDS AS ADJUVANTS • ¯ inflammation • ¯ edema • ¯ spontaneous nerve depolarization } ¯ tumor mass effects

7. CORTICOSTEROIDS: ADVERSE EFFECTS

8. DEXAMETHASONE • minimal mineralcorticoid effects • po/iv/sq/?sublingual routes • perhaps can be given once/day; often given more frequently • If an acute course is discontinued within 2 wks, adrenal suppression not likely

9. Cannabinoids As Adjuvants

10. Cannabis sativa THC content approx. 5% THC content 10 – 20% Marijuana dried leaves, flowers Hashish resin from leaves, buds Isolated pure compounds (>400) Noncannabinoids Cannabinoids • Psychoactive • 8-THC • 9-THC • cannabinol • Active, not • psychoactive • cannabidiol • Inactive • > 60 Kalant, Pain Res Manage 2001

11. Cannabinoid ReceptorsCB1 And CB2 • CB1 • Central and peripheral nervous system • Highest density in globus pallidus, basal ganglia, substantia nigra, cerebellum, hippocampus, afferent spinal cord pathways • Main effect is ¯ neurotransmitter release –dopamine, NE, serotonin • Low levels in cardiorespiratory centres ®high therapeutic index • CB2 – certain nonneural tissues, eg. immune cells • Cannabinoids also bind to NMDA receptors – possible role in neuropathic pain Kumar et al, Anaesthesia 2001; 56

12. Cannabinoids • The only clinical indication is in chemotherapy-induced nausea • Mixed results in human studies for pain control; animal studies suggest possible role for neuropathic pain • Double-blind, placebo-controlled trials indicate a similar analgesic potency to codeine, however high adverse effects

13. Marijuana Use in Pain • Five RCTs on cancer pain • Tetrahydrocannabinol (THC) or nabilone vs placebo or opioids • High rate of side effects • 128 pts total, single dose x-over design • THC = codeine (60, 120 mg) > placebo • Nabilone > placebo • Higher doses had unacceptable S/E • Poor evidence for pain control Campbell et al, BMJ 323:13-16, 2001

14. Increased pulse, BP unaffected or slight ¯ Conjunctival reddening No effect on pupil size, resp. rate, DTRs Initial euphoria then relaxation Appetite stimulation Slowed reaction time, altered perception, impaired coordination May cause paranoia, delusions, hallucinations, depersonalization Marijuana - Acute Effects

15. Inhaled Marijuana • has all (except one) the same chemical carcinogens found in tobacco • > 400 chemicals • High tar content • Respiratory epithelium damage • Obstruction on PFTs • COPD in chronic users • H & N, lung cancer reports

16. What’s A Reasonable Dose Of Inhaled Marijuana For Symptom Control? • Bioavailability of THC in smoked marijuana ranges from 10 – 27%; significantly influenced by technique/experience • Typical cannabis cigarette has a mass between 0.5 - 1 gm • Informal surveys in US of medicinal cannabis users indicate avg. use of 10 - 20 gm/wk, or 1.42 - 2.86 g/day Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs 2004; 7(5):464-470.

17. http://palliative.info

22. College of Physicians & Surgeons of MB Oct. 2001 Newsletter “Physicians who recommend, support the use of, or prescribe this substance, must be fully knowledgeable of the risks, benefits, potential complications, and drug interactions associated with its use. Based on the available scientific evidence, the medicinal use of smoked marijuana is at present generally without valid scientific foundation and physicians should not feel obliged to recommend, support, or prescribe this substance”

23. Oral Cannabinoids • ∆9-tetrahydrocannabinol (THC; Marinol; Dronabinol) • Nabilone – synthetic derivative of THC • 90 – 95% absorbed, but only 10 – 20% reaches circulation due to hepatic first-pass metabolism • 1 hr to peak effect vs. 15 min. if smoked

24. Available Cannabinoids Sources: Provincial Drug List; CPS 2002; Marihuana Medical Access Regulations (MMAR), April 2001, Health Canada

25. Available cannabinoids: Pharmacokinetics Sources: Néron A, Le medecin du Québec 2001; Product monograph NCesamet ICN Canada 2002; Product monograph NMarinol Sanofi-Synthelabo 2002

26. Management of Bone Pain Pharmacologic treatment • Acetaminophen • Opioids • NSAIDs – be aware of adverse effects! • Corticosteroids (not with NSAIDS) • Bisphosphonates: pamidronate (Aredia), clodronate (Bonefos), zoledronate (Zometa)

27. Bisphosphonates Ross et al;Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327(7413):469 • Osteoclast inhibitors • bone metastases: pooled results ® signif. ¯ in all skeletal morbidity end points except spinal cord compression • signif. ­time to first skeletal related event, suggesting they should be started when bone metastases are diagnosed • ¯ skeletal morbidity and should be continued until no longer clinically relevant • do not affect survival • Most evidence supports use of IV aminobisphosphonates, but further studies needed to determine best drug & route

28. BisphosphonatesTolerability And Adverse Effects • Renal toxicity • Flu-like syndrome • Hypocalcemia • Avascular necrosis of the jaw

29. BisphosphonatesRenal Implications • Renal toxicity – IV bisphosphonates • In rare cases can be life-threatening • 9% of patients receiving 4 mg zoledronate and 8% of those receiving 90 mg pamidronate with normal baseline renal function developed increased creatinine levels (Rosen et al; J Clin Oncol 2003) • Should monitor creatinine before each dose, and hold repeat dosing until within 10% of baseline • Make sure patient is well hydrated prior to administration (eg. in hypercalcemia)

30. Bisphosphonates ctd • Flu-Like Reaction • Esp. with intravenous bisphosphonates • Up to 36% of patients • Usually managed with acetaminophen • Hypocalcemia • Usually compensate by increased PTH secretion • Hypomagnesemia, previous parathyroid removal, Vit D deficiency are risk factors • Recommendations are to give 500 mg Calcium and 400 IU Vit. D as daily supplements

31. BisphosphonatesAvascular Necrosis of Jaw • Robinson NA, Yeo JF. Bisphosphonates--a word of caution. Ann Acad Med Singapore 2004; 33(4 Suppl):48-49. • Greenberg MS. Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 98(3):259-260. • Schwartz HC. Osteonecrosis and bisphosphonates: correlation versus causation. J Oral Maxillofac Surg 2004; 62(6):763-764. • Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62(5):527-534. • Pogrel MA. Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 2004; 62(3):391-392. • Carter GD, Goss AN. Bisphosphonates and avascular necrosis of the jaws. Aust Dent J 2003; 48(4):268. • Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21(22):4253-4254. • Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer patients. J Oral Maxillofac Surg 2003; 61(10):1238-1239. • Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61(9):1115-1117.

32. BisphosphonatesAvascular Necrosis of Jaw ctd • Retrospective chart review Feb. 2001 – Nov. 2003 • 63 patients with chronic osteonecrosis of jaw while on bisphosphonates; 7 for osteoporosis • 4 patients during that time period with similar presentation while not on bisphosphonates; 3 of them had prior local radiation for sq. cell CA • Localized vascular insufficiency, similar to osteoradionecrosis • Correlation with dental procedures - suggest a complete dental exam prior to long-term bisphosphonate treatment, and any dental pathology addressed

33. Adjuvants in Neuropathic Pain

34. Gabapentin • a second line anticonvulsant • shown to be effective in neuropathic pain; has become a first-line agent in neuropathic pain • structural analog of GABA, but does not bind to GABA receptors • increases concentration and synthesis of GABA in the brain • GABA receptors have been shown to mediate pre- and postsynaptic inhibition in sensory afferent fibers

35. Gabapentin • Common Starting Regimen • 300 mg hs Day 1, 300 mg bid Day2, 300 mg tid Day 3, then gradually titrate to effect up to 1200 mg tid • Frail patients • 100 mg hs Day 1, 100 mg bid Day 2, 100 mg tid Day 3, then gradually titrate to effect

36. TCAs • increase in monoamine activity in descending pain modulating pathways • inhibition of reuptake of NE and serotonin at spinal dorsal horn synapses • alt. mechanisms include blockade of Na+ channels, GABA effects, K+ channel blockade, adenosine • neuropathic pain, esp. continuous dysaesthesia • anticholinergic adverse effects; amitriptyline > nortriptyline > desipramine • lower doses and earlier response than depression

37. SSRIs And Newer Antidepressants • less convincing evidence for independent analgesic effects; those affecting both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs • newer meds with mixed neurotransmitter effects: • Serotonin and Noradrenergic Reuptake Inhibitors (SNaRI) – eg. Venlafaxine (Effexor), nefazodone (Serzone), duloxetine • Noradrenergic and Specific Serotoninergic Antidepressants (NaSSA) – eg. mirtazapine (Remeron) • Noradrenaline Reuptake Inhibitors (NaRI) – eg. reboxetine

38. Topiramate • Multiple neurostabilizing actions: • anti-glutamate effects at AMPA receptors; blockade of voltage activated Na+ channels; enhancement of GABA-mediated neuroinhibition; inhibition of L-type high voltage-activated Ca++ currents; activation of potassium conductance • Neuropathic Pain • Consider if gabapentin failed • Typically start with 25 mg/day • Effectiveness demonstrated in diabetic neuropathy • Ocular adverse effects include secondary angle-closure glaucoma, transient myopia, and uveal effusions • Decreased serum bicarbonate in up to 67%

39. Ketamine • Disassociative anesthetic • Analgesic in subanesthetic doses • Most potent NMDA receptor antagonist available for clinical use • NMDA-receptor activation is associated with windup, hyperalgesia and reduced opioid sensitivity. • Ketamine is widely used in cancer pain to improve opioid analgesia when tolerance has developed or the pain is considered to be opioid resistant. • Randomised and controlled trials are rare; data from two of these trials suggest potential benefit of ketamine as adjuvant to morphine in cancer pain (Bell et al., 2003).

40. Ketamine • Often use oral dosing of intravenous preparation • A common starting dose is 10 mg qid po (low dose) • Concomitant benzodiazepine administration may attenuate adverse CNS effects (eg. Lorazepam 0.5 – 1 mg sl bid – tid) • Decrease concurrent opioid dose by 25 – 50%

41. Clonidine • alpha-2 agonist • decrease sympathetic transmitter release through pre and post-synaptic inhibition • Considered in refractory neuropathic pain • Literature predominantly regarding spinal administration • Recent literature suggests possible topical role

42. Calcitonin • Osteoclast inhibition • Cochrane review 2003: “The limited evidence currently available for systematic review does not support the use of calcitonin to control pain from bone metastases. Until new studies provide additional information on this treatment, other therapeutic approaches should be considered ”

43. Case Presentation ctd • Rule out opioid-induced neurotoxicity • d/c NSAID • Add gabapentin and dexamethasone • Consider: • CT to determine anatomy; ? Radiation • Methadone • Ketamine • TCA • Topiramate • Spinal analgesia

44. Opioid-Induced Neurotoxicity (OIN) • Potentially fatal neuropsychiatric syndrome of: • Cognitive dysfunction • Delirium • Hallucinations • Myoclonus/seizures • Hyperalgesia / allodynia • Increasing incidence – practitioners more comfortable and aggressive with opioids • NMDA receptor involved • Early recognition is critical

46. Delirium Hyperalgesia OpioidsIncreased Agitation OpioidsIncreased Misinterpretedas Disease-Related Pain Misinterpretedas Pain Spectrum of Opioid-Induced Neurotoxicity Opioidtolerance Mild myoclonus(eg. with sleeping) Seizures,Death Severe myoclonus

47. OIN: Recognition • Myoclonus – twitching of large muscle groups • Delirium • Rapidly escalating dose requirement • Pain “doesn’t make sense”; not consistent with recent pattern or known disease

48. OIN: Treatment • Switch opioid (rotation) or reduce opioid dose; usually much lower than expected doses of alternate opioid required… often use prn initially • Hydration • Benzodiazepines for neuromuscular excitation