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 Presentation Current 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
IMMEDIATE
LONG-TERM
Psychiatric
Hyperglycemia
­ risk of GI bleed
gastritis
aggravation of existing lesion (ulcer, tumor)
Immunosuppression
Proximal myopathy often < 15 days
Cushing’s syndrome
Osteoporosis
Aseptic / avascular necrosis of bone

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. Isolated pure compounds (>400)
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 Receptors CB1 And CB2
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. Marijuana - Acute Effects
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

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 gm
Informal surveys in US of medicinal cannabis users indicate avg. use of gm/wk, or g/day
Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI.
Medicinal cannabis: rational guidelines for dosing.
IDrugs 2004; 7(5):

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
Nabilone is officially indicated for severe nausea and vomiting associated to chemotherapy treatment. (However, the main usage is in pain and body wasting)
Dronabinol is officially indicated for severe nausea and vomiting associated to chemotherapy treatment and also body wasting syndrome, anorexia associated with HIV.
There is an initiative of the Canadian government to allow patients to use cannabis for medical purposes, and pain is one of the most common reasons for these requests.
Nabilone is the sole cannabinoid fully reimbursed by most provincial and private plans. It ’s use is limited in Saskatchewan for body wasting syndrome associated with HIV.
Comparing equivalent dosages according to the body surface, the cost of nabilone is 20% lower than dronabinol
Sources: Provincial Drug List; CPS 2002; Marihuana Medical Access Regulations (MMAR), April 2001, Health Canada

25. Available cannabinoids: Pharmacokinetics
Nabilone is a synthetic cannabinoid. When metabolized, it is converted in the active metabolite carbinol.
Dronabinol is a 9-THC cannabinoid. It is metabolized chiefly in the liver where it is converted to 11-hydroxy-  9-THC and more than 20 other metabolites not clearly identified.
Marijuana contains more than 400 components including more than 60 types of cannabinoids. There is psychoactive, active and non-active cannabinoids. Also, there is hundreds of compounds which are not cannabinoid-type in which contaminants are found.
Nabilone, compared to dronabinol and inhaled marijuana, has a shorter half-life of 2 hours and a longer duration of action between 8-12 hours which reduce the potential for accumulation and toxicity.
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 Osteoclast inhibitors
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. Bisphosphonates Tolerability And Adverse Effects
Renal toxicity
Flu-like syndrome
Hypocalcemia
Avascular necrosis of the jaw

29. Bisphosphonates Renal 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 Hypocalcemia
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. Bisphosphonates Avascular 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):
Schwartz HC. Osteonecrosis and bisphosphonates: correlation versus causation. J Oral Maxillofac Surg 2004; 62(6):
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):
Pogrel MA. Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 2004; 62(3):
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):
Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer patients. J Oral Maxillofac Surg 2003; 61(10):
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61(9):

32. Bisphosphonates Avascular Necrosis of Jaw ctd
Retrospective chart review Feb – 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 Frail patients
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: Neuropathic Pain
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. Misinterpreted as Pain Misinterpreted as Disease-Related Pain
Spectrum of Opioid-Induced Neurotoxicity
Opioid tolerance
Mild myoclonus (eg. with sleeping)
Severe myoclonus
Seizures, Death
Delirium
Agitation
Misinterpreted as Pain
Opioids Increased
Hyperalgesia
Misinterpreted as Disease-Related Pain
Opioids Increased

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