Transcript Palliative Care in Winnipeg

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
Case Presentation
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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
Case Presentation
Current Medications
 Morphine 100 mg po q4h
 Ibuprofen over the counter
 Sennosides, docusate
Adjuvant Analgesics
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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.
Adjuvants Used In Palliative Care
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General / Not specific
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Neuropathic Pain
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corticosteroids
cannabinoids (very uncommonly used)
gabapentin
antidepressants
topiramate
ketamine
clonidine
Bone Pain
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bisphosphonates
(calcitonin)
CORTICOSTEROIDS AS ADJUVANTS
 inflammation
 edema
}
tumor mass
effects
 spontaneous nerve depolarization
CORTICOSTEROIDS: ADVERSE EFFECTS
IMMEDIATE
 Psychiatric
 Hyperglycemia
 risk of GI bleed
 gastritis
 aggravation of
existing lesion
(ulcer, tumor)
 Immunosuppression
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LONG-TERM
Proximal myopathy
often < 15 days
Cushing’s
syndrome
Osteoporosis
Aseptic / avascular
necrosis of bone
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
Cannabinoids
As
Adjuvants
Cannabis sativa
THC content
approx. 5%
THC content
10 – 20%
Marijuana
Hashish
dried leaves, flowers
resin from leaves, buds
Isolated pure compounds (>400)
Noncannabinoids
Psychoactive
• 8-THC
• 9-THC
• cannabinol
Cannabinoids
Active, not
psychoactive
• cannabidiol
Inactive
• > 60
Kalant, Pain Res Manage 2001
Cannabinoid Receptors
CB1 And CB2
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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
Cannabinoids
 The only clinical indication is in chemotherapyinduced 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
Marijuana Use in Pain
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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
Marijuana - Acute Effects
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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
Inhaled Marijuana
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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
What’s A Reasonable Dose Of Inhaled
Marijuana For Symptom Control?
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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.
http://palliative.info
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”
Oral Cannabinoids
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∆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
Available Cannabinoids
Sources: Provincial Drug List; CPS 2002; Marihuana Medical Access
Regulations (MMAR), April 2001, Health Canada
Available cannabinoids: Pharmacokinetics
Sources: Néron A, Le medecin du Québec 2001; Product monograph NCesamet
ICN Canada 2002; Product monograph NMarinol Sanofi-Synthelabo 2002
Management of Bone Pain
Pharmacologic treatment
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Acetaminophen
Opioids
NSAIDs – be aware of adverse effects!
Corticosteroids (not with NSAIDS)
Bisphosphonates: pamidronate (Aredia),
clodronate (Bonefos), zoledronate
(Zometa)
Bisphosphonates
Ross et al;Systematic review of role of bisphosphonates on skeletal morbidity
in metastatic cancer. BMJ 2003; 327(7413):469
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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
Bisphosphonates
Tolerability And Adverse Effects
1. Renal toxicity
2. Flu-like syndrome
3. Hypocalcemia
4. Avascular necrosis of the jaw
Bisphosphonates
Renal Implications
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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)
Bisphosphonates ctd
Flu-Like Reaction
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Esp. with intravenous bisphosphonates
Up to 36% of patients
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Usually managed with acetaminophen
Hypocalcemia
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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
Bisphosphonates
Avascular Necrosis of Jaw
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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.
Bisphosphonates
Avascular Necrosis of Jaw ctd
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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
Adjuvants in
Neuropathic Pain
Gabapentin
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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
Gabapentin
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Common Starting Regimen
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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
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100 mg hs Day 1, 100 mg bid Day 2,
100 mg tid Day 3, then gradually
titrate to effect
TCAs
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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
SSRIs And Newer Antidepressants
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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:
1. Serotonin and Noradrenergic Reuptake Inhibitors
(SNaRI) – eg. Venlafaxine (Effexor), nefazodone
(Serzone), duloxetine
2. Noradrenergic and Specific Serotoninergic
Antidepressants (NaSSA) – eg. mirtazapine
(Remeron)
3. Noradrenaline Reuptake Inhibitors (NaRI) – eg.
reboxetine
Topiramate
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Multiple neurostabilizing actions:
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anti-glutamate effects at AMPA receptors; blockade of
voltage activated Na+ channels; enhancement of GABAmediated neuroinhibition; inhibition of L-type high
voltage-activated Ca++ currents; activation of
potassium conductance
Neuropathic Pain
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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%
Ketamine
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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).
Ketamine
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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%
Clonidine
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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
Calcitonin
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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 ”
Case Presentation ctd
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Rule out opioid-induced neurotoxicity
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d/c NSAID
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Add gabapentin and dexamethasone
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Consider:
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CT to determine anatomy; ? Radiation
Methadone
Ketamine
TCA
Topiramate
Spinal analgesia
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
Spectrum of Opioid-Induced Neurotoxicity
Opioid
tolerance
Mild myoclonus
(eg. with sleeping)
Delirium
Opioids
Increased
Severe myoclonus
Seizures,
Death
Hyperalgesia
Agitation
Misinterpreted
as Pain
Opioids
Increased
Misinterpreted
as Disease-Related Pain
OIN: Recognition
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Myoclonus – twitching of large muscle
groups
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Delirium
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Rapidly escalating dose requirement
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Pain “doesn’t make sense”; not consistent
with recent pattern or known disease
OIN: Treatment
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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