Adjuvant Analgesics In

Palliative And End-Of-Life

Care

dr. Syafruddin Gaus, Ph.D, Sp.An-KMN-KNA

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

Case Presentation
Current Medications

Morphine 100 mg po q4h

Ibuprofen over the counter

Sennosides, docusate

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.

Adjuvants Used In Palliative

Care

General / Not specific

Neuropathic Pain

corticosteroids
cannabinoids (very uncommonly used)
gabapentin
antidepressants
topiramate
ketamine
clonidine

Bone Pain

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)
Immunosuppressio
n

LONG-TERM
Proximal
myopathy often
< 15 days
Cushings
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

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
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

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

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

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

Whats 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.

Oral Cannabinoids

9-tetrahydrocannabinol (THC; Marinol;

Dronabinol)

Nabilone synthetic derivative of THC

90 95% absorbed, but only 10 20%

reaches circulation due to hepatic firstpass 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: Nron A, Le medecin du Qubec 2001; Product monograph NCesamet

ICN Canada 2002; Product monograph NMarinol Sanofi-Synthelabo 2002

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 )

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

Bisphosphonates
Tolerability And Adverse Effects
1.

Renal toxicity

2.

Flu-like syndrome

3.

Hypocalcemia

4.

Avascular necrosis of the jaw

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)

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

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):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

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

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

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

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

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:
1.

2.

3.

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

Topiramate

Multiple neurostabilizing actions:

anti-glutamate effects at AMPA receptors; blockade

of voltage activated Na+ channels; enhancement of
GABA-mediated neuroinhibition; inhibition of Ltype 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 angleclosure glaucoma, transient myopia, and uveal
effusions
Decreased serum bicarbonate in up to 67%

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).

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%

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

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

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

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

Myoclonus twitching of large muscle

groups

Delirium

Rapidly escalating dose requirement

Pain doesnt make sense; not

consistent with recent pattern or known
disease

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