Adjuvant Analgesic Drugs

Syafruddin Gaus

Adjuvant analgesic drugs

Are drugs that have weak or
non-analgesic action when
administered alone but can
enhance analgesic action
when coadministered with
analgesic agents.

 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.

Some adjuvant drugs

3 drugs are very important and
very related to anesthesiologist.

Steroids (dexamethasone)
Clonidine (Alpha 2
agonist)
Ketamine
Pregabalin

 General / Not specific

corticosteroids
cannabinoids (very uncommonly used)
Neuropathic Pain
gabapentin
antidepressants
topiramate
ketamine
clonidine
Bone Pain
bisphosphonates
(calcitonin)

Corticosteroids as
Adjuvants

Corticosteroids
Many uses:
Somatic pain that does
not response to opioids,
hypersensitivity with
NSAIDs
Nerve compression, cord
compression

Dexamethasone
Anti-emetic
Anti-inflammation
Anti-udema
Analgetic in moderate
dose
Dexamethasone

long half-life (>36 h), dose once a day

minimal mineralocorticoid effect
doses of 220 mg/d

CORTICOSTEROIDS: ADVERSE EFFECTS

IMMEDIATE
Psychiatric
Hyperglycaemia
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

CORTICOSTEROIDS AS ADJUVANTS
inflammation
edema

tumor mass
effects

spontaneous nerve depolarization

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

Adjuvants in
Neuropathic Pain

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

Tricyclic Antidepressants (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

TCAs
neuropathic pain, esp. continuous
dysaesthesia
anticholinergic adverse effects;
amitriptyline > nortriptyline >
desipramine
lower doses and earlier response
than depression

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 voltageactivated 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

KETAMINE
Anesthesia Dose > 2 mg/Kg BW

Will implicate in causing Psychomimetic effects, such as;

Excessive sedation
Cognitive Dysfunction
Hallucination
Nightmares

Subanesthesia Doses (Low Dose) < 1

mg/Kg BW
Have significant analgesic

efficacy without those side effects, but may excerts

Dose
of Ketamin
0.15
mg/Kg
BW Should
be combined
nausea,
vomiting,
urinary
retention,
constipation
etc.
pioid
ocal Anesthetic
ther Analgesic Agents

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
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%

KETAMINE
More Frequently Use in Postorthopedic Surgical Pain
Management

Arthroscopic Anterior
Cruciate Ligament Surgery

Outpatient Knee
Arthroscopy

A Single intraoperative injection

of ketamin (0,15 mg/kg)
improved analgesia and passive
knee mobilization 24 hour after
surgery
Improved Postoperative
functional Outcome

When combine with epidural or

Total Knee Arthroplasty
femoral nerve block, increase
postoperative pain relief for total
knee
Astroplasty.
Menigaux C, Guignard B, Fletcher D, Dupont
X, Guirimand
F, Chauvin M. Anesth Analg. 2000;90:129135.

Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X, Chauvin M. Anesth Analg. 2001;93:606612.
Himmelseher S, Ziegler-Pithamitsis D, Agiriadou H, Martin Jjelen-Esselborn S, Koch E. Anesth Analg.
2001;92: 12901295.

Low dose of Ketamine

Low-dose ketamine is not really an
analgesic, but is better to
described as

anti-hyperalgesic
anti-allodynic
tolerance-protective

Clonidine ( Alpha 2 agonist)

It has been using as antihypertensive drug for long time.
It has analgesic effect when give centrally
such as -Spinal analgesia
- epidural analgesia
Clonidine can selectively blocking conduction of Adelta
and C fiber.
1/Kg Bw clonidine given perioperatively is well
` tolerated and little effect of Hypotesion
- bradicardia
- SEDATION
compare to dexmetomidine, dexmetomidine more
selective for alpha2 receptors and shor duration.

GABA
(Gama-amino Butiric Acid is an Amino Acid)

GABA is the major inhibitory

neurotransmitter in the central
nervous system (CNS), with most
neuron undergoing GABA ergic
modulation.

WIDE
WIDE DYNAMIC
DYNAMIC RANGE
RANGE SPINAL
SPINAL
NEURON
NEURON
C

Glutamate
(Subs P)
Glutamate
Glutamate

NMDAr

Wind-up
Gene induction

Inhibitory
Fibers

GABA
Glycine
Opioids
NA, 5HT

Brain

GABAPENTINOID
1. Gabapentin (Neurantin)
2. Pregabalin (Lyrica)

Gabapentin
Structurally related to the neurotransmiter
GABA but mechanism of action is different.
Binds to 2 subunit of voltage-gated calcium
channels in CNS tissues.
Bioavailability is 27-60% and not dose
proportional.
Following oral administration, Cmax within 2-3
hour.
t1/2 is independent of dose and averages 5-7
hour.

PREGABALIN
Pregabalin binds to the 2- subunit of voltage-gated
calcium channels
Pregabalin reduces calcium influx at presynaptic
terminals in hyperexcited neurons
Subsequent to 2- binding, pregabalin reduces
release of excitatory neurotransmitters
e.g. glutamate, substance P, norepinephrine

Analgesic, anxiolytic, anticonvulsant activities

Dose 50 to 75 mg/12 hours
Gee et al. 1996; Fink et al. 2002; Fehrenbacher et al. 2003; Dooley et al. 2002;
Maneuf et al. 2001; Bialer et al. 1999; Welty et al. 1997

Pregabalin Binding
to Voltage-Dependent
Calcium Channels
Ca2+

Ion
Ionchannel
channel

Ca2+
Ca2+

Ca2+

Pregabalin

Gabapentin
Pregabalin/
binding site

Ca2+

Ca2+
-

++

++

Ca2+

Outside
the cell

Cell membrane

Inside
the cell

Adjuvants in
Bone Pain

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
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
Ross et al;Systematic review of role of bisphosphonates on skeletal morbidity in
needed to
determine
drug & route
metastatic
cancer. BMJbest
2003; 327(7413):469

Bisphosphonates
Tolerability And Adverse Effects

1. Renal toxicity
2. Flu-like syndrome
3. Hypocalcemia
4. Avascular necrosis of the jaw

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

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

Thank
You