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 LONG-TERM
Psychiatric Proximal myopathy
Hyperglycaemia often < 15 days
risk of GI bleed Cushings
gastritis syndrome
aggravation of Osteoporosis
existing lesion Aseptic / avascular
(ulcer, tumor) necrosis of bone
Immunosuppression
CORTICOSTEROIDS AS ADJUVANTS

inflammation
tumor mass
edema } 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 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%
 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 nausea, vomiting, urinary retention, constipation etc.
Dose of Ketamin 0.15 mg/Kg BW Should be combined To
Opioid
Local Anesthetic
Other 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

A Single intraoperative injection of ketamin

Arthroscopic Anterior Cruciate
(0,15 mg/kg) improved analgesia and passive
Ligament Surgery
knee mobilization 24 hour after surgery

Outpatient Knee Arthroscopy Improved Postoperative functional Outcome

When combine with epidural or femoral nerve

Total Knee Arthroplasty 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.
Adam F, Chauvin M, Du Manoir B, Langlois M, Sessler DI, Fletcher D. Anesth Analg. 2005;100:475480.
 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 DYNAMIC RANGE SPINAL NEURON
Glutamate
C
(Subs P)

Ad NMDAr
Glutamate
Ab
Glutamate
+ Wind-up Brain
Gene induction

Inhibitory
GABA
-
Fibers
Glycine
Opioids
NA, 5HT
 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-d subunit of voltage-
gated calcium channels
Pregabalin reduces calcium influx at presynaptic
terminals in hyperexcited neurons
Subsequent to 2-d 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
Pregabalin
Ca2+
Ca2+ Ca2+ Gabapentin
Pregabalin/
Ca2+ binding site

Ca2+
-
Outside
the cell

++ ++ d
Cell membrane

Inside
b the cell

Ca2+
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 needed to determine best drug & route

Ross et al;Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.

BMJ 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