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 2–20 mg/d
 CORTICOSTEROIDS: ADVERSE EFFECTS

IMMEDIATE LONG-TERM
 Psychiatric  Proximal myopathy
 Hyperglycaemia often < 15 days
 risk of GI bleed  Cushing’s
 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;90:129–135.
•Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X, Chauvin M. Anesth Analg. 2001;93:606–612.
•Himmelseher S, Ziegler-Pithamitsis D, Agiriadou H, Martin Jjelen-Esselborn S, Koch E. Anesth Analg. 2001;92: 1290–1295.
•Adam F, Chauvin M, Du Manoir B, Langlois M, Sessler DI, Fletcher D. Anesth Analg. 2005;100:475–480.
 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.
• 1µ/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 α2δ 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