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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. cord compression . hypersensitivity with NSAIDs – Nerve 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 .

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tumor)  Immunosuppressio n     LONG-TERM Proximal myopathy often < 15 days Cushing’s syndrome Osteoporosis Aseptic / avascular necrosis of bone .CORTICOSTEROIDS: ADVERSE EFFECTS IMMEDIATE  Psychiatric  Hyperglycaemia  risk of GI bleed  gastritis  aggravation of existing lesion (ulcer.

CORTICOSTEROIDS AS ADJUVANTS ·inflammation · edema } tumor mass effects · spontaneous nerve depolarization .

adrenal suppression not likely . often given more frequently • If an acute course is discontinued within 2 wks.DEXAMETHASONE • minimal mineralcorticoid effects • po/iv/sq/sublingual routes • perhaps can be given once/day.

Adjuvants in Neuropathic Pain .

Gabapentin • Common Starting Regimen – 300 mg hs Day 1. 300 mg bid Day2. 100 mg bid Day 2. 100 mg tid Day 3. 300 mg tid Day 3. then gradually titrate to effect up to 1200 mg tid • Frail patients – 100 mg hs Day 1. then gradually titrate to effect .

adenosine .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. K+ channel blockade. GABA effects. mechanisms include blockade of Na+ channels.

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

and uveal effusions . enhancement of GABA-mediated neuroinhibition.Topiramate • Multiple neurostabilizing actions: – anti-glutamate effects at AMPA receptors. 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. blockade of voltage activated Na+ channels. inhibition of L-type high voltageactivated Ca++ currents.

urinary retention.KETAMINE Anesthesia Dose > 2 mg/Kg BW Will implicate in causing Psychomimetic effects. constipation etc. such as. vomiting. but may excerts Dose of Ketamin 0. •Excessive sedation •Cognitive Dysfunction •Hallucination •Nightmares Subanesthesia Doses (Low Dose) < 1 mg/Kg BW Have significant analgesic efficacy without those side effects.15 mg/Kg BW Should be combined nausea. 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.

. 2003).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. . data from two of these trials suggest potential benefit of ketamine as adjuvant to morphine in cancer pain (Bell et al. • Randomised and controlled trials are rare.

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% .

• Menigaux C. 2001. Guirimand F.KETAMINE More Frequently Use in Postorthopedic Surgical Pain Management Arthroscopic Anterior Cruciate Ligament Surgery Outpatient Knee Arthroscopy A Single intraoperative injection of ketamin (0.93:606–612. • Himmelseher S.92: 1290–1295. Chauvin M. Anesth Analg. Anesth Analg. Martin Jjelen-Esselborn S. increase postoperative pain relief for total knee Astroplasty. Koch E. • Menigaux C. Fletcher D. Chauvin M.90:129–135. 2001. Sessler DI. Agiriadou H. Dupont X. Guignard B. Dupont X. Guignard B. Ziegler-Pithamitsis D. . Fletcher D. 2000.15 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. Anesth Analg.

but is better to described as  ‘anti-hyperalgesic’  ‘anti-allodynic’  ‘tolerance-protective’ .Low dose of Ketamine Low-dose ketamine is not really an ‘analgesic’.

bradicardia . dexmetomidine more selective for alpha2 receptors and shor duration. • 1µ/Kg Bw clonidine given perioperatively is well ` tolerated and little effect of – Hypotesion .epidural analgesia • Clonidine can selectively blocking conduction of Adelta and C fiber.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 . .SEDATION • compare to dexmetomidine.

.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 .

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

 Binds to α2δ subunit of voltage-gated calcium channels in CNS tissues.  Bioavailability is 27-60% and not dose proportional.  .  t1/2 is independent of dose and averages 5-7 hour. Cmax within 2-3 hour.  Following oral administration.Gabapentin Structurally related to the neurotransmiter GABA but mechanism of action is different.

Dooley et al. glutamate. 2003. Fehrenbacher et al. Bialer et al.g. 1996. 2002. pregabalin reduces release of excitatory neurotransmitters • e. norepinephrine – Analgesic. substance P. anticonvulsant activities – Dose 50 to 75 mg/12 hours Gee et al. Fink et al. 2001. anxiolytic.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. Maneuf et al. 1999. 2002. 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 .

zoledronate (Zometa ) .Management of Bone Pain Pharmacologic treatment • Acetaminophen • Opioids • NSAIDs – be aware of adverse effects! • Corticosteroids (not with NSAIDS) • Bisphosphonates: pamidronate (Aredia ). clodronate (Bonefos ).

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.Bisphosphonates • Osteoclast inhibitors • bone metastases: pooled results  signif.Systematic review of role of bisphosphonates on skeletal morbidity in needed to determine drug & route metastatic cancer. 327(7413):469 . but further studies Ross et al.  in all skeletal morbidity end points except spinal cord compression • signif.  time to first skeletal related event. BMJbest 2003.

Hypocalcemia 4. Renal toxicity 2. Avascular necrosis of the jaw . Flu-like syndrome 3.Bisphosphonates Tolerability And Adverse Effects 1.

D as daily supplements . Vit D deficiency are risk factors Recommendations are to give 500 mg Calcium and 400 IU Vit. with intravenous bisphosphonates Up to 36% of patients Usually managed with acetaminophen Hypocalcemia     Usually compensate by increased PTH secretion Hypomagnesemia.Bisphosphonates ctd Flu-Like Reaction     Esp. previous parathyroid removal.

other therapeutic approaches should be considered ” .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.

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Thank You .