Pharmacology of drugs for pain management  important Route of drugs administration  change pharmacodynamic and pharmacokinetic of the drug  must be explore to enrich our modality in pain management Postoperative pain management  not resolved completely  still a problem for most of the physician involved in this area and the patients

1. CURRICULUM VITAE
Dr. Ike Sri Redjeki, dr., SpAnKIC,KMN,M.Kes
• Kepala Departemen Anestesiologi & Terapi Intensif Fakultas
Kedokteran Universitas Padjadjaran Bandung
• Ketua Program Studi Pendidikan Konsultan Intensive Care
(KIC) Fakultas Kedokteran Universitas Padjadjaran Bandung
Alamat : Departemen Anestesiologi & Terapi Intensif Fakultas
Kedokteran Universitas Padjadjaran/RS. Hasan Sadikin
Jalan Pasteur no. 38 Bandung 40161
Telp : 022-2038285/0811224046
Fax : 022-2038306
E-mail : ikesriredjeki@yahoo.co.id

2. Pain Drug Pharmacology : an Update
Perioperative Pain management
Ike Sri Redjeki
RSHS/FK UNPAD
Bandung

3. Perioperative Pain Management
• Treatment of pain after surgery is central to care of
postoperative patients. Failure to relieve pain is morally and
ethically unacceptable”
The Royal College of Surgeon of England, The College of Anesthetist, Commission
on the Provision of Surgical Services. report on the Working Party on pain After
Surgery 1990

4. Why postop pain continue to be undermanaged ?
Some Bariers
 Confusion about who is responsible for postoperative pain
management ?
 Inadequate knowledge of analgesics (opioid & non-
opioid analgesics)
 Administration of analgesic is too late, when the patient
complain of pain
 Using single modality and similar to every surgery

5. Transduction
Transmission
Modulation
Perception

6. Transduction
Transmission
Modulation
Perception

7. CGRP
CGRP
Peripheral sensitization to pain:

8. Heat
H+
VR1
ASIC TRPV3
Bradykinin
B1/B2 DRASIC/mDEG
Mechanical
generator potential
action potentials
Nociception – Transduction
Cold
CRM1
Substance P, glutamat, neurokininA,
peptide,CGRP, prostaglandin
Prostaglandins by themselves
do not cause pain but lower
the threshold of the C fiber
nociceptors.
As a result, lower concentrations of
bradykinin and histamine are
required to activate the nociceptor

9. Peripheral Sensitization
• Sensitization results from the release of  bradykinin,
prostaglandins, leukotriene ect  alter the type and number of
membrane receptors on free nerve endings  lowering the threshold
for nociceptive stimuli
• The depolarized nociceptive sensory endings release substance P
and CGRP along their branches (axon reflex the spread of
edema by producing vasodilation, increase in vascular permeability
and plasma transvasation, spread of hyperalgesia  cause release
of histamine from mast cells
• NSAID block the formation of prostaglandins by inhibiting the enzyme
cyclooxygenase
• Local anesthetic preferentially blocks C fiber conduction  ischemia
blocks first the large myelinated fibers

10. NSAID
• Analgesic, antipyretic
• Anti inflammatory - several days dosing
– must dose constantly at least several days
– prn not significant anti-inflammatory action
• Onset of action / effect 30 – 60 min
• difference in half-life and side effect
• NOTE:
– elderly patients should not be on NSAID's with long half-lives
– can be even more prolonged in elderly

11. Adverse effect of NSAID
• Hypersensitivity/allergy
• GI bleeding
• Platelet inhibition
• Sodium retention, oedema
• Renal toxicity
• Hepatic toxicity
Caution
• Asthma
• GI bleeding/ulceration
• Coagulation disorders
• Hypertension
• Cardiac failure
• ACEI/ARA/diuretics
• Renal impairment
• Gentamicin therapy
• Hepatic impairment

12. NSAID cautions
• Use lowest effective dose for shortest possible time
• Use paracetamol as alternative or to reduce NSAID dose
• COX-2 inhibitors
• similar adverse effects to non-selective
• increase risk of thrombotic events (stroke; MI)!
• Little difference in efficacy between NSAIDs
• Elderly - increased risk of adverse effects
• Continue only if effective. Avoid if possible!

13. Transduction
Transmission
Modulation
Perception
Local anesthetic 
block analgesia

14. Lower Extremity Blocks
Bupivacain 2% + opioid +
corticosteroid
Complex Regional Pain Syndrome Patient

15. Transduction
Transmission
Modulation
Perception

16. • Analgesic, antipyretic, Act centrally (PGs)
• Not useful as an anti-inflammatory
• Few side effect if taken at therapeutic doses
– Onset of effect 30 - 60 min
• Dosing:
– 500 –1000mg ( 4x/day) Max 4g for adult
Paracetamol

17. Paracetamol
• Should be 1st line therapy
– minor, non-inflammatory pain
• As effective as aspirin/NSAID in relieving acute pain
• Similar antipyretic actions to aspirin, NSAID
• No. 1 choice mild to moderate pain in children
• May be given chronically:
– 1g QID, or for example in people with OA

18. Paracetamol
• Dosing in Children - Often under dosed!
• Appropriate:
• 15mg/kg Q4H MAX 60mg/kg (community)
• 15mg/kg Q4H MAX 90mg/kg (hospital)
• Can use in Combination with Ibuprofen

19. Side Effect
• Major risk: is poisoning with overdose
• Paracetamol can damage the liver (mainly OD)
• Risk of toxicity  - dehydrated, malnourished, alcohol
(chronic)
• Common: N/V, dizziness, sedation
• Less common: headache, skin rash
• *NOTE: paracetamol & NSAID can be used together

20. Transduction
Transmission
Modulation
Perception

21. Site of action of Opioid
Descending Inhibition
Brain
Nociceptors
Spinal Cord
Dorsal
Horn
Nociceptive primary afferent
Ascending Activation
Opioids
Opioids
Descending Inhibition
Brain
Nociceptors
Spinal Cord
Dorsal
Horn
Nociceptive primary afferent
Ascending Activation Descending Inhibition
Brain
Nociceptors
Spinal Cord
Dorsal
Horn
Nociceptive primary afferent
Ascending Activation
Opioids
Opioids

22. Opioid
• Interact with specific cell-surface receptors in
– CNS and peripheral nerve system
– other tissues (GIT, immune cells, other tissues)
  
2nd messenger
systems
G-proteins G-protein

23. Pharmacological Effects of
Opioid Agonists
• Desired Action – analgesia
• Unwanted actions
– Analgesic tolerance
– Physical dependence
– Respiratory depression
– Nausea, vomiting sedation

24. Other unwanted effects
– Constipation
• Inhibition of GIT motility
• Slowing of oral-caecal transit times
• Never forget laxatives
– Endocrine effects
• may alter male sex hormones in chronic dosing
• Must monitor in chronic therapy
– Neuro-excitatory  e.g. myoclonus, allodynia, seizures
– very high doses

25. Opioid Precautions
• Hypotension , shock
• Concomitant CNS depression
• Impaired respiration /↓ respiratory reserve
• Elderly
• Hepatic impairment
• Renal impairment
• Epilepsy / recognised seizure risk
• Biliary colic or surgery

26. Opioid
• Moderate to severe pain
• Post operative pain management
• Mu, Kappa, Delta receptors
• Many available
• Typical side effect profile
– Nausea, Drowsiness, Respiratory Depression
– Constipation, Sweating, Itch
• Caution in hepatic and renal impairment

27. Tramadol (Tramal)
• Centrally acting analgesic
• 1st - opioid effects similar to morphine (mu)
– Active Metabolite M1
– M1 - 6x tramadol as analgesic, 200x binding
• 2nd - inhibit re-uptake of Noradrenaline / 5-HT
– descending pain inhibitory pathway
• Hepatic Metab. Via CYP 2D6 (P450)
– similar to codeine

28. Tramadol
•  doses in renal and hepatic impairment
• 50 – 100mg 4-6 hrs (Max 400mg) or equiv.
• Can cause serotonin syndrome by itself!
• Start low – go slow ……. Short term use only!

29. Reaction No. of reports
Confusion 36
Hallucinations 30
Convulsions 26
Serotonin syndrome 20
Increase in blood pressure 14
Hypersensitivity reactions 12
Hepatic reactions 10
Warfarin interaction 5
More serious adverse drug reaction with tramadol
Australian Adverse Drug Reactions Bulletin - Volume 22, Number 1, February 2003
NNT > / = 50% relief 3.5 (2.4 to 5.9)
NNH = 7.7 (4.6 to 20)

30. Transduction
Transmission
Modulation
Perception

31. Route of Drugs Administration
• Bioavailability
– Oral
– Per rectal
– Intravenous
– Per epidural
– Intrathecal
• Perepidural / intathecal  low dose, longer acting,
different pharmacodynamic

32. NMDA
Ca2+
Ca2+ ChannelNa+ Channel
GABAAMPA
Medula spinalis
Na+
C-fiber terminal
Ca2+
Glutamate Glutamate
Ketamin Midazolam

33. Conclusions
• Pharmacology of drugs for pain management 
important
• Route of drugs administration  change
pharmacodynamic and pharmacokinetic of the drug
 must be explore to enrich our modality in pain
management
• Postoperative pain management  not resolved
completely  still a problem for most of the
physician involved in this area and the patients