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 BandungAlamat : Departemen Anestesiologi & Terapi Intensif Fakultas

Kedokteran Universitas Padjadjaran/RS. Hasan Sadikin Jalan Pasteur no. 38 Bandung 40161Telp : 022-2038285/0811224046Fax : 022-2038306E-mail : ikesriredjeki@yahoo.co.id

Pain Drug Pharmacology : an UpdatePerioperative Pain management

Ike Sri RedjekiRSHS/FK UNPAD

Bandung

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

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

Transduction

TransmissionModulation

Perception

Transduction

TransmissionModulation

Perception

CGRP

CGRP

Peripheral sensitization to pain:

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 lowerthe threshold of the C fiber nociceptors.

As a result, lower concentrations of bradykinin and histamine are required to activate the nociceptor

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

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

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

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!

Transduction

TransmissionModulation

Perception

Local anesthetic block analgesia

Lower Extremity Blocks

Bupivacain 2% + opioid + corticosteroid

Complex Regional Pain Syndrome Patient

Transduction

TransmissionModulation

Perception

• 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

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

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

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

Transduction

TransmissionModulation

Perception

Site of action of Opioid

Descending Inhibition

Brain

Nociceptors

Spinal Cord

DorsalHorn

Nociceptive primary afferent

Ascending Activation

Opioids

OpioidsDescending Inhibition

Brain

Nociceptors

Spinal Cord

DorsalHorn

Nociceptive primary afferent

Ascending Activation Descending Inhibition

Brain

Nociceptors

Spinal Cord

DorsalHorn

Nociceptive primary afferent

Ascending Activation

Opioids

Opioids

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

Pharmacological Effects of Opioid Agonists

• Desired Action – analgesia• Unwanted actions

– Analgesic tolerance– Physical dependence– Respiratory depression– Nausea, vomiting sedation

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

Opioid Precautions

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

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

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

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!

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)

Transduction

TransmissionModulation

Perception

Route of Drugs Administration

• Bioavailability – Oral– Per rectal – Intravenous – Per epidural – Intrathecal

• Perepidural / intathecal low dose, longer acting, different pharmacodynamic

NMDA

Ca2+

Ca2+ ChannelNa+ Channel

GABAAMPA

Medula spinalis

Na+

C-fiber terminal

Ca2+

Glutamate Glutamate

Ketamin Midazolam 

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

Thank You for Your Attention