2 December 1951Bukit Tinggi

PhD in Clinical PharmacologyFUSA-Flinders Medical Centre Australia, 1988

ProfessorHead of DepartmentPharmacology & TherapeuticSchool of Medicine, USU

Jln. Tridharma 22Kampus USU, Medan

SpFK, Clinical PharmacologistPB-IDI & FK UI, 1995

MD, FK USU, 1978

Aznan LeloDep. Farmakologi & Terapeutik,

Fakultas KedokteranUniversitas Sumatera Utara8 Oktober 2011, KONKER IPS, Jakarta

Rational prescription (WHO,1995)

Patient receive appropriate medicines

according to their clinical needs

at an appropriate dosage,

administration & duration

and in a waythat encourages

the patient compliance and

at the lowest cost to the community

Appropriate patient( Tepat Pasien )

Appropriate indication( Tepat Indikasi )

Appropriate drug( Tepat Obat )

Appropriate dosage,administration & duration(Tepat dosis, cara & lama pemberian)

Appropriate information ( Tepat Information )

Appropriate cost ( Tepat biaya )

Critical approaches in selecting medicines

Therapeutic effect

Adverse reaction

Minimal Maximal

Maximal Yes ?Minimal ? No

Factors to consider when choosing a pain killer

Drug issues

• Efficacy• Tolerability • Safety • Dosage • Cost

Patient issues

• Type, severity• Risk factors: GI,

platelet, renal and cerebro-cardiovascular system.

• Co-prescription. • Co-morbidity.• Compliance.

BENEFITSefficacy

RISKSsafety

Inappropriate treatment of pain

• This includes :– Non-treatment, – Under-treatment, – Over-treatment, and – Ineffective treatment. – Administration of the wrong medication, – Failure to monitor side effects, – Inappropriate medication prescription, and– Incorrect prescription

opioids are inappropriately used and prescribed

Atluri SL, Sudarshan G. Development of a screening tool to detect the risk of inappropriate prescription opioid use

in patients with chronic pain. Pain Physician 2004; 7:333-338.

• 90 percent of people in the United States receiving treatment for pain management are prescribed opiate medication.

• Of that number, 18 percent to 41 percent had opiate abuse/addiction problems.

Principles of Medical Ethicsin Pain Management

Principles Pharmaco-therapeutic approaches

BENEFICENCE : mengutamakan kepentingan pasien

Pain killer (analgesic), potent, rapid onset

NON MALEFICENCE : tidak memperburuk keadaan pasien

Minimal ADR, not deteriorate other clinical problems

JUSTICE : tidak mendiskriminasikan pasien, apapun dasarnya

Rational

AUTONOMY : menghormati hak pasien dalam memutuskan

Religion, Preference, PRN, pharmaco-economics

Critical approaches in selecting medicines

Therapeutic effect

Adverse reaction

Minimal Maximal

Maximal Yes ?Minimal ? No

NNHSMALLESTGREATEST

(> 100)NNT

GREATEST

SMALLEST(2-4)

There are two reasons to withdraw from the treatment either no efficacy (NNT very high) or serious adverse reactions (NNH very low).

number needed to treat (NNT) for at least 50% pain relief over 4-6 hours in patients with

moderate to severe pain, all oral analgesics except morphine, pethidine and ketorolac

plateletaggregation

plateletaggregation

GIbleeding

GIbleeding

GIbleeding

plateletaggregation

COX-1inhibitor

COX-2inhibitor

moremoreheart attackheart attack

fewerfewerheart attackheart attack

Celecoxib vs Etoricoxib

CV & Renal Safety Profile Blood pressure change

Zhang J et al. JAMA 2006;296:1619-32; Schwartz JI et al. J Clin Pharmacol 2007;47:1521-31

NSAID GI Toxicity

generally varies

with half-life of the agent

NSAID Diclofenac Naproxen Piroxicam

Dose (mg/d) 100 750 20

Half-life (hr) 1.5 14 50

24 hr fecal blood loss (mL) 0.53 +/- 0.21 2.76 +/- 2.22 1.16 +/- 0.62

Henry, et al. BMJ.312:1563,2000; Scharf, et al. Aust N Z J Med 28(4):436,1998

Shortest half-life

Lowest G

I risk

Mild vs Severe PainMild Severe

Drug Low dose High dose

Potent agent

Acute vs Chronic PainAcute Chronic

Drug Rapid onset Long durationDuration of

painShort, self limiting, well-characterized

Persists after healing, 3 months

Component Nociceptive NociceptiveNeuropathic

Slowly Chronic

Correlation between absorption, T-max and onset of action

Time

Co

nce

ntr

atio

n

Effective concentration

Acute

NSAID short half life

rapid onset but short duration

NSAID long half life

long duration but slow onset

NSAID medium half life

http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020998s018,019lbl.pdf

US FDA APPROVAL for Celecoxib on Acute Pain

do not care ………………………….to the correct and clear drug prescription

citalopram (Celexa®). a selective serotonin (5-HT) reuptake inhibitor

CELEXA® for CELEBREX®? A Case of Medication Sample Error

Moyer B, Shrading W, Burkhart KKInt J Med Toxicol 3(2):7,2000

Mixed Type(eg, Postoperative pain,

chronic back pain)

Classification of Pain by Pathophysiology

NociceptivePain

Neuropathic Pain

VisceralAbdominalObstetrical

HeadHeadacheOrofacial

PostherpeticNeuralgia

Low Back Pain

CRPS

CRPS = complex regional pain syndrome.

Central Poststroke Pain

TrigeminalNeuralgia

DistalPolyneuropathy (eg, diabetic, HIV)

MusculoskeletalOsteoarthritisRheumatoid ArthritisLow Back Pain

OtherPostoperativeCancer Pain

AdjuvantANALGESIC

NSAID

International Association for the Study of Pain. IASP Pain Terminology.Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57

BRAIN

Pharmacologic Agents Affect Pain Differently

Descending Modulation

Central SensitizationPNS

AnticonvulsantsOpioidsTricyclic/SNRI Antidepressants

CNSSpinalCord

PeripheralSensitization

Dorsal

Horn

Inhibition ofAscending Pain Pathways

NSAIDsAntiarrhythmicLocal AnestheticsTopical AnalgesicsAnticonvulsantsTricyclic AntidepressantsOpioids

Opioids

Alpha-2 Delta agonists

Anticonvulsants

Opioids

NMDA-Receptor Antagonists

Tricyclic/SNRI Antidepressants

FDA-Approved Treatments for

Neuropathic PainAdjuvant Analgesia

Trigeminal Neuralgia

PHN PDN

Carbamazepine + +

Duloxetine +

Gabapentin +

Pregabalin + +

Lidocaine +

TCA + +

NNT and NNH adjuvant analgesia

Drug NNT NNHPhenytoin 2.1 9.5

TCAs 2.4 2.7Carbamazepine 3.3 1.9

Pregabalin 3.3 3.7Gabapentin 4.7 2.7Mexiletine 10 5–10Codeine 18 2

Do surgical patients benefit from perioperative gabapentin/pregabalin?

A systematic review of efficacy and safety.Tiipana EM, Hamunen K, Kontinen VK, Kalso E.

Anesth Analg. 2007 Jun;104(6):1545-56.

Systematic analysis of 22 RCTs on perioperative administration of gabapentinoids for postoperative pain relief demonstrated the both agents effectively • reduce postoperative pain, • opioid consumption (20-67%), and • opioid-related adverse effects after surgery.

Pregabalin

S-(+)-3-isobutyl GABA Readily crosses blood-brain barrier Not metabolically converted to GABA Not a GABA agonist or antagonist binds to the α2-δ subunit of voltage-

gated calcium channels in the CNS– not a vascular calcium channel inhibitor,

and does not effect heart function– 6 X more potent than gabapentin– can be effective in gabapentin failures

Silverman et al.1991, Taylor CP 1995; Vartanian et al. 2003

Pregabalin binds to the α2-δ subunit of voltage-gated Ca2+ channels in the CNS

Taylor. CNS Drug Rev. 10:183-8,2004

Pregabalin Binds to the 2- Subunit of Voltage-Gated Ca2+ Channels in the Central Nervous System

Schematic representation of pregabalin’s proposed mechanism of action

• Pregabalin selectively binds to 2- subunit of calcium channels• Modulates calcium influx in hyperexcited neurons• Reduces neurotransmitter release• Pharmacologic effect requires binding at this site• The clinical significance of these observations in humans is currently unknown

Taylor. Taylor. CNS Drug Rev. CNS Drug Rev. 2004;10:1832004;10:183--188.188.

Presynaptic α2-subunit

Ca2+

channel

Neurotransmitters

Postsynaptic

Presynapticα2-

subunit

Ca2+

channel

Neurotransmitters

Postsynaptic

Pregabalin

Modulates calcium influx in hyper-excited neurons Reduces excitatory neurotransmitter release e.g.

– glutamate, Substance P, noradrenaline

NNT and NNH Pregabalinin patients with chronic painCondition Dose (mg) NNT (95%CI)

Post-Herpetic Neuralgia

300 4 ( 3 – 7)

Painful Diabetic Neuropathy

300 7 ( 5 – 17)

Fibromyalgia 300 10 (7 – 17)Central Neuropathic

Pain600 4 (3 – 7)

NNH (95%Cl)All conditions 300 7 (6 – 9)

The Rational of Pain Management

• COX-1 specific inhibitor (Ketorolac) will cause GI events, while COX-2 specific inhibitor (Etoricoxib) will cause CV events

• Preferential COX-2 inhibitor (Celecoxib) will give less both GI and CV events

• Mixed pain needs a combination of NSAID with adjuvant analgesic

• α2-δ subunit of voltage-gated calcium channels blockers (ex. Pregabalin) offer additional treatment options

• Opioids are not recommended to be regularly prescribed

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Pharmacologic Profile of Antidepressants

Type of Action Receptor Type TCAs SNRIs SSRIs

Amitriptyline

Clomipramine

Imipramine

Desipramine

Maprotiline*

Nortriptyline

Duloxetine

Venlafaxine

Citalopram

Fluoxetine

Paroxetine

Ion channel

blockade

Sodium channel

Calcium channel

+

+

+

+

(±)

?

(±)?

?

?

Monoamine

transporter

blockade

5-HT

Norepinephrine

Dopamine

+

+

–

(±)

+

–

+

+

–

+

–

–

Receptor

blockade

α-Adrenergic

H1-Histaminergic

Muscarinic-cholinergic

NMDA

+

+

+

+

+

+

+

+

–

–

–

–

–

–

–

–*Tetracyclic antidepressant.+=present; (+)=weak; –=not present; ?=unknown; 5-HT=serotonin. Sindrup S, Jensen T. Hansson P, Fields H, Hill R, Marchettini P, eds. Neuropathic Pain: Pathophysiology and Treatment Progress in Pain Research and Management. Seattle, Wash: IASP Press;2001:169-183.