the rational pain treatment risk of un-appropriate pain treatment.ppt
TRANSCRIPT
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.