Analgetik

Analgesics
Jarir At Thobari
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Aspirin consumption worldwide

12
15x10 tablets per year or 45,000 tons per year
Burden of pain
15% moderate to severe
at least 50% of time
Seriously ill
Hospitalized patients
15% dissatisfied with
pain treatment
50% incidence
of pain
Pain
Pain is subjective
and difficult to
quantify
Pain scale, 1-10
Analog scale
Numeric Scale
0
No Pain
10
Worst Pain
Simple (Category) Descriptive Scale
No Pain
Mild
Moderate
Severe
Very Severe
Worst
Visual-Analogue Scale
No Pain
Worst Pain
Usually 0-10 cm long line.

Placed either vertical or horizontal.
VAS: Coloured Analogue Scale
Wong-Baker FACES
Pain Rating Scale
Photographic/ Numeric Pain Scale
Pain Treatment Methods

Physical
Physical Methods
Methods
Psychological
Psychological Method
Method
Removed
Removed the
the cause
cause of
of pain
pain
Regional
Regional Anesthesia
Anesthesia
Medication
Medication
WHO Pain Ladder
Overall Management Pain

Mild pain
Non opioid analgesics paracetamol
NSAIDs
aspirin, ibuprofen
Moderate pain
Low efficacy opioid
dihydrocodeine
low efficacy opioid + NSAID dihydrocodeine + ibuprofen
Moderate efficacy
opioid + NSAID
meptazinol + ibuprofen
Severe pain
High efficacy opioids morphine
High efficacy opioids + NSAIDS
morphine + ibuprofen
Overwhelming pain
High efficacy opioid + anxiolytic
morphine + diazepam
and/or major tranquilliser morphine + chlorpromazine
Analgesics
Non Opioid analgesics

Opioid analgesics
Drugs for neuropathic and functional pain
Antimigraine drugs
Acetaminophen (APAP)
Mechanism of action unclear

No anti-inflammatory effects
Causes liver toxicity at high doses
Max dose: 4 gm/day, if no liver disease
Newest recommendation 2.6 gm/day
Decreases opioid requirements
NSAIDs
Efficacy is similar amongst NSAIDs
Differences in potency, time of onset, &
duration of action
Side effects:
GI bleeding
renal dysfunction
platelet dysfunction
For what conditions are NSAIDs

used?
Rheumatoid Arthritis
Osteoarthritis
Inflammatory arthritis,
psoriatic arthritis,
Reters syndrome
Acute gout
Metastatic bone pain
Dysmenorhea
Headache, migraine
Postoperative pain
Pyrexia ( fever)
Ileus
Renal colic
Prostaglandin and Thromboxane

Biosynthesis
Membrane-bound phospholipids
Phospholipase A2
NSAIDs, ASA
Arachidonic acid
COX-1
O2
COX-2
PGG2
Coxibs
PGH2
Tissue-specific isomerases
PGD2
PGE2
PGF2
PGI2
TxA2
COX = cyclooxygenase; coxibs = COX-2 inhibitors; PG = prostaglandin; TxA2 = thromboxane A2;

NSAID = nonsteroidal anti-inflammatory drug; ASA = aspirin.
Mechanism of Action of NSAIDs

CO2
H
Arachidonic acid
COX-1
Constitutive
Non-specific NSAIDs
COX-2
Inducible
COX-2 NSAIDs
GI Mucosa
Prostaglandins
GI mucosal
Protection
Platelet
Thromboxane
Hemostasis
Prostaglandins
Mediate pain,
inflammation, and fever
Physiological stimulus
Macrophages/other cells
COX-1
constitutive
TXA2
PGI2
platelets stomach mucosa

endothelium
Inhibition of COX-1
causes G I damage
Inflammatory stimulus
COX-2
induced
PGE2 Proteases
kidney
PGs
Other
inflammatory
mediators
Inflammation
Inhibition of COX-2 is antiinflammatory
Classification NSAID
Acetic acid derivatives
Arthrotec
(diclofenac/misoprostol)
Diclofenac
Ketorolac
Tolmetin
Etodolac
Indomethacin
Sulindac
Enolic acid derivatives
Meloxicam
Piroxicam
Tenoxicam
Napthylkanone derivatives
Nabumetone
Classification NSAID
Propionic acid derivatives
Flurbiprofen
Ketoprofen
Oxaprozin
Ibuprofen
Naproxen
Carboxylic acid derivatives

Diflunisal
Salsalate
COX-2 inhibitor
Celecoxib
Rofecoxib
Valdecoxib
NSAIDs: COX-2 vs COX-1 Selectivity

6-MNA
COX-2 IC50 (M)
100.00
Naproxen
Acetaminophen
Ibuprofen
10.00
Meloxicam
Nimesulide
1.00 Indomethacin
Celecoxib
Rofecoxib
0.10
Diclofenac
0.01
0.01
0.10
1.00
10.00 100.00
COX-1 IC50 (M)

6-MNA = 6-methoxy-2-naphthylacetic acid;
IC50 = drug concentration at which the enzymatic activity is inhibited by 50%.
FitzGerald and Patrono. N Engl J Med. 2001;345:433.
CLASS Trial: Upper GI Complications

Alone and With Symptomatic Ulcers
= celecoxib
p = 0.02
= NSAIDs (ibuprofen + diclofenac)
All Patients
Patients Not Taking Aspirin
Patients Taking Aspirin
Annualized Incidence %
p = 0.09
11 / 1441
20 / 1384
49 / 1384
30 / 1441
p = 0.02
p = 0.04
5 / 1143
14 / 1101
32 / 1101
16 / 1143
p = 0.49
17 / 283
14/ 298
p = 0.92
6 / 298
6 / 283
Silverstein et al. JAMA 2000; 284:1247-1255

Ulcer Complications
Symptomatic Ulcers and

Ulcer Complications
CLASS Trial: Time to Complicated Ulcer

2
Log-rank P values:
(%) 1
Celecoxib vs NSAIDs
0.450
Celecoxib vs diclofenac
0.640
Celecoxib vs ibuprofen
0.414
Ibuprofen 800 mg TID
Diclofenac 75 mg BID
Celecoxib 400 mg BID
0
0
80
160 180
Days
240
320
Risk factors for upper GI bleeding

associated with NSAID use
Lanas A Rheumatology 2010;49:ii3-ii10
Gastro protection:
Misoprostol (MUCOSA trial)
% of patients with serious upper GI complications at 6 months
p=0.049
40% reduction in GI
complications
Placebo + NSAID
(n=4439)
Misoprostol + NSAID
(n=4404)
Silverstein et al.
Ann Intern Med
1995;123:241249
Gastro protection:
Proton Pump Inhibitors
% of patients with recurrent upper GI bleeding at 6 months
p=0.005
76% reduction in upper

GI bleeding
Chan et al. N Engl J
H. pylori eradication
Omeprazole + NSAID
Med 2001;344:967
+ NSAID
973
(n=75)
(n=75)
Results of Case-Control and Cohort Studies Reporting

on Cardiovascular Risks With Nonselective NSAIDs.
McGettigan, P. et al. JAMA 2006;296:1633-1644
Case-Control and Cohort Studies Reporting

on Cardiovascular Risks With Cyclooxygenase 2 Inhibitors.
McGettigan, P. et al. JAMA 2006;296:1633-1644
NSAIDs & Renal Effect

Coxibs
Arachidonic acid
NSAIDs
COX-1
COX-2
PGE2
Sodium retention
Peripheral edema
Blood pressure
CHF (rarely)
Brater. Am J Med. 1999;107:65S.
PGI2
Hyperkalemia
Acute renal
failure
Others : Nephrotic syndrome

interstitial nephritis
During pregnancy
NSAIDs are not recommended during pregnancy,
particularly during the third trimester.

While NSAIDs as a class are not direct teratogens, they
may cause premature closure of the fetal ductus arteriosus
and renal ADRs in the fetus. Additionally, they are linked
with premature birth.
In contrast, paracetamol (acetaminophen) is regarded as
being safe and well-tolerated during pregnancy.
Doses should be taken as prescribed, due to risk of
hepatotoxicity with overdoses
Salicylates
Aspirin (ASA)
Effective as APAP for
acute pain at similar
doses
Worse side effect
profile than APAP
Salicylates Salts
Safer than ASA
No platelet effects
Examples:
Diflunisal (Dolobid)
Magnesium salicylates
(Doans)
Aspirin (Acetyl salicylate)

Actions
Analgesic - central and peripheral action
Antipyretic - act in hypothalamus to lower the set
point of temperature control elevated by fever, also
causes sweating
anti-inflammatory - inhibition of peripheral
prostaglandin synthesis
respiratory stimulation - direct action on respiratory
centre, indirectly by CO2 production

Uricosuric effects
reduces renal tubular reabsorption of urate but treatment of

gout requires 5-8g/d, < 2g/d may cause retention of urate.
antagonises the uricosuric action of other drugs
Reduced platelet adhesion- irreversible inhibition of COX by
acetylation, prolongs bleeding time, useful in arterial
disease
Note: low doses are adequate for this purpose since the
platelet has no biosynthetic capacity and can not
regenerate the enzyme
Hypothrombinaemia : occurs with large doses ie >5g/day

OVERDOSAGE
Ingestion of > 10 g can cause moderate/severe
poisoning in an adult
Clinical features - salicylism
tremor, tinnitus, hyperventilation, nausea,
vomiting, sweating
Management- mainly supportive
Daily Aspirin Dose and

Admission for Ulcer Bleeding
Aspirin Dose
Odds Ratio (95% Cl)
75 mg (n=27)
2.3 (1.2-4.4)
150 mg (n=22)
3.2 (1.7-6.5)
300 mg (n=62)
3.9 (2.5-6.3)
Weil J et al. BMJ. 1995;310:827-830.
Risk of UGI bleeding with Different Formulations of

Low-Dose Aspirin (< 325mg)
Relative Risk
3.2
Plain ASA
3.6
2.6
Coated ASA
2.6
2.4
2.6
Buffered ASA
550 cases of UGIB
admitted to hospital
with melena or
confirmed
hematemesis
Gastric bleeding
Duodenal bleeding
Kelley et al, Lancet 1996; 348; 1413
Risk of Combining Low-Dose Aspirin

with NSAIDs
National cohort study in Denmark

27,694 people on aspirin 100-150 mg qd
Treatment regimen
Low-dose aspirin
Low-dose aspirin + NSAIDs
Increased incidence
over general
population
95% CI
2.6
2.2 - 2.9
5.6
4.4 - 7.0
Sorensen et al, Am J Gastroenterol 2000; 95; 2218
Opioids
Originally derived from
poppies
Body possesses
endogenous opioids
enkephalins
endorphins
Opiate Receptors
mu ( )
delta ( )
kappa ( )
sigma ( )
Papaver somniferum
Pharmacology of Opioids
1: inhibit transmission of pain
2: respiratory depression, euphoria,
constipation, physical dependence
: inhibit transmission of pain
: inhibit transmission of pain
Pharmacology of Opioids
Opioid Therapy in Pain Related to

Medical Illness
Opioid therapy is the mainstay approach for
Acute pain
Cancer pain
AIDS pain
Pain in advanced illnesses
But undertreatment is a major problem
Opioid Therapy in Chronic

Nonmalignant Pain
Supporting evidence
>1000 patients reported in case series and
surveys
Small number of RCTs
Common Side Effects of Opioids

Constipation
very common, tolerance is unlikely

stool softeners + stimulant +/metoclopramide
Nausea/Vomiting
tolerance usually develops

pretreat with prochlorperazine
Common Side Effects of Opioids

Urticaria/Pruritis
due to histamine release
treat with antihistamine
Sedation
tolerance usually develops
Delirium
rare in patients with normal renal function
Side Effects of Opioids

Respiratory Depression
preceded by somnolence
tolerance develops
use caution in patients with underlying
pulmonary dysfunction
if RR <8 bpm, consider naloxone (Narcan)
Opioid Therapy: Prescribing Principles
Prescribing principles
Drug selection
Dosing to optimize effects
Treating side effects
Managing the poorly responsive patient
Opioid Therapy: Drug Selection

Immediate-release preparations
Used mainly
For acute pain
For dose finding during initial treatment of chronic pain
For rescue dosing
Can be used for long-term management in select
patients

Immediate-release preparations
Combination products
Acetaminophen, aspirin, or ibuprofen combined with
codeine, hydrocodone, dihydrocodeine
Single-entity drugs, eg, morphine

Tramadol

Extended-release preparations
Preferred because of improved treatment
adherence and the likelihood of reduced risk in
those with addictive disease
Morphine, oxycodone, fentanyl,
hydromorphone, codeine, tramadol,
buprenorphine
Adjust dose every 23 days
Opioid Selection:
Poor Choices for Chronic Pain
Meperidine
Poor absorption and toxic metabolite
Propoxyphene
Poor efficacy and toxic metabolite
Mixed agonist-antagonists (pentazocine,

butorphanol, nalbuphine, dezocine)
Compete with agonists withdrawal
Analgesic ceiling effect
Opioid Therapy: Routes of Administration

Oral and transdermalpreferred
Oral transmucosalavailable for fentanyl
and used for breakthrough pain
Rectal routelimited use
ParenteralSC and IV preferred and feasible
for long-term therapy
Intraspinalintrathecal generally preferred for
long-term use
Opioid Therapy: Side Effects

Common
Constipation
Somnolence, mental clouding
Less common
Nausea
Sweating
Myoclonus
Amenorrhea
Itch
Sexual dysfunction
Urinary retention
Headache
Opioid Therapy and Chemical Dependency
Physical dependence
Tolerance
Addiction
Pseudoaddiction
Opioid Therapy: Monitoring Outcomes

Critical outcomes
Pain relief
Side effects
Functionphysical and psychosocial
Drug-related behaviors
Adjuvant Pain Medications

drugs that are used
primarily for treating
conditions other than
pain, but may be
analgesic in selected
circumstances
-AMA
Common Adjuvant Medications
Antidepressants
Anticonvulsants
Corticosteroids
Topical Anesthetics
Calcitonin
Bisphosphonates

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Analgesics

Aspirin consumption worldwide

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Simple (Category) Descriptive Scale

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Usually 0-10 cm long line.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

VAS: Coloured Analogue Scale

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Photographic/ Numeric Pain Scale

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Pain Treatment Methods

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

WHO Pain Ladder

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Overall Management Pain

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Non Opioid analgesics

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Mechanism of action unclear

Decreases opioid requirements

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

For what conditions are NSAIDs

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Prostaglandin and Thromboxane

COX = cyclooxygenase; coxibs = COX-2 inhibitors; PG = prostaglandin; TxA2 = thromboxane A2;

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Mechanism of Action of NSAIDs

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

platelets stomach mucosa

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Enolic acid derivatives

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Carboxylic acid derivatives

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

NSAIDs: COX-2 vs COX-1 Selectivity

COX-2 IC50 (M)

COX-1 IC50 (M)

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

CLASS Trial: Upper GI Complications

= NSAIDs (ibuprofen + diclofenac)

Patients Not Taking Aspirin

Patients Taking Aspirin

Silverstein et al. JAMA 2000; 284:1247-1255

Symptomatic Ulcers and

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

CLASS Trial: Time to Complicated Ulcer

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Risk factors for upper GI bleeding

Lanas A Rheumatology 2010;49:ii3-ii10

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

76% reduction in upper

Chan et al. N Engl J

Results of Case-Control and Cohort Studies Reporting

McGettigan, P. et al. JAMA 2006;296:1633-1644

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Case-Control and Cohort Studies Reporting

McGettigan, P. et al. JAMA 2006;296:1633-1644