ANALGESIC DRUGS

Dr. Jim Amisi

Analgesics
• Are the Drugs which selectively relieves pain by acting in the CNS or
on peripheral pain mechanisms, without significantly altering the
consciousness
Pain
• Pain is defined by the International Association for the Study of Pain
(IASP) as “an unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or described in
terms of such damage”
• Individuals may describe their pain in terms of its severity, duration
and type
Pain – According to Duration

Acute pain
• Pain of recent onset and probable limited duration

Chronic pain
• Pain lasting for long periods of time
• It commonly persists beyond the time of healing of an injury and
frequently there may not be any clearly identifiable cause
Type pain based on etiology

Nociceptive Pain
• Nociceptive pain refers to the normal, acute pain sensation evoked by
activation of specialized primary afferent nerve fibres (nociceptors)
located in undamaged or previously undamaged skin, viscera and
other organs in the absence of sensitization
..based on etiology
Neuropathic Pain
• Neuropathic pain is defined by the IASP as pain due to a dysfunction of, or
damage to, a nerve or group of nerves, primarily peripheral nerves,
although pain due to central nervous system (CNS) damage (“central pain”)
may share these characteristics
• Examples of peripheral neuropathic pain are painful diabetic neuropathy,
post-herpetic neuralgia (post-shingles pain), HIV-AIDS (human
immunodeficiency virus-acquired immunodeficiency syndrome) neuropathy
and chemotherapy-induced neuropathic pain.
• The most common types of central neuropathic pain are post-stroke pain,
pain in multiple sclerosis and spinal cord injury pain
Pain..
• Pain is one of the classical features of inflammation
• Others are: redness, heat and swelling
What is inflammation?
• Response of the body to injurious stimuli
Pathophysiology of pain
• Read on this…
Classification of Analgesic drugs
• Analgesics can be classified as: opioid and non- opioid analgesics.
• Non-opioid dugs include:
a) Non Steroidal Anti-inflammatory Drugs (NSAIDs)
b) Paracetamol
Classification of NSAIDS
A. Nonselective COX inhibitors (traditional NSAIDs)
1. Salicylates: Aspirin
2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
3. Anthranilic acid derivative: Mephenamic acid
4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
5. Oxicam derivatives: Piroxicam, Tenoxicam.
6. Pyrrolo- pyrrole derivative: Ketorolac
7. Indole derivative: Indomethacin.
8. Pyrazolone derivative: phenylbutazone, Oxyphenbutazone
Classification..,
B. Preferential COX-2 inhibitors
• Nimesulide, Meloxicam, Nabumeton.
C. Selective COX-2 inhibitors
• Celecoxib, Etoricoxib, Parecoxib.
Mechanism of action
• The mechanism of action of NSAIDS in pain is similar to that of
inflammation
• They act by inhibiting the synthesis of prostaglandins by binding to
cyclooxygenase enzyme
Cyclooxygenase enzyme
• Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum.
It exists in 3 isoforms:
• COX-1 (constitutive) acts in physiological conditions.
• COX-2 (inducible) is induced in inflammatory cells by pathological
stimulus.
• COX-3 (in brain).
Cyclooxygenase enzyme
• COX-1 is constitutively expressed in nearly all tissues. COX-1 is
responsible for generating the prostaglandins required for protection
of the gastrointestinal tract, renal perfusion and platelet function
• COX-2 is responsible for the increased prostaglandin synthesis
associated with inflammation, fever, and pain responses

• Inhibition of the COX-1 enzyme is linked to an increased risk of

bleeding and risk of gastric ulceration, while the desired anti-
inflammatory and analgesic properties are linked to inhibition of the
COX-2 enzyme
Aspirin
• Aspirin is Acetylsalicylic acid converts to salicylic acid in body,
responsible for action
Pharmacological actions of Asprin
• Analgesic
• Antipyretic
• Antiinflammatory
Mechanism of action of Aspirin
• Aspirin is non-selective and irreversibly inhibits both cyclooxygenase
1 and 2
• The analgesic action is mainly due to obtunding of peripheral pain
receptors and prevention of PG-mediated sensitization of nerve
endings.
Pharmacokinetics of Aspirin
• Aspirin is absorbed from the stomach and small intestines.
• Its poor water solubility is the limiting factor in absorption: microfining
the drug particles and inclusion of an alkali (solubility is more at higher
pH) enhances absorption.
• Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other
tissues to release salicylic acid which is the major circulating and active
form.
• It slowly enters brain but freely crosses placenta.
• The metabolites are excreted by glomerular filtration as well as tubular
secretion.
Adverse effects of Aspirin
1. Gastrointestinal effects
Most common adverse effects of high-dose aspirin use (70% of patients):
• nausea
• vomiting
• diarrhea or constipation
• dyspepsia (impaired digestion)
• epigastric pain
• bleeding, and ulceration (primarily gastric)- decrease in the production and
cytoprotective activity of prostaglandins, which leads to gastric tissue
susceptibility to damage by hydrochloric acid.
Adverse effects of Aspirin
2. Hypersensitivity (intolerance)
Hypersensitivity is relatively uncommon with the use of aspirin (0.3% of
patients); hypersensitivity results in:
• rash
• bronchospasm
• rhinitis
• edema, or an anaphylactic reaction with shock, which may be life threatening.

• The incidence of intolerance is highest in patients with asthma, nasal polyps,

recurrent rhinitis, or urticaria.
• Aspirin should be avoided in such patients.
Adverse effects of Aspirin
3) Reye's syndrome
• An illness characterized by vomiting, hepatic disturbances, and
encephalopathy that has a 35% mortality rate
• The use of aspirin and other salicylates to control fever during viral
infections (influenza and chickenpox) in children and adolescents is
associated with an increased incidence of Reye's syndrome
• Aspirin should not be given to children under 16 years of age unless
specifically indicated, e.g. for juvenile arthritis (paracetamol is
preferred).
Contd..,
4) Tinnitus ( with high dose Aspirin)
Rare adverse effects
• May decrease the glomerular filtration rate, particularly in patients
with renal insufficiency
• Occasionally produce mild hepatitis
Contraindications of Aspirin
• Patients with bleeding disorders including duodenal and peptic ulcer
conditions
• Children under 16 years of age
• Pregnancy (they may cause postpartum hemorrhage and premature
closure of the fetal ductus arteriosus)
Other indications of Aspirin
• Acute rheumatic fever
• Rheumatoid arthritis and other forms of arthritis
• Anti-platelet therapy
Drug interactions of Aspirin
Drugs Result
• Diuretics Decrease diuresis
• Beta-blockers Decrease antihypertensive effect
• ACE inhibitors Decrease antihypertensive effect
• Anticoagulants Increase of GI bleeding
• Sulfonylurea Increase hypoglycemic risk
• Cyclosporine Increase nephrotoxicity
• Alcohol Increase of GI bleeding
Propionic acid derivatives
Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
• Analgesic, antipyretic and anti-inflammatory efficacy is lower than
aspirin (low potency) – all inhibits PG synthesis (Naproxen – most
potent)
Adverse Effects
-Better tolerated than aspirin and Indomethacin
• GI effects: gastric discomfort, nausea, vomiting
• CNS effects: headache, dizziness, blurring of vision, tinnitus and
depression
• Rash, itching and hypersensitivity are less

NB: These drugs are capable of precipitating aspirin induced asthma

Pharmacokinetics
• All are well absorbed orally
• 90-99% plasma protein bound
DI
• Inhibits platelet function – use with anticoagulants are avoided
• Decreases antihypertensive and diuretic actions of furosemide,
thiazides and beta-blockers
CI
• Not given in pregnancy and Peptic ulcer patient
Indications
• Dysmenorrhoea, rheumatoid arthritis, osteoarthritis and
musculoskeletal disorders
• Pain prominent conditions like fractures, vasectomy, tooth extraction,
postpartum and post operative pain

Naproxen – preferred in acute gout – stronger anti-inflammatory and

inhibition of leucocyte migration – longer half-life (12-16 hours)
Fenamates-Mephenamic acid
• Analgesic, antipyretic and weak anti-inflammatory
• Inhibits PG synthesis
• Have a peripheral + central analgesic effect
ADRS
• Diarrhoea, epigastric distress, skin rash, dizziness and other CNS ADRs
Uses
• As analgesic in muscle, joint and soft tissue pain
• Dysmenorrhoea
Enolic acid derivatives - Piroxicam
• Multiple action NSAID
• Long acting, good anti-inflammatory, good analgesic and antipyretic
action
• Reversible, non-selective COX inhibition
• Inhibits PG synthesis and inhibits platelet aggregation
ADRS
• More GI effects than Ibuprofen but less than Indomethacin, lesser
ulcerogenic
• Rash, pruritus and serious skin reactions
Pharmacokinetics
• Rapid complete absorption
• 99% plasma bound,
• Half life 2 days
• Excreted in bile and urine
Indications
• Long term anti-inflammatory – rheumatoid arthritis, osteo-arthritis,
ankylosing spondylosis, acute gout etc.
• Not first choice for any conditions
• Relative higher toxicity
Indomethacin
• Potent anti-inflammatory and prompt antipyretic
• Relieves only inflammatory and injury related pain
• Highly potent inhibitor of PG and neutrophil motility
Indications
• Reserve drug - ankylosing spondylitis, destructive arthropathies,
psoriatic arthritis, postoperative pain, malignancy associated fever,
medical closure of PDA
Pharmacokinetics
• Well absorbed orally
• 90% plasma protein bound
• Half life 2 – 5 Hours
ADRS
• High incidence of gastric and CNS side effects (COX-1 related)
• Gastric irritation, nausea, anorexia, bleeding and diarrhoea
• CNS: Frontal headache, dizziness, ataxia, mental confusion,
hallucination, depression and psychosis
• Leucopenia,
• hypersensitivity, rash etc.
• Increased risk of bleeding –
• low platelet aggregation •
• Contraindications: machinery operators, drivers, psychiatric &
epileptic patients kidney disease, pregnancy & children
Ketorolac
• Potent analgesic
• Modest anti-inflammatory
• Used for post operative pain –equal efficacy with Morphine (but no
receptor interaction)
• Inhibits PG synthesis – inhibits pain peripherally
Uses
• Given IM and orally
- Post-operative, dental, musculo-skeletal pain
– also in renal colic, migraine – short term management of moderate
pain
-Not to be used for more than 5 days
PKS
• Ketorolac is rapidly, and completely absorbed after oral administration
with a bioavailability of 80% after oral administration
• Half life is about 5– 7 Hrs
• Metabolism-liver
• Elimination-kidney

• Adverse effects increases with higher doses of ketorolac AND

duration of use
Contraindications
• Include those of Aspirin
• Inhibits platelet function and is, therefore, CONTRAINDICATED in
patients with suspected or confirmed cerebrovascular bleeding,
patients with hemorrhagic diathesis, incomplete hemostasis and
those at high risk of bleeding
•  Is not indicated for use in pediatric patients and it is NOT indicated
for minor or chronic painful conditions.
ADRS
• Can cause peptic ulcers, gastrointestinal bleeding and/or perforation
of the stomach or intestines, which can be fatal. These events can
occur at any time during use and without warning symptoms
Nimesulide
• Weak PG synthesis inhibitor, moderate COX-2 selective
• Completely absorbed and 99% plasma protein bound
• Half life – 4-5 hours and excreted in urine
Indications
• Sinusitis
• dental surgeries
• renal colic
• Arthritis
• postoperative inflammatory condition
• Fever
• low back pain

Note: There is no cross reaction of aspirin and other NSAIDS related

bronchospasm – specific usefulness
ADRS
• Epigastric pain
• nausea
• loose motion
• heart burn
• Rash
• Pruritus
• somnolence and dizziness
• Fulminant hepatic failure
Selective COX-2 inhibitors
Examples: Celecoxib, Etoricoxib and Parecoxib
• Less peptic ulcer occurrence, less ulcer bleeds
• Do not depress TXA2 production (COX-1) of platelets – Do not inhibit
platelet aggregation & do not prolong bleeding time

Disadvantage: Reduce PGI2 production by vascular endothelium

leading to increase prothrombotic effect & enhance cardiovascular risks
• Uses : Patients with high risks of PU, perforation at lowest dose and
shortest period
• Contraindications: History of IHD, hypertension, CHF and CVA
Paracetamol (acetaminophen)
• Analgesic
• Antipyretic
• Raises pain threshold but no PG inhibition except COX inhibition in
brain
• Negligible/ no antiinflammatory action(not used as an anti-
inflammatory drug)
• Poor inhibition of PG in peripheral tissues – but high in CNS !!
Pharmacokinetics
• Orally absorbed
• plasma protein bound,
• Half life is around 3 – 5 hours;
• Metabolism by conjugation with glucoronic acid and sulfate
Uses
Most commonly used – over the counter drug
• Headache, mild migraine, musculoskeletal pain, dysmenorrhoea etc.
• Osteoarthritis, not effective in Rheumatoid arthritis
• Safest Antipyretic in children – no Reye`s syndrome
Advantages
1) lesser gastric irritation, ulceration and bleeding (can be given in
ulceration)
2) does not prolong bleeding time
3) Hypersensitivity rarely
4) no metabolic disturbances
5) can be given in all age group – pregnancy and lactation
6) No significant drug interactions