ANALGESIC

 INTRODUCTION
 OPOID ANALGESIC
 NSAID’S

 Pain is an “an unpleasant sensory and emotional
experience associated with actual or potential tissue
damage, or described in terms of such damage.
- THE INTERNATIONAL ASSOCIATION
FOR THE STUDY OF PAIN.

1. Intensity theory
2. Specificity theory
3. Pattern theory
4. Gate control theory
5. Hydrodynamic theory:
OTHER THEORIES INCLUDE:
 Protopathic and epicritic theory
 Chemical theory
 Lindhal’s biochemical theory

 It was given by Erb in 1874
 According to this theory pain is a non-specific sensation and pain is
produced only whenever there is stimulation of high intensity.
 This theory is not accepted ,because in trigeminal neuralgia, patient can
suffer excruciating pain even when the stimulus is no greater than gentle
touch provided.
 Altough this theory is not accepted, it remains true that intensity of
stimulation is a factor in causing pain.

 It was given by von frey in 1895.
 According to this theory body has a separate sensory system for
perceiving pain, just has for hearing and vision i.e meissner corpuscles for
sensation of touch, ruffini end organs for warmth, krause end organs for
cold, and nociceptors for pain.
 This theory got disapproved as it does not account for the wide range of
psychological factors that affect our perception of pain.

 It was given by goldscheider in 1894.
 goldscheider proposed that stimulus intensity and central summation are
the critical determinants of pain.
 The theory suggested that particular patterns of nerve impulses that evoke
pain are produced by the summation of sensory input within the dorsal
horn of the spinal column. For example: touch plus pressure plus heat
might add up in such a manner that pain was the modality experienced.

 It was proposed by melzack and wall in 1965.
 According to his theory, pain stimulation is carried by small, slow fibers
that enter the dorsal horn of the spinal cord; then other cells transmit the
impulses from the spinal cord up to the brain.
 The gate control theory postulates the following:
 information about the presence of injury is transmitted to the central
nervous system by small peripheral nerves.
 Cells in the spinal cord or nucleus of the fifth cranial nerve, which are
excited by these injury signals, are also facilitated or inhibited by other
large peripheral nerves that also carry information about innocuous
events.(for ex: temperature or pressure.)
 Descending control systems originating in the brain modulate the
excitability of cells that transmit information about injury.

 When no input comes in, the inhibitory neuron prevents
the projection neuron from sending signals to the brain
( gate is closed)
 Normal somatosensory input happens when there is
more large-fibre stimulation or only large-fibre stimulation.
both the inhibitory neuron and the projection neuron are
stimulated, but the inhibitory neuron prevents the
projection neuron from sending signals to the brain
(gate is closed.)
 Nociception(pain reception) happens when there is
more small-fibre stimulation or only small-fiber stimulation.
This inactivates the inhibitory neuron, and the projection
neuron sends signals to the brain informing it of pain
(gate is closed)

Therapeutic uses:
 The mechanism of gate control theory can be used therapeutically. Gate control
theory thus explains how stimulus that activates only nonnociceptive nerves can
inhibit pain.
 In transcutaneous electrical nerve stimulation, nonnociceptive fibres are selectively
stimulated with electrodes in order to produce this effect and thereby lessen pain.
 One are of the brain involved in reduction of pain sensation is the periaqueductal
gray matter that surrounds the third ventricle and the cerebral aqueduct of the
venricular system. Stimulation of this area produces analgesia by activating
descending pathways that directly and indirectly inhibit nociceptors in the laminae of
the spinal cord. Descending pathways also activate opioid receptor containing parts
of the spinal cord.
 Afferent pathways interfere with each other constructively, so that the brain can
control the degree of pain that is perceived, based on which pain stimuli are to be
ignored to pursue potential gains. The brain determines which stimuli are profitable
to ignore over time. Thus, the brain controls the perception of pain quite directly, and
can be "trained" to turn off forms of pain that are not "useful". This understanding led
Melzack to assert that pain is in the brain.

 The Hydrodynamic or Fluid Movement theory is one of the main theories
in dentistry to explain the mechanism by which a tooth perceives the sensation of
pain. It is currently the most widely accepted theory used to explain tooth sensitivity.
 There are three main theories of dentine hypersensitivity:
1. Direct Innervation (DI) Theory
2. Odontoblast Receptor (OR) Theory
3. Fluid Movement/Hydrodynamic Theory
 The hydrodynamic theory, first proposed by
M. Brännström in 1966 suggested that dentin
hypersensitivity is due to the abrupt movement of
fluid within the dentinal tubules in response to cold
and heat (thermal), osmotic (e.g. eating sugary foods),
mechanical (e.g. chewing) and evaporative stimuli (e.g. air blasts).
 Cold, osmotic and evaporative stimuli cause an outward flow of fluid and
mechanical and hot stimuli cause an inward flow.
 The movement of dentinal fluid leads to mechanical deformation and activation of
the sensory nerve terminals of low-threshold Aδ fibres located in close contact
with odontoblasts

 The perception of the pain is indicated through voluntary actions. Chemical
mediators are important components of the nociceptive reflex and offer a
target of pharmacologic modulation.
 Pain mediators include:
 Adrenocorticotropic hormone (ACTH)
 Glucocorticoids
 Vasopressin, oxitocin, catecholamines
 Brain opiods
 Angiotensin II
 Substance p
 Prostaglandins, leukotrienes
 Bradykinin, histamine, serotonin, potassium and proteolytic enzymes.

 Bradykinin causes vasodilatation and increase in the vascular permeability,to produce hypotension.
 Pro-inflammatory effects of substance P include: plasmatic vasodilatation and extravasations; mast cell
degranulation, with the consequent histamine release.
 Serotonin (5-hidroxytryptamine [5-HT]) is stored
in granules of the dense body of platelets.
 The 5-HT has vasoconstrictor activity, it increases
the vascular permeability and promotes fibrosis.
 Prostaglandins (PGs), in addition to being mediators
of pain, also play a substantial role in the development
of pain and oedema.

 A nociceptor ("pain receptor") is a sensory neuron that responds to damaging or
potentially damaging stimuli by sending “possible threat” signals to the spinal cord
and the brain. If the brain perceives the threat as credible, it creates the sensation of
pain to direct attention to the body part, so the threat can hopefully be mitigated; this
process is called nociception
 nociceptors develop from neural-crest stem cells. The neural crest is responsible for
a large part of early development in vertebrates. It is specifically responsible for
development of the peripheral nervous system (PNS). The neural-crest stem cells
split from the neural tube as it closes, and nociceptors grow from the dorsal part of
this neural-crest tissue. They form late during neurogenesis. Earlier forming cells
from this region can become non-pain sensing receptors, either proprioceptors or
low-threshold mechanoreceptors. All neurons derived from the neural crest,
including embryonic nociceptors, express the TrkA, which is a receptor to nerve-
growth factor (NGF).

 Types and functions:
1. Thermal:
 Thermal nociceptors are activated by noxious heat or cold at various temperatures.
 There are specific nociceptor transducers that are responsible for how and if the specific nerve
ending responds to the thermal stimulus. The first to be discovered was TRPV1 and it has a
threshold that coincides with the heat pain temperature of 42 °C. Other temperature in the warm–hot
range is mediated by more than one TRP channel. The interactions between all these channels and
how the temperature level is determined to be above the pain threshold are unknown at this time.
The cool stimuli are sensed by TRPM8 channels. Its C-terminal domain differs from the heat
sensitive TRPs. Although this channel corresponds to cool stimuli, it is still unknown whether it also
contributes in the detection of intense cold.
2. Mechanical:
 Mechanical nociceptors respond to excess pressure or mechanical deformation. They also
respond to incisions that break the skin surface. The reaction to the stimulus is processed as
pain by the cortex, just like chemical and thermal responses. These mechanical nociceptors
frequently have polymodal characteristics. So it is possible that some of the transducers for
thermal stimuli are the same for mechanical stimuli. The same is true for chemical stimuli,
since TRPA1 appears to detect both mechanical and chemical changes.

3.Chemical:
 Chemical nociceptors have TRP channels that respond to a wide variety of spices.
The one that sees the most response and is very widely tested is capsaicin. Other
chemical stimulants are environmental irritants like acrolein a World War I chemical
weapon and a component of cigarette smoke. Apart from these external stimulants,
chemical nociceptors have the capacity to detect endogenous ligands, and certain
fatty acid amines that arise from changes in internal tissues. Like in thermal
nociceptors, TRPV1 can detect chemicals like capsaicin and spider toxins.
4.Sleeping/silent:
 Although each nociceptor can have a variety of possible threshold levels, some do
not respond at all to chemical, thermal or mechanical stimuli unless injury actually
has occurred. These are typically referred to as silent or sleeping nociceptors since
their response comes only on the onset of inflammation to the surrounding tissue.
5. Polymodal:
 Many neurons perform only a single function; therefore, neurons that perform these
functions in combination are given the classification "polymodal.

A Drug that selectively relieves pain by acting
in the central nervous system or on
peripheral pain mechanisms, without
significantly altering consciousness.
IT IS CLASSIFIED INTO:
 OPIOID ANALGESICS.
 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS.(NSAID’S)

 Analgesic, antipyretic and anti-inflammatory actions.
 Compared to morphine,they are weaker analgesics; do not depress
CNS, do not produce physical dependence and have no abuse
liability.
 They are also called nonnarcotic, nonopioid or aspirin like
analgesics.
 They act primarily on peripheral pain mechanisms but also in CNS
to raise pain threshold.

 A. NONSELECTIVE COX INHIBITORS:
1. salicylates: aspirin, diflunisal.
2. pyrazolone derivatives: phenylbutazone, oxyphenbutazone.
3. Indole derivatives: indomethacin, sulindac.
4. Propionic acid derivatives: ibuprofen, naproxen, ketoprofen,
flurbiprofen.
5.Anthranilic acid derivative: mephenamic acid.
6. aryl-acetic acid derivatives: diclofenac.
7. Oxicam derivatives: piroxicam, tenoxicam
8. pyrrolo-pyrrole derivative: ketorolac.
 B. PREFERENTIAL COX-2 INHIBITORS:
nimesulide, meloxicam, nabumetone.

 C. SELECTIVE COX-2 INHIBITORS:
Celecoxib, rofecoxib, valdecoxib
 D. ANALGESIC-ANTIPYRETICS WITH POOR
ANTIINFLAMMATORY ACTION:
1. paraaminophenol derivative: paracetamol
(acetaminophen)
2. pyrazolone derivatives: metamizol (dipyrone), propiphenazone.
3. benzoxazocine derivative: nefopam.

 Most NSAIDs act as nonselective inhibitors the enzyme
cyclooxygenase(COX), inhibiting both the cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is
competitively reversible (albeit at varying degrees of reversibility), as
opposed to the mechanism of aspirin, which is irreversible inhibition.[ COX
catalyzes the formation
of prostaglandins and thromboxane from arachidonic acid (itself derived
from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins
act (among other things) as messenger molecules in the process
of inflammation.
 COX-1 is a constitutively expressed enzyme with a "house-keeping" role in
regulating many normal physiological processes. One of these is in
the stomach lining, where prostaglandins serve a protective role,
preventing the stomach mucosa from being eroded by its own acid. COX-2
is an enzyme facultatively expressed in inflammation, and it is inhibition of
COX-2 that produces the desirable effects of NSAIDs

 When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and
naproxen) lower stomach prostaglandin levels, ulcers of
the stomach or duodenum internal bleedin can result.
 The discovery of COX-2 led to research to the development of selective COX-2
inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs
 NSAIDS have antipyretic activity and can be used to treat fever.it work by inhibiting
the enzyme COX, which causes the general inhibition of prostanoid biosynthesis
(PGE2) within the hypothalamus.PGE2 signals to the hypothalamus to increase the
body's

 Aspirin is an acetylsalicylic acid.
 It is rapidly converted in the body to salicylic acid which is responsible
for most of the actions.
 It is one of the oldest analgesic – antiinflammatory drugs and is stil
widely used.

 Aspirin causes several different effects in the body, mainly the reduction of
inflammation, analgesia (relief of pain .
 Much of this is believed to be due to decreased production of prostaglandins and TXA2.
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its
irreversible inactivation of the cyclooxygenase (COX) enzyme
 Aspirin acts as an acetylating agent where an acetyl group is covalently attached to
a serine residue in the active site of the COX enzyme.

 PHARMACOLOGICAL ACTIONS:
1. ANALGESIC,ANTIPYRETIC AND ANTIINFLAMMATORY ACTION:
the analgesic action is mainly due to obtunding of peripheral pain receptors
and endings.
2. RESPIRATION: at antiinflammatory doses respiration is stimulated by
peripheral and central actions.
3. GIT: aspirin and released salicylic acid irritate gastric mucosa which
causes epigastric distress, nausea and vomiting.
4. CVS: larger doses increase cardiac output to meet increased peripheral o2
demand and cause direct vasodilation.
5.BLOOD: aspirin inhibits TXA2 synthesis by platelets and interferes with
platelet aggregation.

 PHARMACOKINETICS:
 aspirin is absorbed from stomach and small intestines. its poor water
solubility is the limiting factor in absorption.
 Aspirin is rapidly deacetylated in the gut wall, liver, plasma and pther
tissues to release salicylic acid.
 It slowly enters brain but freely crosses placenta.
 The plasma t1/2 of aspirin is 15-20 min.
 INDICATION:
Effective analgesic for mild to moderate pain
DOSE: 325-650 mg 4-6 hourly.

 DOSE: aspirin 350 mg tab, colsprin 100, 325, 650 mg tab,
ecosprin 75, 150, 325 mg tabs, disprin 350 mg tab,
loprin 75,162.5 mg tabs.
- Generally, aspirin isn't recommended during pregnancy unless certain medical
conditions. Low-dose aspirin — 60 to 100 milligrams (mg) daily — is sometimes
recommended for pregnant women with recurrent pregnancy loss, clotting
disorders and preeclampsia.

 ADVERSE EFFECTS:
 Side effects: nausea, vomiting, epigastric distress, increased occult blood loss in
stools.
 Hypersensitivity and idiosyncrasy: itching, urticaria, rhinorrhoea, angioedema, asthma
and anaphylactoid reaction.
 Antiinflammatory doses.
 Acute salicylate poisoning.
 Reye syndrome: Reye syndrome is a rapidly worsening brain disease. Symptoms
may include vomiting, personality changes, confusion, seizures, and loss of
consciousness. It is contraindicated in children now.
 USES:
1. As analgesic: for headache, backache, myalgia, joint pain, pulled muscle,
toothache, neuralgias.
2. As antipyretic: in fever.
3. Acute rheumatic fever
4. Rheumatoid arthritis
5. Osteoarthritis
6. Postmyocardial infarction and poststroke

 Potent anti-inflammatory drug.
 Poor analgesic and antipyretic activity.
 MECHANISM OF ACTION:Phenylbutazone binds to and inactivates prostaglandin H
synthase and prostacyclin synthase through peroxide (H2O2) mediated deactivation. The
reduced production of prostaglandin leads to reduced inflammation of the surrounding tissues.
 PHARMACOKINETICS: It is absorbed orally. 98% bound to plasma protein and
completely metabolized in liver by hydroxylation and glucuronidation.
DOSE: 100-200 mg BD or TDS after meals
( ZOLANDIN 100-200 mg Tab)
ADVERSE EFFECTS: nausea, vomiting, epigastric distress and peptic ulceration are
common. Edema due to Na+ retention.
USES: 1. acute gout: to suppress the attack
2.rheumatoid arthritis.

 Potent anti-inflammatory, antipyretic and good analgesic.
 It is well absorbed orally, rectal absorption is slow. It is 90% bound to plasma,
partlymetabolized in liver to inactive products and excreted by kidney.
 MECHANISM OF ACTION:
1. it has potent anti inflammatory effect.
2. it is highly potent inhibitor of prostaglandin synthesis.
3. it inhibits the migration of neutrophils to inflamed area.
4. it relieves only inflammatory or tissue injury related pain.
USES:Ankylosing spondylitis, acute exacerbations of destructive
arthropathies and psoriatic arthritis.
DOSE: 25-50 mg BD/TDS (INDOCAP, IDICIN)
ADVERSE EFFECTS: 1.gastric irritation, nausea, anorexia, gastric bleeding, and diarrhoea are
prominent.
2. frontal headache, dizziness, ataxia, mental
confusion, hallucination, depression.
3. leukopenia, rashes and other
hypersensitivity reactions.
CONTRAINDICATIONS:1. asthma
2. Angioedema
3.Renal failure

 Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the
arylalkanoic acid class that is marketed as Clinoril.
 MECHANISM OF ACTION: Sulindac is a prodrug, derived
from sulfinylindene, that is converted in the body to the active NSAID.
 the agent is converted by liver enzymes to a sulfide that is excreted in the
bile and then reabsorbed from the intestine.
 sulindac is relatively less irritating to the stomach than other NSAIDs except
for drugs of the COX-2 inhibitor class.
 The exact mechanism of its NSAID properties is unknown, but it is thought
to act on enzymes COX-1 and COX-2, inhibiting prostaglandin synthesis.

 DOSAGE: The usual dosage is 150 to 200 milligrams twice a day, with food.
 USES: It is widely available around the world, with indications for osteoarthritis,
rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute
subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis and
osteomyelitis.
 ADVERSE EFFECTS: . Sulindac is much more likely than other NSAIDs to
cause damage to the liver or pancreas, though it is less likely to cause
kidney damage than other NSAIDs.
 CONTRAINDICATION: It should not be used by persons with a history of major
allergic reactions (urticaria or anaphylaxis) to aspirin or other NSAIDs, and should
be used with caution by persons having pre-existing peptic ulcer disease

 Analgesic,antipyretic and anti-inflammatory activity is lower than
aspirin
 Inhibit platelet aggregation and prolong bleeding time.
MECHANISM OF ACTION:
. ibuprofen work by inhibiting the cyclooxygenase (COX) enzymes, which
convert arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by
other enzymes to several other prostaglandins (which are mediators of pain,
inflammation, and fever) and to thromboxane A2 (which
stimulates platelet aggregation, leading to the formation of blood clots).
. ibuprofen is a nonselective COX inhibitor, in that it inhibits two isoforms of
cyclooxygenase, COX-1 and COX-2. The analgesic, antipyretic, and anti-
inflammatory activity of NSAIDs appears to operate mainly through inhibition of
COX-2, which decreases the synthesis of prostaglandins involved in mediating
inflammation, pain, fever, and swelling

 PHARMACOKINETICS: Absorbed orally and is highly bound to
plasma protein. Metabolized in liver and excreted in urine and bile.
It enters brain, synovial fluid and cross placenta.
 ADVERSE EFFECTS: 1.gastric discomfort, nausea , vomiting.
2. Headache, dizziness, blurring of vision.
3. rashes, itching, and other hypersensitivity
reactions.
4. they are not to be prescribed to pregnant
women andshould be avoided in peptic ulcer patient.
 DOSE: 400-800 mg TDS ( BRUFEN,EMFLAM, IBUGESIC)
For post surgical pain: 200-400mg; 4 to6 hourly

 USES: 1. Used as a simple analgesic and antipyretic.
2. rheumatoid arthritis, osteoarthritis and other musculokeletal disorders,
specially where pain is prominent.
3. they are also indicated in soft tissue injuries, fractures , tooth extracton it
suppress swelling and inflammation.
 Postoperative prescription of choice for acute nociceptive orofacial pain: a combination of
ibuprofen 600 mg plus acetaminophen 1000mg administered every 6 hours for 24 days.
 CONTRAINDICATION: 1. Ibuprofen tablets are contraindicated in patients with
known hypersensitivity to ibuprofen.
2.Asthma. 3.Heart attack. 4.Liver problems.
5. Kidney disease.

 Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory
drugs (NSAID) with analgesic and antipyretic effects.[It acts by inhibiting the body's
production of prostaglandin.
 MECHANISM OF ACTION: Ketoprofen undergoes metabolism in the liver via conjugation
with glucuronic acid, CYP3A4 and CYP2C9 hydroxylation of the benzoyl ring, and reduction
of its keto function.Ketoprofen is used for its antipyretic, analgesic, and anti-inflammatory
properties by inhibiting cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes reversibly,
which decreases production of proinilammatory prostaglandin precursors.
 USES:
 ketoprofen is used to relieve minor aches and pain from headaches, menstrual periods,
toothaches, the common cold, muscle aches, and backaches, and to reduce fever.
 DOSE: 1. ketoprofen in a dose range of 12.5 mg to 37.5mg
it is a safe and effective analgesic for the relief of
post-operative dental pain
ADVERSE EFFECTS: upset stomach,heartburn,unusual tiredness,
bloating,

 it is a nonsteroidal anti-inflammatory drug (NSAID) used to treat
pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis,
and fever.
 Onset of effects is within an hour and last for up to twelve hour.
 Mechanism of action:
 Naproxen works by reversibly inhibiting both the COX-1 and COX-
2 enzymes as a non-selective coxib. This results in the inhibition
of prostaglandin synthesis.
 Prostaglandins act as signaling molecules in the body, inducing inflammation.
Thus, by inhibiting COX-1/2, naproxen induces an anti-inflammatory effect.
 Pharmacokinetics:
 Naproxen is a minor substrate of cytochrome p450 CYP1A2 and CYP2C9. It is
extensively metabolized in the liver to 6-O-desmethylnaproxen, and both the
parent drug and the desmethyl metabolite undergo further metabolism to their
respective acylglucuronide conjugated metabolites.
 naproxen sodium reaches peak plasma concentrations within 1–2 hours.

 USES: 1.Mostly used for postoperative pain.
2. Naproxen is used to relieve pain from various conditions such as headache,
muscle aches, tendonitis, dental pain, and menstrual cramps. I
3. it also reduces pain, swelling, and joint stiffness caused by arthritis, bursitis, and
gout attacks.
 Dosage: naproxen sodium 220 mg.
 ADVERSE EEFECTS:
 Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and
gastrointestinal upset.
 Heavy use is associated with increased risk of end-stage renal disease and kidney failure.
 Naproxen may cause muscle cramps in the legs in 3% of people.
 naproxen can cause gastrointestinal problems,
such as heartburn, constipation,ulcers and
stomach bleeding.
 It can also cause myocardial infarctions.

 Mefenamic acid is a member of the anthranilic acid derivatives (or fenamate) class
of NSAID drugs, and is used to treat mild to moderate pain, including menstrual
pain, and is sometimes used to prevent migraines
 DOSE: initial dose: 500 mg orally once
Following initial dose: 250 mg orally every 6 hours as needed
Duration of therapy: Usually not to exceed 1 week
Use: For the relief of acute pain
 USES: soft tissue pain and postoperative
dentalpain.
 ADVERSE EFFECTS:
Cardiovascular Thrombotic Events
GI Bleeding, Ulceration and Perforation
Hepatotoxicity
Hypertension

 Diclofenac, sold under the trade names Voltaren is a nonsteroidal anti-inflammatory
drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth
or applied to the skin.
MECHANISM OF ACTION:The primary mechanism, is thought to be inhibition of prostaglandin
synthesis by inhibition of the transiently expressed prostaglandin-endoperoxide synthase-2
(PGES-2) also known as cycloxygenase2 (COX-2). It also appears to exhibit bacteriostatic
activity by inhibiting bacterial DNA synthesis
 Besides the COX-inhibition, it alsohelps in Blockage of voltage-dependent sodium
channels (after activation of the channel, diclofenac inhibits its reactivation also known as
phase inhibition) and Blockage of acid-sensing ion channels (ASICs)
USES: arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental
pain, temporomandibular joint (TMJ) pain, spondylarthritis,
ankylosing spondylitis, gout attacks,and pain management in cases
of kidney stones and gallstones.
DOSE:
18 mg, 25 mg, and 35 mg

ADVERSE EFFECTS: 1.Liver damage occurs infrequently, and is usually reversible.
2.Hepatitis
3.indigestion, gas, stomach pain, nausea, vomiting;
diarrhea, headache, dizziness, drowsiness; itching, increased sweating;
4.increased blood pressure; or swelling or pain in your arms.
CONTRAINDICATION:
 Hypersensitivity against diclofenac.
 History of allergic reactions (bronchospasm, shock, rhinitis, urticaria)
 Third-trimester pregnancy
 Active stomach and/or duodenal ulceration or gastrointestinal bleeding
 Inflammatory bowel disease such as Crohn's disease or ulcerative colitis
 Severe congestive heart failure (NYHA III/IV)

 Ketorolac, sold under the brand name, is a nonsteroidal anti-inflammatory drug used
to treat pain. Specifically it is recommended for moderate to severe pain.
 It is used by mouth, by injection into a vein or muscle, and as eye drops. Effects
begin within an hour and last for up to eight hours.
MECHANISM OF ACTION: The primary mechanism of action responsible for
ketorolac's anti-inflammatory, antipyretic and analgesic effects is the inhibition of
prostaglandin synthesis by competitive blocking of
the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor. It is
considered a first-generation NSAID.

 USES:
1. Ketorolac is used for short-term management of moderate to severe
pain
2. Ketorolac is effective when administered with paracetamol to control
pain in newborns because it does not depress respiration as
do opioids.
3. Ketorolac is also an adjuvant to opioid medications and improves
pain relief.
4. It is also used to treat dysmenorrhea.
5.Ketorolac is used to treat idiopathic pericarditis, where it reduces
inflammation.
6. Ketorolac is also used as an eye drop. It can be given during eye
surgery to help with pain, and is effective in treating ocular itching.

 ADVERSE EFFECTS: 1..sleepiness, dizziness, abdominal pain, swelling, and nausea.
2. Serious side effects may include stomach bleeding, kidney failure, heart
attacks, bronchospasm, heart failure, and anaphylaxis.
3. Use is not recommended during the last part of pregnancy or
during breastfeeding.
4. Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2),
thereby decreasing production of prostaglandins.
5. stroke, myocardial infarction, GI bleeding, Stevens-Johnson Syndrome, toxic
epidermal necrolysis
 CONTRAINDICATION: Ketorolac is contraindicated in those with hypersensitivity, allergies to
the medication, cross-sensitivity to other NSAIDs, prior to surgery, history of peptic ulcer
disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular
bleeding, nasal polyps, angioedema, and asthma.

 Nimesulide is a nonsteroidal anti-inflammatory drug with pain medication and
fever reducing properties.
 It is almost completely absorbed orally,99% plasma protein bound, extensively
metabolized and excreted mainly in urine with a t1/2 of 2 to 5 hours.
 MECHANISM OF ACTION: 1. Weak inhibitor of PG synthesis.
 2. inhibition of platelet activating factor synthesis
and tumor necrosis factor release.
 3. inhibition of metalloproteinase activity.
 INDICATION: acute pain 100mg twice a day.
 DOSE: 100mg BD; NIMULID,NIMEGESIC,NIMODOL 100mg tab, 50mg/5 ml
susp.
 ADVERSE EFFECTS: 1.GIT: heart burn, nausea, loose motions
2. Dermatological: rash, pruritus
3.CNS: dizziness.
4. hematuria is reported in few children.
5. hepatic failure.

 USES: 1.short lasting painful inflammatory conditions like sports
injuries, sinusitis and other ear –nose throat disorders.
2. dental surgery
3.low backache
4.postoperative pain
5.osteoarthritis
6.fever

 Paracetamol the deethylated active metabolite of phenacetin,was also introduced in
the last century but has come into common use only since 1950.
 Paracetamol is well absorbed orally, only about 1/3 is protein bound in plasma and it
is uniformly distributed in the body.
 It is conjugated with glucuronic acid and sulfate and is excreted rapidly in urine.

 Acetaminophen, also known as paracetamol, is a nonsteroidal anti-inflammatory
drug with potent antipyretic and analgesic actions but with very weak anti-
inflammatory activity.
 it reduces levels of prostaglandin metabolites in urine but does not reduce synthesis
of prostaglandins by blood platelets or by the stomach mucosa. Because
acetaminophen is a weak inhibitor in vitro of both cyclooxygenase (COX)-1 and
COX-2, the
possibility exists that it inhibits a
so far unidentified form of COX,
perhaps COX-3.

PHARMACOKINETICS: metabolism is in liver. Excretion is
in urine. Plasma t1/2 is 2-3 hours. Effects after an oral dose last 3-5
hours.
INDICATION: mild to moderate pain
dosage: 1. up to 1 year: 60-120 mg
2. 1-5 years: 120-240 mg
3. 6-12 years: 240-480 mg
repeat every 4-6 hours
DOSE: 0.5-1 gm TDS 500 mg Tab. ( CROCIN, PARACIN,
METACIN, PYRIGESIC)

ADVERSE EFFECTS: 1.IT is safe and well tolerated.
2.nausea and rashes occur occasionally, leukopenia is rare.
3. high dose can cause hepatic necrosis.
USES: 1. most commonly used analgesic for headache, musculoskeletal pain etc.
2. it is recommended as first choice analgesic for osteoarthritis.
3. it is much safer than aspirin in terms of gastric
irritation,ulceration,bleeding.
4. can be used in all age groups( infants to elderly, pregnant/lactating women
and in patients in whom aspirin is contraindicated.)
 CONTRAINDICATION: Potentially fatal liver damage.
kidney damage
Patients with liver problems
High blood pressure

 Celecoxib, sold under the brand name Celebrex among others, is a COX-2 selective nonsteroidal
anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute
pain in adults, rheumatoid arthritis, ankylosing spondylitis, painful menstruation, and juvenile
rheumatoid arthritis.
MECHANISM OF ACTION: A highly selective reversible inhibitor of the COX2 isoform
of cyclooxygenase. celecoxib inhibits the transformation of arachidonic acid to prostaglandin
precursors. Therefore, it has antipyretic, analgesic and anti-inflammatory properties
DOSE: initial dose: 400 mg orally once followed by an additional 200 mg orally if needed
USES: Celecoxib is used for osteoarthritis, rheumatoid arthritis, acute pain, musculoskeletal pain,
painful menstruation, ankylosing spondylitis, and to reduce the number of colon and rectal polyps in
people
 ADVERSE EFFECTS: 1.High blood pressure, Chest pain or heart attack .
2. Skin reactions, including rash or blisters
3.Allergic reactions. stomach pain
4.constipation
5.diarrhea
6.gas
7.heartburn
8.nausea
9.vomiting
10.Dizziness

 Nefopam, sold under the brand name Acupan among others, is a centrally acting, non-
opioid painkilling medication that exerts non-narcotic effects. It is primarily used to treat
moderate to severe, acute or chronic pain
MECHANISM OF ACTION:Nefopam acts in the brain and spinal cord to relieve pain via novel
mechanisms: antinociceptive effects from triple monoamine reuptake inhibition,
and antihyperalgesic activity through modulation of glutamatergic transmission.
USES: 1. pain after an operation or a serious injury,
2. dental pain, joint pain or muscle pain, or pain from cancer.
3. It's also used for other types of long-standing pain when weaker painkillers no longer
work.
ADVERSE EFFECTS: Common side effects include nausea, nervousness, dry mouth, light-
headedness and urinary retention.
Less common side effects include vomiting, blurred vision, drowsiness,
sweating, insomnia, headache, confusion, hallucinations, tachycardia, aggravation of angina
and Overdose.

 CLASSIFICATION:
1. NATURAL OPIUM ALKALOIDS: Morphine, codeine
2. SEMISYNTHETIC OPIATES: Diacetylmorphine (heroin),
pholcodeine.
3. SYNTHETIC OPIOIDS: Pethidine(meperidine), fentanyl,
methadone, dextropropoxyphene, tramadol, ethoheptazine.

OPIUM: The dark brown, resinous material obtained from poppy( papaver
somniferum) capsule is called opium. It contains two types of alkaloids.
 Phenanthrene derivatives : morphine(10% in opium)
codeine(0.5% in opium)
thebaine(0.2% in opium),(non-analgesic)
 Benzoisoquinoline derivatives: papaverine(1%)
noscapine(6%) (non-analgesic)
MORPHINE PAPAVERINE

 Opioid receptors are coupled with inhibitory G- protein and their activation has a number of
actions: -
- closing of votage sensitive calcium channels.
- stimulation of potassium efflux leading to hyperpolarization and reduced cyclic
adenosine monophosphate production.
 They are also involved in: 1. postsynaptic hyperpolarization ( increasing K+ efflux )
2. reducing presynaptic Ca+ influx.
MECHANISM OF ACTION:
Morphine binds opioid receptors and thus impairs the norma sensory pathways through:
- Blockade of calcium channels which lead to decreased release of substance p and glutamate
from the first neuron of the sensory pathway (in substantia gelatinosa in spinal cord)
- Decreased c-AMP which leads to opening of K-channels and hyperpolarization of the second
neuron of the sensory pathway.
Morphine is the principle alkaloid in opium and still widely used, therefore described as prototype.

PHARMACOLOGICAL ACTIONS:
1. CNS:
 Analgesia: morphine is a strong analgesic. nociceptive pain
arising from stimulation of peripheral pain receptors is relieved
better than neuretic pain due to inflammation or damage of
neural structures.
 Sedation: drowsiness and indifference to surroundings as well
as to own body occurs without motor incoordination, alatxia or apparent excitement.
High doses causes sleep and coma.
 mood and subjective effects: it has a claming
effect, loss of apprehension, feeling of deatachment,
inability to concentrate. Patient in pain or anxiety and
addicts specially perceive it as pleasurable.(euphoric-
Effect).
 Respiratory centre: rate and tidal volume are both
decreased, death in poisoning is due to respiratory
failure.

 Cough centre: it is depressed; more sensitive to morphine than respiratory
centre.
 Temperature regulating centre: it is depressed; hypothermia occurs in cold
surroundings.
 Vasomotor centre: it is depressed at higher doses and contributes to the fall
in BP.
MORPHINE STIMULATES :
1. CTZ (CHEMORECEPTOR TRIGGER ZONE): Nausea, vomiting specially if
stomach is full.
2. EDINGER WESTPHAL NUCLEUS: of III nerve is stimulated producing miosis. this
is a central action; no miosis occurs on topical application of morphine to the eye.
3. VAGAL CENTRE: It is stimulated and can cause bradycardia
MIOSIS

2. NEURO-ENDOCRINE: Decreases levels of FSH, LH, ACTH, while prolactin and GH
levels are reduced. Morphine can reduce urine volume.
3. CVS: Morphine causes vasodilation due to:
I. direct action decreasing tone of blood vessels.
II. Histamine release.
III. Depression of vasomotor centre.
4. GIT: Constipation is a prominent feature
5. OTHER SMOOTH MUSCLES:
I. BILIARY TRACT: it causes spasm of sphincter of oddi due to which intrabiliary
pressure is increased which may cause biliary colic.
II. URINARY BLADDER: Difficulty in micturition. Contractions of ureter are also
increased.
III. BRONCHI: Morphine releases histamine which can cause bronchoconstriction.

PHARMACOKINETICS:
 oral absorption is unreliable,it has high first pass metabolism.
 Distribution is wide; concentration in liver, spleen and kidney is higher than that in plasma.
 Freely crosses the placenta and can affect foetus more than the mother.
 Plasma t1/2 of morphine averages 2-3 hours. Effect of parenteral dose lasts 4-6 hours
DOSE: 10-15 mg i.m/s.c
MORPHINE SULPHATE : 10,15 mg inj.
USES:
1.As analgesic- used in severe pain of any type. however they can only provide symptomatic
relief without affecting the cause.
2. Preanaesthetic medication: morphine and pethidine have been used.
3.Relief of anxiety and apprehension: specially in myocardial infarction and internal bleeding.
4. Acute left ventricular failure(cardiac asthma).
5. Cough: codeine is used for suppressing dry, irritating cough.
6. Diarrhoea.

ADVERSE EFFECTS:
1. SIDE EFFECTS: I. Sedation, mental clouding, lethargy. vomiting and constipation is common.
II. respiratory depression, blurring of vision, urinary retention are other side
effects.
2. IDIOSYNCRASY AND ALLERGY: urticaria, itch, swelling of lips.
3. APNOEA: can occur in newborn when morphine is given to mother during labour.
NALOXONE 10ug is treatment of choice.
4. ACUTE MORPHINE POISONING: treatment is naloxane 0.4-0.8 mg i.v repeated every 2-3
min till respiration picks up.
5. TOLERANCE AND DEPENDENCE.
a localized reaction to intravenous morphine caused by Apnoea
Histamine release in the veins.

CONTRAINDICATIONS:
1. Bronchial asthma
2. Head injury
3. Hypothyroidism, liver and kidney disease patients.
4. Undiagnosed acute abdominal pain.
5. Hypotensive states and hypovolemia exaggerate fall in BP due to
morphine.
6. It is dangerous in patients with respiratory insufficiency.(emphysema,
pulmonary fibrosis)
7. Infants and the elderly are more susceptible to the respiratory depressant
action of morphine.

 It is a methyl-morphine occurs naturally in opium and is partly
converted in the body to morphine.
 It is less potent than morphine, also less efficacious: the degree of
analgesia is comparable to aspirin (60 mg codeine ≥600 mg aspirin.)
 It is more selective cough suppressant, subanalgesic doses (10-30mg)
suppress cough.
 It has a good activity by oral route
(oral:parenteral ratio 1:2). A single dose
acts for 4-6 hours.
 Constipation is a common side effect,it
is used to control diarrhoea.

 Pethidine was synthesized as an atropine substitute in1939.
 It interacts with opioid receptors and its action are blocked by naloxone.
 DOSE: 50-100 mg i.m, s.c/orally. (pethidine HCL 100mg/2ml inj. ,50-
100mg TAB)
 SIDE EFFECTS: 1. Dry mouth,blurred vision,
2.excitatory effects- tremors, mydriasis, hyperreflexia
and convulsions.
 USES: as analgesic and in preanaesthetic
medication, but not for cough or
diarrhoea.

 A pethidine congener, 80-100 times more potent than morphine,
both in analgesia and respiratory depression.
 Transdermal fentanyl has become available for use in cancer or
other types of chronic pain for patients requiring opioid analgesia.
 DOSE: 100-200 ug i.v

 A synthetic opioid, chemically very similar to morphine,
has analgesic, respiratory depressant, emetic,
antitussive, constipating and biliary actions similar to
morphine.
 It has high oral:parenteral activity(1:2).
 It is more potent than morphine.
 DOSE: 10 mg inj. PHYSEPTONE

 Synthetic centrally acting analgesic.
 It causes less respiratory depression, sedation, constipation, urinary
retention than morphine.
 Oral bioavailability is good. (oral: parenteral dose ratio 1:2)
 Side effects are: dizziness, nausea, sleepiness, dry mouth and
sweating.
 It is indicated for medium intensity short- lasting pain due to diagnostic
procedures, injury, surgery etc,
as well as for chronic pain including cancer
pain, but is not effective in severe pain.
 DOSE: 50-100 oral/i.m./slow i.v. infusion
( children 1-2 mg/kg) 4-6 hourly.
CONTRAMAL, DOMADOL

 patient is allergic to any NSAID, you will have to avoid them.
 Paracetamol is the safest NSAID.
 Ibuprofen is contraindicated in asthma patients as it causes
bronchoconstriction.
 ACETAMINOPHEN is analgesic of choice for asthma patients.
 If the patient is taking aspirin, then no surgery or even simple
extraction should be done.
 - as it can lead to profuse bleeding because of its antiplatlet action.
Aspirin should be stopped before 7-10 days of any surgical
procedure till 2-3 days after procedure.
 - young children are highly susceptible to aspirin poisoning.

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