Nonnarcotic Analgesics: Nonsteroidal Anti-inflammatory Drugs
classes of anti-inflammatory agents:
- Nonsteroidal Anti-inflammatory Drugs: celecoxib, diclofenac, ibuprofen
indomethacin ketoprofen, mefenamic acid, naproxen, piroxicam
- Related Drugs: acetaminophen
The inflammatory response
- The inflammatory response is designed to protect the body from injury and
- It employs a variety of potent chemical mediators to produce the reaction that
helps to destroy pathogens and promote healing.
- As the body reacts to these chemicals, it produces some signs and symptoms of
disease, such as
- pain, and aches,
- Occasionally, the inflammatory response becomes a chronic condition and can
actually result in body damage, leading to increased inflammatory reactions.
- Anti-inflammatory agents generally block or alter the chemical reactions
associated with the inflammatory response to stop one or more of the signs and
symptoms of inflammation.
Prostaglandins play an important role in the following conditions:
1- Inflammation. Increased prostaglandin play a role in inflammation.
2- Pain. Prostaglandins appear to help mediate painful stimuli in a variety of
conditions including inflammation. They increase the sensitivity of pain receptors to
3- Fever. Prostaglandins appear to be pyretogenic; that is, they help produce the elevated body
temperature during fever.
4- Dysmenorrhea. The painful cramps that accompany menstruation in some women have been
attributed at least in part to increased prostaglandin production in the endometrium of the uterus.
5- Thrombus Formation. The thromboxanes, especially TXA2, cause platelet aggregations that result in
blood clot formation.
Synthesis of prostaglandins
Arachidonic acid is the primary precursor of the prostaglandins. Arachidonic acid is
present as a component of the phospholipids of cell membranes. As a result of
physical trauma, noxious chemicals, or microbiologic agents inflammation is
produced. Inflammation is the body's effort to inactivate or destroy invading
organisms, remove irritants, and set the stage for tissue repair.
Free arachidonic acid is released from tissue phospholipids by the action of
phospholipase A2. There are two major pathways in the synthesis of the eicosanoids
(Prostaglandins) from arachidonic acid.
Cyclooxygenase pathway: where the prostaglandins, thromboxanes, and
prostacyclins are synthesized via the cyclooxygenase pathway. Two
cyclooxygenase enzymes have been described.
a- Cyclooxygenase-1 (COX-1) is responsible for the physiologic production of
b- cyclooxygenase-2 (COX-2) causes the elevated production of prostanoids that
occurs in sites of disease and inflammation. COX-1 regulates normal cellular
processes, such as gastric cytoprotection, vascular homeostasis, platelet
aggregation, and kidney function.
COX-2 is active in many tissues such as the brain, kidney, and bone. Its
activity at other sites is increased during states of inflammation.
Formation of prostaglandins. A stimulus of the cell membrane leads to the final formation of
prostaglandins through the enzymes cyclooxygenase (COX1 and COX2
A- Non-selective COX inhibitors
1 - Aspirin (Acetyl salicylic acid) is one of the salicylates
2 - Nonsteroidal anti-inflammatory drugs (NSAIDs)
3- Selective COX2 inhibitors (Celexocib)
4 - Acetaminophen also is a widely used agent. It has antipyretic and analgesic
properties but does not have the anti-inflammatory effects of Aspirin or the NSAIDs.
Mechanism of action: Aspirin irreversibly inhibits cyclooxygenase enzymes. The
other NSAIDs, are all reversible inhibitors of cyclooxygenase.
Aspirin as a result has the following effects:
1- Anti-inflammatory actions: Because aspirin inhibits COX activity, it diminishes
the formation of prostaglandins and, thus, modulates aspects of inflammation in
which prostaglandins act as mediators but it does not arrests the progress of the
disease nor induces remission.
2- Antipyretic, Aspirin lower body temperature in patients with fever by impeding
PGE2 synthesis and release and causing peripheral vasodilation and sweating. Aspirin
has no effect on normal body temperature.
3- Analgesic effects. Aspirin and other NSAIDs repress the sensation of pain.
Aspirin is used mainly for the management of pain of low to moderate intensity
arising from musculoskeletal disorders rather than that arising from the viscera.
4-Gastrointestinal effects: As a result of inhibition of prostaglandins ,
(prostacyclin (PGI2) aspirin, causes increased gastric acid secretion and diminished
mucus protection. This may cause epigastric distress, ulceration, hemorrhage.
5- Antiplatelet action (anti-thrombotic action): TXA2 enhances platelet
aggregation, whereas PGI2 decreases it. Low doses of aspirin can irreversibly inhibit
thromboxane production in platelets, platelet aggregation (the first step in thrombus
formation) is reduced, producing an anticoagulant effect with a prolonged bleeding
time (antiplatelet action).
2- Other NSAIDs (Non-selective COX inhibitors)
Ibuprofen and ketoprofen .
All have strong anti-inflammatory, analgesic, and antipyretic activity. Piroxicam
(given once daily) because it have long half-life. They inhibits both COX-1 and COX-
2, but Piroxicam has some preferential binding for COX-2..
They can alter platelet function and prolong bleeding time. They have gained wide
acceptance in the chronic treatment of RA and osteoarthritis, because their GI effects
are generally less intense than those of aspirin. These drugs are reversible inhibitors of
3- Selective Cyclooxygenase-2 Inhibitor
Celecoxib (Celebrex) is used for
the acute and long-term treatment of arthritis, particularly in patients who cannot
tolerate the GI effects of other NSAIDs;
The NSAIDs have a variety of uses that vary depending on the drug selected. NSAIDs
are used for the following conditions:
• Relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and other
• Mild to moderate pain relief
• Primary dysmenorrhea
• Fever reduction as antipyretic
•Aspirin as antithrombotic at low dose to prevent the risk of death and MI in patients
with history of MI, prevention of transient ischemic attacks.
• fever reduction.
• gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip.
Contraindications for NSAIDs
- Allergy to salicylates,
- bleeding abnormalities
- impaired renal function, because the drug is excreted in the urine;
- chickenpox or influenza, because of the risk of Reye's syndrome in children.
- surgery or other invasive procedures scheduled within 1 week, because of the risk
of increased bleeding; and
- pregnancy or lactation, because of the potential adverse effects on the neonate or
• Gastrointestinal tract nausea, vomiting, diarrhea, constipation, epigastric pain,
indigestion, abdominal distress or discomfort, peptic ulceration, bleeding, stomatitis,
jaundice, bloating, anorexia, and dry mouth as a result of COX1 inhibition
- Central nervous system dizziness, anxiety, lightheadedness, vertigo, headache,
drowsiness, insomnia, confusion, depression, and psychic disturbances -
- Blood loss, bleeding abnormalities.
-Metabolic effects such as decreased appetite, hyperglycemia, flushing, etc…
4- Related Drugs
- Acetaminophen (Paracetamol)
- Acetaminophen is used to treat moderate to mild pain and fever and often is used
in place of the NSAIDs or Aspirin
- used to prevent and suppress arthritis in selected patients with rheumatoid arthritis
- Pharmacological Action
- Acts directly on the thermoregulatory cells in the hypothalamus to cause sweating
and vasodilation; this in turn causes the release of heat and lowers fever.
- Has no anti-inflammatory effect
- Treatment of pain and fever associated with a variety of conditions.
- For the prophylaxis of children receiving diphtheria–pertussis–tetanus (DPT)
- For the relief of musculoskeletal pain associated with arthritis.
- Adverse Effects
- hemolytic anemia,
- renal dysfunction, skin rash, and fever.
- Hepatotoxicity specially with chronic use or overdose.
- The inflammatory response, which is important for protecting the body from injury
and invasion, produces many of the signs and symptoms associated with disease,
including fever, aches and pains, and lethargy.
- NSAIDs block prostaglandin synthesis at cyclooxygenase-1 and -2 sites. This
blocks inflammation but also blocks protection of the stomach lining.
- There are many different NSAIDs. If one does not work, another one might.
- Acetaminophen causes heat release, lowering fever and working to relieve pain.
- Acetaminophen can cause liver failure. It is found in many OTC products.
Special Concerns in Rehabilitation Patients
● Aspirin and the other NSAIDs are among the most frequently used drugs in the
● Aside from the possibility of stomach discomfort, these drugs have a remarkable
lack of adverse effects that could directly interfere with physical and occupational
therapy. When used for various types of musculoskeletal pain and inflammation, these
drugs can often provide analgesia without sedation effects associated with opioid
● The limitation of NSAIDs is that they may not be as effective in moderate-to-severe
pain or in severe, progressive inflammation.
●Still, these agents are a beneficial adjunct in many painful conditions and can
usually help facilitate physical rehabilitation by relieving pain.
●Acetaminophen is also frequently employed for pain relief in many physical
rehabilitation patients. Remember that this drug is equal to an NSAID in analgesic
properties, but lacks anti-inflammatory effects.