**2.1 Mechanism of action**

Prostaglandins are lipid compounds that are physiologically active and have a diverse range of homeostatic and inflammatory effects in the human body that modulate fever and pain. They are the primary mediators of inflammatory cascades resulting in peripheral sensitization, hyperalgesia and chronic pain. Prostaglandin H2 (PGH2) is a common precursor for prostaglandins (PGE2, PGI2, and PGF2) and thromboxane. It is synthesized from arachidonic acid via the rate limiting enzyme cyclooxygenase (COX) (**Figure 1**). By inhibiting the cyclooxygenase (COX) enzymes and thus inhibiting prostaglandin synthesis, NSAIDs are able to produce their analgesic and anti-inflammatory effects. COX exists in two isoforms, COX-1 and COX-2. COX-1 is expressed throughout the body and is a normal component of most cells. It is a necessary in the production of protective gastric mucosal secretions and regulation of gastric acid, promotion of platelet aggregation and the maintenance of renal blood flow [9]. COX-2, however, is minimally expressed and tightly regulated under normal conditions but is induced with the pro-inflammatory stimuli seen with cellular injury (IL-1, TNF-alpha tumor necrosis factor–alpha, and cytokines) [10]. Given some of the beneficial aspects of COX-1 and the specific pro-inflammatory aspect of COX-2, newer NSAIDs are directly targeted at selective

**259**

**Table 1.**

*\**

*•*

*Adapted from [11].*

*and renal failure.*

*are the best way to determine the effects of NSAIDs in patients.*

*Safety comparison of some of the most commonly used NSAIDs.\**

*NSAIDs, Opioids, and Beyond*

**NSAID COX-2** 

**selectivity•**

affinity (**Table 1**).

**2.2 Side effects**

*DOI: http://dx.doi.org/10.5772/intechopen.93843*

inhibition of COX-2 and are collectively referred to as coxibs. NSAIDs are otherwise non-selective in their inhibition of COX-1 and COX-2 although with varying

The same mechanism of action that provides the therapeutic effect of NSAIDs is also most commonly responsible for the side effects associated with chronic use. By inhibiting prostaglandin synthesis, NSAIDs increase the risk of gastrointestinal bleeding [12–16], thrombosis [17], and myocardial infarction [18]. COX-1 mediated synthesis of PGE2 is responsible for gastric mucosa integrity. Inhibiting PGE2

**Cardiovascular** 

**Clinical use**

cardiovascular events, mild pain, and inflammation

rheumatoid arthritis, fever, dysmenorrhea, mild to moderate pain, headache, migraine,

rheumatoid arthritis, fever, dysmenorrhea, mild to moderate pain,

rheumatoid arthritis, bursitis, tendinitis, mild to moderate pain, or severe pain

to moderate pain, tendonitis, fever, rheumatoid disorders, osteoarthritis, dysmenorrhea, migraine prevention

rheumatoid arthritis

rheumatoid arthritis, acute pain, dysmenorrhea

ankylosing spondylitis,

myalgia

migraine

**risk**

**Gastrointestinal** 

Aspirin Low Moderate Low Prevention of

Ibuprofen Moderate Low Moderate to high Osteoarthritis,

Diclofenac High Moderate High Osteoarthritis,

Indomethacin Low Moderate to high Moderate to high Osteoarthritis,

Naproxen Low Moderate to high Low Gouty arthritis, mild

Meloxicam High Low Moderate to high Osteoarthritis,

Celecoxib High Low Moderate to high Osteoarthritis,

*Only generic names provided. List not all inclusive. Keep in mind NSAIDs carry varying risks of rare liver toxicity* 

*Selectivity is based on in vitro assay studies and should be interpreted with caution as different assay methods give different results. No assay method can predict what will happen when the drug is given to patients. Clinical studies* 

**risk**

#### **Figure 1.**

*Production and actions of prostaglandins and thromboxane (adapted from [8]).*

inhibition of COX-2 and are collectively referred to as coxibs. NSAIDs are otherwise non-selective in their inhibition of COX-1 and COX-2 although with varying affinity (**Table 1**).
