Gastrointestinal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) remains a significant clinical problem. Other adverse effects of NSAIDs, including those associated with the renal and cardiovascular systems impairment, are of growing concern to practitioners.28 The using of NSAIDs often has constraints by the presence of gastrointestinal side effects from mild dyspepsia to the occurrence of severe complications such as bleeding due to perforation of the stomach and duodenum. It is predicted between 10-20% of NSAID users have complaint of dyspepsia. Non-steroidal anti-inflammatory drugs are mostly acidic and inhibit the synthesis of prostaglandins by inhibiting the activities of cycloxygenase enzymes. Various efforts have been attempted to reduce the occurrence of side effects particularly on the gastrointestinal tract. The mode of administration (parenteral, suppositories, topical) and enteric-coated drug use are some effort of them. Through these ways the gastric side effects still occur, although the numbers are reduced. Recently there are 2 types of iso-enzymes cycloxygenase (COX) which have been found, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Cyclo-oxygenase-1 is an enzyme that the body needs to maintain the physiological homeostasis. By inhibiting this enzyme the physiological homeostasis will be disrupted and will result in the side effects of drugs. Cyclooxygenase-2 occur in pathological conditions, such as inflammation. Non-steroidal anti-inflammatory drugs work more selectively suppressing the COX-2 than COX-1 promising less gastrointestinal side effects.29 The differences of both enzyme activities have led to the hypothesis that the roles of these two enzymes are different. Cycloxygenase-1 maintain the physiological functions of various organs such as maintaining the thickness of the gastric mucosa, increases gastric mucus production and improving the renal blood flow. Cycloxygenase-2 has some effects on pathological processes such as inflammation. Experiments on animals and clinical findings strengthen the evidence of the influence of COX-2 in chronic inflammatory disorders and malignancy. The Presence of COX-2 on peripheral nerve endings and on the central nervous system has proven instrumental in helping the transmission of pain. The development of knowledge about the biology of COX-1 and COX-2 has given the impression of simplicity of understanding, where COX-1 is considered as a constitutive enzyme and COX-2 as an inducible enzyme. In fact it is not simple, because in various specific tissues the COX-2 enzyme also plays a role of physiological processes such as in ovulation and implantation.30