sign in sign up
<<
Home , Dexibuprofen, Droxicam, Licofelone, Loxoprofen

REVIEW ARTICLE

&XUUHQW3UHYHQWLRQDQG0DQDJHPHQWRI1RQVWHURLG $QWL,QÀDPPDWRU\'UXJV$VVRFLDWHG*DVWURHQWHURSDWK\

Fransiscus Ari*, Dadang Makmun** *Department of Internal Medicine, Faculty of Medicine, University of Indonesia Dr. Cipto Mangunkusumo General National Hospital, Jakarta **Division of Gastroenterology, Department of Internal Medicine University of Indonesia/Dr. Cipto Mangunkusumo General National Hospital, Jakarta

ABSTRACT 1RQVWHURLGDQWLLQÀDPPDWRU\GUXJV 16$,'V DUHWKHPRVWIUHTXHQWO\XVHGGUXJVWRWUHDWLQÀDPPDWLRQ and are used almost in the whole world. However, NSAID is one of the important causes of gastroenteropathy development. NSAIDs enteropathy is frequently undetected because most of them are asymptomatic and required sophisticated examinations to diagnose. Not only non-selective cyclo-oxygenases (COX) inhibitor that can cause NSAID gastropathy, but selective COX-2 inhibitors may also cause gastrointestinal complications. NSAID gastroenteropathy require further evaluation and it may differ between patients. Currently, there is no effective treatment available to treat gastrointestinal damage associated with NSAIDs DGPLQLVWUDWLRQ,GHQWL¿FDWLRQRISURWHFWLYHIDFWRUVLQJDVWURLQWHVWLQDOFRPSOLFDWLRQGXHWR16$,'VXVHLVVWLOOD serious challenge. In this review, we will discuss the effect of NSAID administration towards gastrointestinal system, also the prevention and management strategies.

Keywords: QRQVWHURLGDQWLLQÀDPPDWRU\GUXJVJDVWURHQWHURSDWK\&2;LQKLELWRUSUHYHQWLRQWUHDWPHQW

ABSTRAK 2EDWDQWLLQÀDPDVLQRQVWHURLG 2$,16 DGDODKREDW\DQJSDOLQJVHULQJGLJXQDNDQXQWXNWHUDSLLQÀDPDVL dan digunakan hampir di seluruh dunia. Namun, OAINS merupakan salah satu penyebab penting terjadinya gastroenteropati. Enteropati OAINS seringkali tidak terdeteksi karena sebagian besar asimtomatik dan membutuhkan pemeriksaan yang canggih untuk mendiagnosisnya. Tidak hanya penghambat cyclo-oxygenases (COX) non-selektif yang menjadi penyebab gastropati OAINS, melainkan inhibitor COX-2 selektif dapat menimbulkan komplikasi gastrointestinal. Gastroenteropati OAINS membutuhkan pengkajian lebih lanjut dan berbeda antar pasien. Sampai saat ini belum ada terapi yang efektif untuk kerusakan gastrointestinal terkait penggunaan OAINS. ,GHQWL¿NDVLGDULIDNWRUIDNWRUSURWHNWLISDGDNRPSOLNDVLJDVWURLQWHVWLQDODNLEDWSHQJJXQDDQ2$,16PDVLK merupakan tantangan yang serius. Dalam makalah ini dibahas mengenai efek penggunaan OAINS terhadap sistem gastrointestinal serta strategi pencegahan dan tatalaksananya.

Kata kunci: REDWDQWLLQÀDPDVLQRQVWHURLGJDVWURHQWHURSDWLSHQJKDPEDW&2;SHQFHJDKDQWDWDODNVDQD

INTRODUCTION therapy is elderly with higher morbidity and mortality 1RQVWHURLGDQWLLQÀDPPDWRU\GUXJV 16$,'V LV towards the occurrence of drug toxicity effect.2 the most frequently prescribed drug group in the world.1 NSAIDs are used widely to treat clinical symptoms The main population target which often receive this LQLQÀDPPDWRU\FRQGLWLRQDQGDOVRWRRYHUFRPHSDLQ

Volume 15, Number 3, December 2014 161 Fransiscus Ari, Dadang Makmun

Additionally, low dose (acetylsalicylate acid or 16$,'6 *$6752(17(523$7+<3+<6,2/2*< ASA) is used for primary and secondary prevention $63(&7 of cerebrovascular and cardiovascular diseases.3 This 1RQVWHURLGDQWLLQÀDPPDWRU\GUXJV 16$,'V FDQ group of drugs inhibit biosynthesis to EHFODVVL¿HGLQWRVHYHUDOJURXSVEDVHGRQWKHFKHPLFDO produce therapeutic effects.4 structure and mechanism of action (Table 1). This Main adverse effects in NSAIDs administration GUXJGHFUHDVHVSDLQDQGLQÀDPPDWLRQWKURXJKWKH include disturbance in the gastrointestinal, nervous blocking of cyclo-oxygenases (COX), required system, kidney, and allergy. NSAIDs toxicity towards for prostaglandin production. Most NSAIDs inhibit gastrointestinal has been widely known, particularly in two cyclo-oxygenases, which are COX-1 and COX- gastroduodenal region.2 Gastrointestinal disturbances 2.3 COX-2 are mostly found in joints and which happen vary from dyspepsia complaints muscles and contribute to the appearance of and to gastroduodenal ulcer and bleeding.1 NSAIDs LQÀDPPDWLRQ16$,'VPD\FDXVHEOHHGLQJGXHWRWKH gastropathy (aspirin) is initially found by Douthwaite effect of these drugs in inhibiting COX-1 enzyme that DQG/LQWRWWLQWKURXJKHQGRVFRS\¿QGLQJV5 A is important in mucosal protection towards gastric acid. meta-analysis study showed, based on endoscopy Morbidity and mortality rate due to gastrointestinal examination, approximately one third patients who complication in the use of NSAIDs increase along with received long term NSAID had gastric or duodenal the increase of age (Table 2).11 Besides age, there are ulcer.6 other several risk factors which have high risk in the Based on data from Arthritis, Rheumatism, and occurrence of gastrointestinal complications, including Aging Medical Information System (ARAMIS), there previous peptic ulcer history, Helicobacter pylori were 1.3% patients who were treated with NSAID (H. pylori)LQIHFWLRQLQWKH¿UVWPRQWKRI16$,'V were hospitalized due to severe gastrointestinal administration, high dose NSAID usage, and other complications in USA and Canada population, with comorbid conditions (particularly cardiovascular), and 1 year mortality rate ranges between 0.11-0.22%.7 the use of anticoagulants and corticosteroid.1 Based on other reports, gastric erosion is found in

50% patients consuming NSAIDs, with 2-4% from Table 2. Risk of gastrointestinal bleeding in 1 year administration WKLVJURXSVXIIHUHGIURPVLJQL¿FDQWJDVWURLQWHVWLQDO of NSAIDs11 ulcer and bleeding.8 Meanwhile, in a patient autopsy Age group Bleeding risk Mortality rate due data based study, patients who use long term NSAIDs (Years old) 5LVNLQ\HDULVLQ to bleeding 16-45 2100 12353 had the incidence of small intestinal ulcer of 8% as 45-64 646 3800 compared to 0.6% in patients who had no history of 65-74 570 3353 >75 110 647 NSAIDs administration.9 Enteropathy due to the use of NSAIDs received less attention because they usually caused no symptoms and are not easy to detect.10

7DEOH16$,'VFODVVL¿FDWLRQ4 Types Chemical components General name of drugs Salicylates Second generation - hydroxybenzoic acid $VSLULQGLÀXQLVDODQGVDOVDODWH () Proprionate acid “profens” derivatives Derivatives of arylacetic acids , , , , , , ÀXUELSURIHQR[DSUR]LQDQGOR[RSURIHQ derivatives Acetic acid derivatives Indomethacin, , , , , , and Derivatives of Enolic acid “” Fourth generation-hydroxy benzothiazine , , , Heterocycle , , and Derivatives of “fenamates” Derivatives of anthranilic acid 0HIHQDPLFDFLGÀXIHQDPLFDFLG , and Phenylpyrazolones First generation-aryl-3,5- , Pyrazolidinedione Selective COX-2 inhibitor Diaryl-5-membered heterocycles , , and Anilides and Sulphoanilides Acetamides from aniline with or without Acetaminophen, , and 4-hydroxy or 4-alkoxy

162 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy Current Prevention and Management of Non Steroid Anti Inflammatory Drugs Associated Gastroenteropathy

NSAIDs, including aspirin, cause damage to the increase leukotriene production. Leukotriene may gastric mucosa through two mechanisms, which are: VWLPXODWHLQÀDPPDWLRQDQGWLVVXHLVFKHPLDZKLFK systemic inhibition of endogenous prostaglandin cause the occurrence of gastric mucosal damage. synthesis in the mucosa and direct irritation or )XUWKHUPRUHRWKHULQÀDPPDWRU\PHGLDWRUVLQFOXGLQJ topical effect to the gastric epithelium. Inhibition of tumour necrosis factors are also increased. endogenous prostaglandin synthesis in the mucosa is Damage to the small intestinal mucosa (enteropathy) caused by inhibition of COX enzyme, which converts even until the bowel (colopathy) have different into prostaglandin.12 This adverse pathophysiology to the damage of gastroduodenal effect occurs due to the non-selective feature of mucosa.14,15 The incidence of enteropathy have NSAIDs and inhibition of COX-1 enzyme, where the more complex pathophysiology and may proceed in DQWLLQÀDPPDWRU\UROHRIWKLVGUXJLVWKURXJK&2; much longer time compared to NSAIDs gastropathy. 2 enzyme inhibition. Currently, the use of selective Decrease of prostaglandin synthesis due to NSAIDs COX-2 (such as celecoxib) has been reported to have use resulted in fragile small intestinal mucosa towards weaker gastrointestinal effect. However, the use of damage and the process of mucosal recovery also selective COX-2 inhibitor also causes gastrointestinal decreases. However, different from what happened in complication. Hypothesis which explain this is that NSAIDs gastropathy, in enteropathy the suppression COX-2 also plays role in defence mechanism and of COX enzymes is not the main reason. Prostaglandin recovery process of damaged mucosa.13 in the intestinal mucosa can be suppressed but the NSAIDs also have direct cytotoxic effect to the ulcer or bleeding does not appear. The increase of gastric mucosa. Several studies showed that this mucosal permeability is caused by topical NSAIDs cytotoxic effect is not associated with inhibition irritation effect. The essential pathophysiology in ulcer activity of COX enzyme. Topical effect found in formation in the intestine is the presence of NSAIDs NSAIDs has acid characteristic (for example, aspirin), reabsorption in ileum and through enterohepatic which cause accumulation of the ionized non-steroidal circulation, again secreted in the duodenum. Bile duct DQWLLQÀDPPDWRU\GUXJV 16$,' DOVRNQRZQDV³LRQ ligation is said to prevent the happening of NSAIDs trapping” phenomenon and decrease hydrophobicity enteropathy by inhibiting enterohepatic circulation. of mucosal gel layer in gastric mucosa. This leads to Damage due to NSAIDs in the intestinal mucosa may increase membrane permeability and result in damage also progress if they are combined with bile acid. of the gastric mucosa. NSAIDs may also induce Oxidative phosphorylation reaction is suspected to be necrosis and apoptosis of the gastric mucosal cells. the main mechanism in the occurrence of epithelial Administration of other preparation of NSAIDs, such layer damage.14 Leukocyte adhesion in the vascular as , parenteral preparation, rectal, and enteric- endothelia has an important role in the occurrence coated may decrease damage to the mucosa due to of NSAIDs gastropathy, is not proved to happen in topical effect. However, this group of drugs can still 16$,'VHQWHURSDWK\$OWKRXJKQHXWURSKLOLQ¿OWUDWLRQ cause gastrointestinal complication through inhibition may play role in the tissue damage if ulceration has effect of endogenous protective prostaglandin.4 occurred. There was evidence of tumour necrosis In addition to these two mechanisms, the use factor-alpha 71)Į LQYROYHPHQWLQ16$,'V of NSAID is also followed by leukocyte adhesion enteropathy, but not directly associated with leukocyte (particularly neutrophil) to the vascular endothelium in adhesion in vascular endothels.14 gastrointestinal microcirculation. This play important role in the development of gastric ulcer.13 Mechanism of Clinical Manifestation and Diagnostic Aspect of NSAIDs Gastroenteropathy gastropathy development due to neutrophil adhesion is DUHVXOWRIPHFKDQLFDOREVWUXFWLRQRIWKHFDSLOODU\ÀRZ Clinical manifestation of NSAIDs gastropathy and the formation of protease and free radicals during varies on the severity degree from the occurring neutrophil activation.3 Free radicals which formed will erosion or ulcer. Upper digestive tract bleeding, react with polyunsaturated fatty acids in the mucosa perforation, and obstruction are the most serious and cause lipid peroxidation and tissue damage. and life-threatening clinical symptoms. Depending Other resources add one more mechanism, which is on the bleeding site, it may be in the form of occult WKURXJKWKHSURGXFWLRQRIDGGLWLRQDOSURLQÀDPPDWRU\ bleeding, melena, or hematemesis. Clinical symptoms mediators. The inhibition of prostaglandin production of NSAIDs gastropathy can be seen in Table 3.3 by NSAIDs activates pathway and

Volume 15, Number 3, December 2014 163 Fransiscus Ari, Dadang Makmun

Table 3. Clinical manifestations of NSAIDs gastropathy3 Increase of small intestinal permeability can also be Epigastric pain, or may be accompanied detected in NSAID enteropathy. The frequently used General complaints by severe upper gastrointestinal complications. marker is saccharide (lactulose, manitol), poly ethylene Signs Loss of body weight with nausea, vomitus, glycol, and radionuclide (51Cr-EDTA) which level is and anorexia. Complications may be in the form of detected later in the urine after oral administration. bleeding, perforation, or obstruction 7KLVH[DPLQDWLRQLVQRWVSHFL¿FZLWKVHQVLWLYLW\RI Symptoms Abdominal pain Nocturnal pain (midnight up to 3 am) which 60-80%, but has low specificity value. Intestinal awakened patient from sleep. LQÀDPPDWLRQFDQEHGHWHFWHGLQSDWLHQWVDQG Heartburn, burping, and bloating that may persist up to 16 weeks after NSAIDs cessation. accompanied abdominal pain. Nausea, vomitus, and anorexia (often This can be detected through the increase of Indium111 associated with gastric ulcer) level in faeces or small intestine after intravenous Symptoms may present seasonal, worsened in spring or autumn. administration. Other examination that could be used Appear in episodes in several weeks is calprotectin examination (protein produced by and may experience remission in several weeks or months, even years neutrophils, monocytes, and macrophages) in faeces, which showed the presence of migration of these cells into the intestine. This examination also has low Clinical manifestations of NSAIDs are more vary, VSHFL¿FLW\YDOXH2 XQVSHFL¿FDQGXVXDOO\DV\PSWRPDWLFDOWKRXJKVHULRXV Invasive procedures are needed to confirm clinical symptoms, including bleeding, ileus, and diagnosis. In NSAIDs gastropathy, fiber optic perforation may also happen and be life-threatening. endoscopy examination to the upper digestive tract The most frequent clinical symptoms are occult and radiography examination using barium can be gastrointestinal bleeding. Bleeding is associated with performed.3 Through endoscopy, lesion can be observed LQÀDPPDWLRQSURFHVVDQGUDQJHVIRUP/SHU directly, and biopsy can be conducted as an additional day.12 Obvious and acute bleeding rarely happen. This examination. While enteroscopy examination can be may occur in erosion and ulceration. In patients with used to detect lesion with direct visualization of the NSAIDs enteropathy, there were only 5-10% patients small intestine and performing biopsy. The presenting with obvious gastrointestinal bleeding complaint.16 appearance may vary, ranging from mucosal oedema, Other clinical manifestation which may be present erosion, bleeding, up to the presence of small intestinal LVSURWHLQORVVIURPLQWHVWLQDOPXFRVDLQÀDPPDWLRQ stricture. Lesion is usually located in the distal ileum process. Usually mild and may happen up to 16 months and caecum, caused by enterohepatic circulation and after the cessation of NSAIDs. Jejunum dysfunction H[FUHWHGVORZO\7KHVSHFL¿FDSSHDUDQFHLVVPDOO in NSAIDs enteropathy may reveal cause diarrhoea intestinal diaphragms, which is clinically marked by symptoms, which resembles absorption disturbance intestinal obstruction. Small-intestinal diaphragms are in celiac disease. Disturbance in vitamin B12 and bile in the shape of multiple thin rings accompanied with acid absorption may happen in ileum dysfunction.2 PXFRVDODQGVXEPXFRVDO¿EURVLV&DSVXOHHQGRVFRS\ Intestinal perforation has been reported to occur in long examinations can also be used as a non-invasive term use of NSAIDs (indomethacin), in patients with procedure in NSAID enteropathy.2,18 .17 Small intestinal stricture also 0DLGHQHWDOFODVVL¿HGFDSVXOHHQGRVFRS\¿QGLQJV become a pathognomonic sign in NSAIDs enteropathy. into 5 groups, including reddened folds, denuded The signature appearance of stricture is circumferential area, red spots, mucosal breaks, and bleeding. While, VKDSH¿EURXVPXOWLSOH FDQUHDFKGR]HQV WKLQ  Graham categorized it into red spots, small erosions, mm) and may cause severe intestinal obstruction.2 large erosions, and ulcers. Compared to capsule In patients with gastroenteropathy who experienced endoscopy, enteroscopy has superiority, which is bleeding, there was also the presence of decreased therapy can be applied directly after the findings haemoglobin and haematocrit level, also the presence of bleeding lesion and its ability in performing of faecal occult blood. Hypoalbuminemia can also be histopathology examination, although this procedure found in 5-10% patients. Anaemia is found in 1-5% is invasive and require long time.2,20 patients who received NSAIDs. Anaemia may happen as a result of chronic gastrointestinal bleeding, Fe and YLWDPLQ%GH¿FLHQF\PDOQXWULWLRQRUDSSHDUDQFHRI anaemia in chronic disease.3

164 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy Current Prevention and Management of Non Steroid Anti Inflammatory Drugs Associated Gastroenteropathy

35(9(17,9($1' 0$1$*(0(17 675$7(*,(6 absorption. H2 antagonist and proton ,116$,'*$6752(17(523$7+< pump inhibitors (PPIs) may protect gastric mucosa not only through inhibiting gastric acid secretion, Based on literature review, there are several but also through antioxidant characteristic and preventive and management strategies in patients decrease free radicals.1 Before PPIs are available, with NSAIDs gastroenteropathy. The most general H2 receptor antagonist is a standard therapy for strategy being used is combining NSAIDs with NSAIDs associated peptic ulcer. Although proven gastroprotective drugs, use of COX-2 selective, and to be effective in treating ulceration in the stomach, H. pylori eradication. However, there are several other WKLVGUXJGRHVQRWKDYHVLJQL¿FDQWHIIHFWLQJDVWULF therapy options that have been developed and some of bleeding, therefore currently doubling the dose them are still need further study.1,4 (famotidine 40 mg twice per day) can decrease the incidence in six months after gastric ulcer Combination of NSAIDs with Gastroprotective has developed.1 While the formation of duodenal Drugs ulcer can be prevented and upper gastrointestinal ‡ Prostaglandin analog symptoms can ameliorate in administration of H2 Prostaglandin analog is given together in receptor antagonist. 1 combination with NSAIDs to substitute the The use of PPIs habeen proven to be effective prostaglandin which synthesis is inhibited compared to H2 receptor antagonist and currently by NSAIDs. The type of preparation being has become the standard therapy for peptic ulcer used is . 1,4 In a meta-analysis, DQGJDVWURRHVRSKDJHDOUHÀX[GLVHDVH *(5'  misoprostol had been proven to decrease the Omeprazole 20 mg once per day has been proven incidence of gastrointestinal ulcer due to NSAIDs to be significantly more effective compared to administration.210LVRSURVWROZDVVLJQL¿FDQWO\ ranitidine 150 mg twice per day or misoprostol 200 proven to decrease the incidence of gastric ulcer mg twice per day. In several studies, omeprazole in acute or chronic administration of NSAIDs, had been proven to be more effective in decreasing while for duodenal ulcer only in long term use of dyspepsia symptoms due to NSAIDs and could be NSAIDs.1 In MUCOSA study, administration of well tolerated in comparison to misoprostol. In a misoprostol 200 mg four times per day showed study, administration of lansoprazole was proven decreased NSAIDs complication as much as 40%.1 to be effective and superior compared to placebo, ‡ Sucralfate/antacid but not with misoprostol in preventing NSAIDs In addition to its effect in decreasing exposure of associated gastric ulcer. At the end of week 12 in the damaged mucosa towards gastric acid by forming study, absence of ulcer were found in 51% patients protective gel (sucralfate) or neutralize gastric acid from placebo group, 92% from misoprostol group, (antacids), both of these drugs were thought to and 82% from lansoprazole group.1 Administration induce several other gastroprotective mechanisms. of Esomeprazole, isomer-S of omeprazole, exhibited Only few data showed sucralfate administration higher bioavailability and better effectivity in could prevent damage of the gastric mucosa in suppressing acid secretion compared to other PPIs.20 long-term use of NSAIDs. Although in a small In a study, it was proven that combination of PPIs study, sucralfate could be used in preventing and NSAIDs had similar effectivity in decreasing short-term gastrointestinal complications due to NSAID gastropathy compared to the use of COX-2 the use of NSAIDs, a clinical trial by Agrawal selective inhibitor. 21 failed to prove the benefit in administering Long-term use of PPIs is reported to be safe, sucralfate to prevent gastric ulcer compared to EHFDXVH33,VDFWLRQLVYHU\VSHFL¿FDQGKDVUDUH misoprostol. Uses of antacids were also quite adverse effects. Before administering PPIs in long disappointing. From several studies, antacids did term, H.pylori eradication needs to be conducted if not exhibit clinical effects particularly in long-term it was suspected or there was evidence of infection administration of NSAIDs.1 by this bacterium. The weakness of PPIs, this drug ‡ Gastric Acid Secretion Inhibitor cannot protect mucosal damage due to NSAIDs in Acid may worsen the mucosal damage caused the distal part of intestine (for example, colon).1,4 by NSAIDs use, increase proteolitic enzyme (pepsin) activity, and increase acidic NSAIDs

Volume 15, Number 3, December 2014 165 Fransiscus Ari, Dadang Makmun

‡ Administration of COX-2 selective Inhibitor recommendation is different from patients who COX-2 selective inhibitor, in line with its name, will use low dose aspirin, because it will increase is a group of drugs, which selectively inhibit the cost considering the number of patients using COX-2 enzyme, thus have anti-inflammatory aspirin as prophylaxis of cardiovascular disease, effect, but still maintain gastroprotective effects but in patients with peptic ulcer history, this through COX-1 pathway. Celecoxib and rofecoxib examination is still recommended. 1 are drugs from this group which are proven to be effective and are more superior compared to 1(:7+(5$3< non-selective COX inhibitor to gastrointestinal complications.4 In a study, celecoxib in comparison ‡ NSAIDs to combination of diclofenac and omeprazole had NSAIDs Prodrug is potential in increasing relatively similar ulcer bleeding incidence (4.9% antioxidant effect, water solubility, and produce 1 vs. 6.4%). nitric oxide (NO) and hydrogen sulphide (H2S). Although COX-2 selective inhibitor decreased the NO has gastroprotective characteristic through the toxicity effect towards gastrointestinal, there was increase of blood circulation, mucous production, increase cardiovascular risk due to myocardial and bicarbonate secretion in gastric mucosa. NO infarct and thrombosis. COX-2 selective inhibitor may also decrease neutrophil adhesion in blood inhibits blood vessels’ production. vessels’ endothelia. Therefore, currently new Prostacyclin has vasodilation effect and inhibit therapy nitric oxide releasing NSAIDs (NO- platelet aggregation. Long term study of celcoxib NSAIDs), is being developed. Administration of (CLASS) and cardiovascular effect in rofecoxib NO-NSAIDs does not interfere gastroduodenal (VIGOR) cause the use of these drugs to be mucosa. NO naproxen is reported to have higher controversial.4 Second generation from “coxibs” DQWLLQÀDPPDWRU\DQGDQDOJHVLFHIIHFW12DVSLULQ such as valdecoxib, , lumaricoxib, and is also reported to have better anti-thrombotic , have higher selectivity towards COX- effect compared to conventional aspirin. Hydrogen

2. Based on a study report, it was proven that Sulphide Releasing NSAID (H2S NSAID) also has this drug group had higher effectivity in treating gastroprotective effect and may improve ulceration LQÀDPPDWLRQDQGSDLQEXWLWVDVVRFLDWLRQZLWK that has happened. Derivatives of naproxen, 1 1 adverse effects of NSAIDs was still unclear. diclofenac, and indomethacin can produce H2S. ‡ Helicobacter pylori Eradication NSAIDs effect in distal intestinal mucosa, as Relationship between NSAIDs and Helicobacter KDVEHHQGHVFULEHGSUHYLRXVO\LVLQÀXHQFHGE\ Pylori (H. pylori) is still debatable. A meta-analysis enterohepatic cycle. Combination of this drug with revealed the presence of synergic role between bile may result in NSAIDs enteropathy. Addition of NSAIDs administration and H. pylori infection in phosphatidylcholine (PC) in NSAID (PC-NSAID) the incidence of peptic ulcer. Peptic ulcer is more has been reported to decrease the cytotoxic effect common to occur in NSAIDs user with positive of NSAIDs.10 H. pylori positive (41.7%) compared to those who  6HYHUDOVWXGLHVKDYHEHHQFRQGXFWHGWR¿QGQHZ were negative (25.9%).1 Konturek et al reported NSAID, which has gastrointestinal protection that H. pylori might disrupt gastric adaptation to without cardiovascular adverse effect. Prodrug aspirin, but H. pylori eradication alone did not diclofenac, 1-(2,6-dichlorophenyl) indolin-2-1, decrease ulcer risk or dyspepsia symptoms in long has been reported to decrease PGE2, COX-2 term use of NSAIDs and not effective in preventing expression, and ulceration. Ibuprofen isomer R(-) upper gastrointestinal tract bleeding. Effects of is better in preventing gastrointestinal complication H. pylori in patients who do not use NSAIDs are compared to isomer S(+) due to shorter half-life in VLJQL¿FDQWO\GLIIHUHQWFRPSDUHGWRWKRVHZKRXVH the plasma.1 NSAIDs. Therefore, it is advised that H. pylori ‡ Dual COX/5-LOX inhibitors examination is performed in all patients who are Besides prostaglandin, leukotriene is also planned to receive long term NSAIDs. 4 Based on metabolized through the arachidonic avid pathway a study by Hawkey and Langman suggested H. by lipoxygenase (5-LOX) enzyme. Leukotriene pylori eradication was required before starting is an important inflammatory mediator other therapy with selective COX-2 inhibitor. This than prostaglandin. Based on experimental study,

166 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy Current Prevention and Management of Non Steroid Anti Inflammatory Drugs Associated Gastroenteropathy

cystenil leukotriene contributed in the damage of but also in inhibition of oxidative phosphorylation gastric mucosa through microvascular disturbance in mitochondria of intestinal cells.26 and decrease mucosal defence. Inhibition of COX ‡ Sulfasalazine enzyme increases leukotriene synthesis. Therefore,  6XOIDVDOD]LQHLVDQDQWLLQÀDPPDWRU\GUXJVXVXDOO\ the use of COX/5-LOX inhibitors () is used in treating inflammatory bowel disease, GHYHORSHGWRLQFUHDVHDQWLLQÀDPPDWRU\HIIHFWDQG including ulcerative colitis and Crohn’s disease. decrease the adverse effects to the gastric mucosa. 7KLVWKHUDS\LVSURYHQWRGHFUHDVHLQÀDPPDWLRQ In an endoscopy study, it was reported that there and NSAIDs bleeding. Although the role in was normal results after four weeks administration NSAIDs enteropathy is still unclear, sulfasalazine of licofelone 200 mg twice daily as much as 93%, may improve ileitis in long-term use of NSAIDs.1 licofelone 400 mg as much as 89%, and naproxen In the latest clinical study, , an active 500 mg twice daily as much as 37%.22 In a double form of sulfasalazine, has been proven to improve blind clinical study, gastroduodenal ulcer appear mucosal damage due to long term use of NSAIDs in 1.5% patients who consume licofelone 200 (naproxen). In this study 18 patients consuming mg twice daily compared with 15,3% patients naproxen in the long term underwent capsule with naproxen 500 mg twice daily, while both endoscopy examination before and after four have equal effect.23 In controlling pain weeks of mesalazine administration, and proved licofelone 200 mg twice daily also has the equal that mesalazine might improve moderate to severe effect to celecoxib 200 mg once daily. Different intestinal mucosal damage..27 from selective COX-2 inhibitor, licofelone showed ‡ Rebamipide gastroprotective effect when in concurrent use with Rebamipide increases mucous production low dose aspirin.27 Other advantages of licofelone and synthesis of prostaglandin, which has use compared to selective COX-2 is the anti- gastroprotective characteristic. This drug also thrombotic effect and inhibition of thrombocyte KDVDQWLLQÀDPPDWRU\HIIHFWDQGKDVDQWLR[LGDQW aggregation.25 characteristic towards free radicals in the gastrointestinal. In a study, it was reported that rebamipide might decrease small intestinal damage 27+(5&+2,&(62)7+(5$3< caused by administration of diclofenac compared ‡ Lactoferrin to placebo.28 Rebamipide does not only improve A case report showed the ability of bovine colostrum mucosal damage in NSAIDs enteropathy, but to prevent gastric ulceration due to NSAIDs. Other also improve nutritional status.29 In a systematic study stated the role of human’s recombinant review and meta-analysis, rebamipide proved to lactoferrin in decreasing gastrointestinal bleeding be effective and safe in preventing damage in the due to NSAIDs and gastric ulcer. Lactoferrin gastroduodenal and low gastrointestinal due to (C-lobe) decreases the incidence of gastrointestinal NSAIDs.30 LQÀDPPDWLRQDQGEOHHGLQJLQWKHDGPLQLVWUDWLRQRI ‡ Probiotics NSAIDs and selective COX-2 inhibitors. This is Several studies have been performed to evaluate the because this molecule can bind to other free drug effect of probiotic in NSAID gastroenteropathy. In molecules.1 a study, Lactobacillus casei, could decrease small ‡ Metronidazole intestinal damage in the use of low dose aspirin in Metronidazole is an antibiotic used to treat long term.31 In a clinical study, it was also reported anaerobic microbial infection. Administration that probiotic use could decrease faecal calprotein of metronidazole 800 mg/day may decrease level (used as a marker of intestinal damage) in and intestinal bleeding due to patients using indomethacin.32 However, clinical 16$,'VKRZHYHUWKHUHLVQRLQÀXHQFHWRZDUGV evidences regarding the role of probiotic in intestinal permeability. Sensitive microbes gastrointestinal protection are still weak. towards metronidazole have chemoattractant ‡ Nutritional intervention effect to neutrophil in NSAIDs enteropathy. Other Several ‘pharmaconutrients’ can be used as a antibiotics have not been proven to decrease prophylaxis. The use of these pharmaconutrients NSAIDs enteropathy. This is caused by the role has several benefits because they have lower of metronidazole is not only in intestinal bacteria, risk compared to that have many

Volume 15, Number 3, December 2014 167 Fransiscus Ari, Dadang Makmun

adverse effects. Lactoferrin recombinant has TP. Current Perspectives in NSAID-Induced Gastropathy. been available in the form of oral supplement 0HGLDWRUV,QÀDPP 5. Douthwaite AH, Lintott GAM. Gastroscopic observation of and as have been described before, have anti- effect of aspirin and certain other substances on stomach. inflammatory, antioxidant, and bactericidal Lancet 1938;2:1222–25. effects. Fish protein, hydrolysate, is a fermentation 6. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori IURP¿VKSURGXFWVDOVRJRRGIRULQWHVWLQDOE\ LQIHFWLRQDQGQRQVWHURLGDODQWLLQÀDPPDWRU\GUXJVLQSHSWLF improving disturbance of intestinal permeability ulcer disease: a meta-analysis. Lancet 2002;359:14–22. 7. Singh G, Rosen Ramey D. NSAID induced gastrointestinal due to NSAIDs. Glutamine, non-essential amino complications: the ARAMIS perspective—1997. Arthritis, acids, is reported to be effective in preventing Rheumatism, and Aging Medical Information System. J the increase of intestinal mucosa permeability in Rheumatol Suppl 1998;51:8–16. the short-term use of NSAIDs. Bovine colostrum 8. Wallace JL, Vong L. NSAID-induced gastrointestinal damage and the design of GI-sparing NSAIDs. Current Opinion in contains growth factors (such as insulin like Investigational Drugs 2008;9:1151-56. growth factor), immunoglobulin, and antimicrobial 9. Allison MC, Howatson AG, Torrance CJ. Gastrointestinal peptides. The use of bovine colostrum together GDPDJHDVVRFLDWHGZLWKWKHXVHRIQRQWHURLGDODQWLLQÀDPPDWRU\ with glutamine is effective in decreasing intestinal drugs. N Engl J Med 1992;327:751–4. damage and bacterial translocation in the short- 10. Lim YJ, Chun HJ. Recent advances in NSAIDs-induced enteropathy therapeutics: new options, new challenges. 11 term use of NSAIDs. In an animal study using Gastroenterol Res Pract 2013;2013:761060. mouse reported the administration of grape seed 11. Peterson K, McDonagh M, Thakurta S, Dana T, Roberts C, proanthocyanidin extracts (GSPEs) in the damage &KRX5HWDO'UXJFODVVUHYLHZQRQVWHURLGDODQWLLQÀDPPDWRU\ of gastric mucosa due to NSAIDs. High dose drugs (NSAIDs). Update 4 final report. [cited 2013 Jan 7]. Available from: URL: KWWSGHUSRKVXHGXDERXW¿QDO GSPEs had been proven to have gastroprotective document-display.cfm effects to mucosal damage, which is suspected 12. Berardi RR, Fugit RV. Peptic ulcer disease. In: DiPiro JT, through antioxidant effect which it possess.33 Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York: The McGraw-Hill Companies 2011. CONCLUSION 13. Wallace JL, Vong L. NSAID-induced gastrointestinal damage Review regarding gastrointestinal and cardiovascular and the design of GI-sparing NSAIDs. Curr Opin Investig Drugs 2008;9:1151-6. risk becomes an important factor in determining 14. Wallace JL. NSAID gastropathy and enteropathy: distinct therapy. In patients who have to use long term NSAIDs, pathogenesis likely necessitates distinct prevention strategies. suitable regiment and prophylaxis strategies may be British Journal of Pharmacology 2012;165:67–74. used to prevent gastrointestinal complication. Several 15. .OHLQ0/LQQHPDQQ'5RVHQEHUJ-1RQVWHURLGDODQWLLQÀ new therapies have been developed, including the ammatory drug–induced colopathy. BMJ Case Reports 2011; 10: 3436. XVHRIORZWR[LFLW\DQWLLQÀDPPDWRU\GUXJVVXFKDV 16. Wallace JL, Denou E, Vong L, Syer S, McKnight W, Jury J,

NO- and H2S- NSAIDs, and dual inhibitor COX/5- et al. Proton pump inhibitors and low-dose aspirin markedly /2;VKRZHGTXLWHVLJQL¿FDQWGHFUHDVHRIWR[LFLW\ exacerbate NSAID-induced small intestinal injury: link to Selective COX-2 inhibitors, prostaglandin derivatives, dysbiosis? Gastroenterology 2011;140:S-87. 17. Sidhu R, Sanders DS, McAlindon ME, et al. Capsule endoscopy PC-NSAIDs, and probiotics revealed protective IRUWKHHYDOXDWLRQRIQRQVWHURLGDODQWLLQÀDPPDWRU\GUXJ effect to any damage of the intestinal mucosa due to induced enteropathy: United Kingdom pilot data. Gastrointest NSAIDs. The use of other therapy in the preventive and Endosc 2006;64:1035. management strategies of NSAIDs gastroenteropathy 18. Park SC, Chun HJ, Kang CD, Sul D. Prevention and management of non-steroidal anti-inflammatory drugs- still requires further research. induced small intestinal injury. World J Gastroenterol 2011;17:4647-53. REFERENCES 19. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal WR[LFLW\RIQRQVWHURLGDODQWLLQÀDPPDWRU\GUXJV7KH1HZ 1. Becker JC, Domschke W, Pohle T. Current approaches to England Journal of Medicine 1999;341:1888–99. prevent NSAID-induced gastropathy – COX selectivity and 20. Yeomans ND, Hawkey CJ, Jones R. Esomeprazole provides beyond. Br J Clin Pharmacol 2004;58:587-600. effective control of NSAID-associated upper GI symptoms 2. 7DFKHFt,.RSiþRYi05HMFKUW6%XUHã-1RQVWHURLGDO in patients continuing to take NSAIDs. Gastroenterology DQWLLQÀDPPDWRU\GUXJLQGXFHGLQMXU\WRWKHVPDOOLQWHVWLQH 2003;124: A107. Acta Medica (Hradec Králové) 2010;53:3–11. 21. Ray WA, Chung CP, Stein CM, Smalley WE, Hall K, Arbogast 3. Schellack N. An overview of gastropathy induced by PG, et al. Risk of peptic ulcer hospitalizations in users of nonsteroidal anti inflammatory drugs. S Afr Pharm J NSAIDs with gastroprotective cotherapy versus coxibs. 2012;79:12-18. Gastroenterology 2007;133:790–8. 4. Sinha M, Gautam L, Shukla PM, Kaur P, Sharma S, Singh

168 The Indonesian Journal of Gastroenterology, Hepatology and Digestive Endoscopy Current Prevention and Management of Non Steroid Anti Inflammatory Drugs Associated Gastroenteropathy

22. Palmer R, Bias P, Buchner A, Elsässer R. Licofelone (ML3000). An inhibitor of COX-1, COX-2 and 5-LOX, is associated with less gastric damage than naproxen and is similar to placebo in man. Gastroenterology 2002;122:A54. 23. Reginster JY, Bias P, Buchner A. First clinical results of licofelone (ML3000), an inhibitor of COX-1, COX-2 and 5-LOX, for the treatment of . Ann Rheum Dis 2002; 61:116. 24. Buchner A, Bias P, Lammerich A. Twice the therapeutic dose of licofelone – an inhibitor of COX-1, COX-2 and 5-LOX – UHVXOWVLQDVLJQL¿FDQWO\ORZHUJDVWURLQWHVWLQDOXOFHULQFLGHQFH than naproxen in osteoarthritis patients, when administered with or without concomitant low-dose aspirin [EULAR 2003; abstract FRI0214]. Ann Rheum Dis 2003;62. 25. Tries S, Laufer S, Radziwon P, Breddin HK. Antithrombotic and platelet function inhibiting effects of ML3000, a new DQWLLQÀDPPDWRU\GUXJZLWK&R[/2;LQKLELWRU\DFWLYLW\ ,QÀDPP5HV± 26. )RUWXQ3-+DZNH\&-1RQVWHURLGDODQWLLQÀDPPDWRU\GUXJV and the small intestine. Curr Opin Gastroenterol 2007;23:134- 141. 27. 5iF],6]DODL0.RYiFV95HJĘF]L+.LVV*+RUYiWK= Mucosal healing effect of mesalazine granules in naproxen- induced small bowel enteropathy. World J Gastroenterol 2013;19:889-896. 28. Niwa Y, Nakamura M, Ohmiya N, Maeda O, Ando T, Itoh A, HWDO(I¿FDF\RIUHEDPLSLGHIRUGLFORIHQDFLQGXFHGVPDOO intestinal mucosal injuries in healthy subjects: a prospective, randomized, double-blinded, placebo-controlled, cross-over study. J Gastroenterol 2008;43:270-276. 29. Kurokawa S, Katsuki S, Fujita T, Saitoh Y, Ohta H, Nishikawa K, et al. A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with ORZGRVHDVSLULQDQGRUQRQVWHURLGDODQWLLQÀDPPDWRU\GUXJ induced small bowel injury. J Gastroenterol 2014;49:239-44. 30. Zhang S, Qing Q, Bai Y, Mao H, Zhu W, Chen Q, et al. Rebamipide helps defend against nonsteroidal anti- LQÀDPPDWRU\GUXJVLQGXFHGJDVWURHQWHURSDWK\DV\VWHPDWLF review and meta-analysis. Dig Dis Sci 2013;58:1991-2000. 31. +(QGR7+LJXUDVKL.+RVRQR(I¿FDF\RI/DFWREDFLOOXV casei treatment on small bowel injury in chronic low- dose aspirin users: a pilot randomized controlled study. J Gastroenterol 2011;46:894–905. 32. Montalto M, Gallo A, Curigliano V, D’Onofrio F, Santoro L, Covino M, et al. Clinical trial: the effects of a probiotic PL[WXUHRQQRQVWHURLGDODQWLLQÀDPPDWRU\GUXJHQWHURSDWK\ – a randomized, doubleblind, cross-over, placebo-controlled study. Aliment Pharmacol Ther 2010;32:209–14. 33. Kim TH, Jeon EJ, Cheung DY, Kim CW, Kim SS, Park SH, et al. Gastroprotective effects of grape seed proanthocyanidin H[WUDFWVDJDLQVWQRQVWHURLGDQWLLQÀDPPDWRU\GUXJLQGXFHG gastric injury in rats. Gut and Liver 2013;7:282-9.

Correspondence: Dadang Makmun Division of Gastroenterology Department of Internal Medicine Dr. Cipto Mangunkusumo General National Hospital Jl. Diponegoro No.71 Jakarta Indonesia Phone: +62-21-3153957 Facsimile: +62-21-3142454 E-mail: [email protected]

Volume 15, Number 3, December 2014 169