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Original Research (Original Article) 


Yaman Mazen Almerstani et al, 2019;3(7):597–600.

International Journal of Medicine in Developing Countries

NSAID associated with an increased risk of peptic ulcer among patient with arthritis

Yaman Mazen Almerstani1, Abdulkader Aljuhani1, Sara Abdullah Alsaad1*, Bashaer Mahboub Alalwani1, Ahmed Mohammad Alsahlawi1, Turky Mehssen Alyamy1, Razan Mohammad Aljohani1, Ameera Mishal Alosaimi1

Correspondence to: Sara Abdullah Alsaad

*Ibn Sina National College, Jeddah, Saudi Arabia.

Email: sosonx [at] hotmail.com

Full list of author information is available at the end of the article.

Received: 23 January 2019 | Accepted: 04 February 2019


ABSTRACT

Background:

Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents used as an analgesic and antipyretic in the management of inflammatory conditions and pain control in rheumatoid arthritis (RA). NSAIDs have been considered as one of the main causative factors for peptic ulcer and have been found to increase the risk of upper gastrointestinal tract perforation/bleeding by 2- to 4-folds. The current study was performed to investigate the associated risk between NSAIDs and the risk of peptic ulcer disease among patients with arthritis in Saudi Arabia.


Methodology:

A cross-sectional study was conducted during the period from February to July 2018 in four rheumatology clinics in four selected tertiary and specialized hospitals in Saudi Arabia.


Results:

Among the total 169 RA patients included in the study, 121 of them (82.31%) successfully completed the study, of which 96 (79.3%) patients were included in the final analysis as per the eligibility criteria. Peptic ulcer associated symptoms with NSAID use were assessed. Most of the responders reported epigastric pain or burning pain in the stomach (67.7%) and esophageal pain or heartburn (62.5%). Responders reported the development of increased pain after eating (51%), which was relieved after taking an antacid in 66.6% of the subjects. Hematochezia or blood in stool (12.5%) and hematemesis or vomiting of blood (4.1%) were the least of the reported manifestations.


Conclusion:

This study found that patients with RA taking NSAIDs were at high risk of developing peptic ulcer disease with persistence of gastrointestinal symptoms. Use of NSAIDs even for less than 6 months was associated with gastrointestinal effects.


Keywords:

NSAID, peptic ulcer, arthritis.


Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents as an analgesic, antipyretic, in the management of inflammatory conditions, and pain control in rheumatoid arthritis (RA). However, there is overwhelming evidence to connecting these agents to many gastrointestinal tract complications [1]. NSAIDs have been considered as one of the main causes of peptic ulcer and shown to increase the risk of upper gastrointestinal tract perforation/bleeding by 2- to 4-folds [24]. The serious upper gastrointestinal tract complications related to NSAIDs use constitute a major public health concern because of widespread use of NSAIDs worldwide [14]. It has been estimated that 16,500 patients with arthritis have died every year from the gastrointestinal (GI) toxicity of NSAIDs [5]. Patients with arthritis generally require more NSAIDs; therefore, they are particularly at higher risk of NSAID’s complications and side effects [6]. There are several studies conducted to find co-therapies that can be used to reduce the risk of ulcer and its complications [7,8]. Current evidence indicates that the risk of ulcers can be reduced by proton-pump inhibitors or misoprostol [9]. Proton-pump inhibitors are well tolerated in patients at higher risk of ulcers and associated with acceleration of ulcer healing, so it has been recommended to be used as prophylaxis [7,8]. Many prophylactic strategies have been investigated to reduce the toxicity among long-term users of NSAIDs. As an alternative to reduce the toxicity in a patient with arthritis is to replace conventional NSAIDs with COX-2 selective NSAIDs. There is good evidence that supports the effect of COX-2 selective NSAIDs as anti-inflammatory agents among long-term users of NSAIDs [1012].


Subjects and Methods

This was a cross-sectional study conducted during the period from February to July 2018, in four rheumatology clinics in four selected tertiary and specialized hospitals in Saudi Arabia, to determine the NSAID associated risk of peptic ulcer among patient with arthritis.

We began by purposively selecting four hospitals to approximate a representative sample for this study. It includes King Faisal Hospital in Taif, King Fahad University Hospital in Khobar, King Saud Medical City in Riyadh, and Alamosa Hospital in Alhsa’a. In the next stage of sampling, selection of respondents was based on eligibility criteria. Eligible respondents were those who have been diagnosed with RA, aged 18 years old and above, and taking NSAIDs for 6 months or less. However, those who are in long-term use of NSAIDs (i.e., more than 6 months), under the treatment of Helicobacter pylori, underwent any gastric or bariatric surgery, with a prior diagnosis of peptic ulcer disease, concomitant drug use to treat arthritic pain, and those taking COX-2 selective NSAIDs were excluded.

With the assumption that the risk level of peptic ulcer among arthritis patient is 25%, study power is 80%, and the degree of precision is +5% at a 95% level of significance. The sample size was determined to be at least 169 attendants [13].

A self-administered questionnaire prepared by the authors was employed. The content was validated by experts in the field and evaluated for construct and face validity. The questionnaire consisted of three parts. The first part dealt with the demographical data of the respondents, which included questions regarding their age, gender, and weight. The respondents were also asked about the name of NSAIDs used to relieve the arthritic pain and the duration of use. The second part consisted of nine questions about the NSAIDS associated peptic ulcer symptoms present among the respondents. The third part consisted of four questions to assess the awareness of the patients about the common side effects of NSAIDs use. Ethical approval from the Institutional Review Board/Ethics Committee of Ibn Sina National College—Research Center, Jeddah has been obtained. Informed written consent of all participants was obtained. Confidentiality of data was assured and that data used only for the stated purpose of the survey.

The collected data were entered into a computer using the Statistical Package for Social Sciences (SPSS version 20). Descriptive statistics for the respondents’ demographic profile and NSAID associated peptic ulcer symptoms were calculated and presented by frequencies, percentages, means and standard deviations. Binary logistic regression was used to analyze the relationship between independent variables (i.e., demographic profile) and a dependent variable (i.e., abdominal pain) and yields a predictive equation. A two-sided p-value of <0.05 was used as a level of significance.


Result

Out of 169 RA patients who were asked to participate, 121 (82.31%) participated in the study. However, based on the eligibility criteria, 96 (79.3%) patients were included in the final analysis.

Females represented 54.2% (52 patients) of the study population, while males represented 45.8% (44 patients). The majority were at the age range of 46–55 years (33.3%), while those at the age below 25 years represent 6.3 % of the sample. Patients mean weight was 95 kg (ranges from 47 to 140 kg). Forty-six (47.9%) were taking NSAIDs under propionic acid groups, followed by 34 (35.4%) for those who were taking NSAID under phenylacetic acid group. Forty-two (43.7%) were on NSAID for 3–4 months, 36 (37.5%) for 5–6 months, and 18 (18.75%) for 1–2 months.

Peptic ulcer associated symptoms with NSAID use were assessed; most of the respondents reported epigastric pain or burning pain in the stomach (67.7%) and esophageal pain or heartburn (62.5%). Respondents reported increased pain after eating (51%) and relieved after taking an antacid (66.6%). Hematochezia or blood in stool (12.5%) and hematemesis or vomiting of blood (4.1%) were the least of the reported manifestations.

In regards to patients’ awareness on the symptoms of peptic ulcer associated with the NSAID use, 72 (75.0%) were aware of the side effect abdominal pain while 24 (25.0%) were not. Fifty-five (57.29%) patients were aware of esophageal pain or heartburn, while 39 (40.6%) were not. Twenty-seven (28.1%) of the patients were aware of the side effect nausea and vomiting, 7 (7.2%) for blood in stool, and 5 (5.2%) for vomiting of blood.

In the logistic regression analysis, the two significant predictors of epigastric/gastric pain associated with NSAID use of arthritis patients were age (OR = 1.48, 95% CI = 1.09–8.93) and NSAID use duration (OR = 2.38, 95% CI = 1.24–4.76). Since the OR of 1.48 for the age variable (i.e., significant in 25–35 years old), it indicates that those who are at the age range of 25–35 years are 48% less likely to have epigastric or gastric pain associated with NSAID use. Moreover, the OR of 2.38 for the NSAID use duration (i.e., significant at 4 to 6 months duration) indicates that those who are taking NSAID for 4–6 months duration are 138% more likely to have the epigastric or gastric pain.


Discussion

The use of NSAIDs has been associated with the development of GI injury ranging from mild to very high-risk problems like bleedings and perforations [14]. This can often result in patients’ non-compliance to the regimen because of its effect on reducing their quality of life [15]. The risk of developing peptic ulcer disease varies with specific NSAIDs use, its dosages, duration, and patients profile characteristics. In this study, the female has slight predominance among RA patients similar to the findings of the previous local studies [16,17] and they were the most likely to experience abdominal and esophageal pain as compared to male. Females tended to be high in prevalence because of significantly lower gastric mucosal blood flow (GMBF) in the antrum compared to male. The prevalence of antral ulcer in RA patients taking NSAIDs, according to the kind of NSAIDs taken, was highest in phenylacetic acids group. In this study, despite the majority of the patients were taking NSAIDs under the classification of propionic acids group, the prevalence of epigastric pain is significantly higher in phenylacetic acid groups (p = 0.033). In one study, GMBF in the antrum of phenylacetic acids group was the lowest among the other groups of NSAIDs (i.e., oxicams and propionic acids). These results indicate that long-term use of NSAIDs may selectively inhibit GMBF in the antrum, leading to impairment of the protective mechanism in the gastric wall and subsequent occurrence of the antral ulcer. These chemicals present in the type of NSAIDS are said to be the culprit of the increasing esophageal and epigastric pain more than minor nausea and vomiting [18]. This is consistent with the findings of this study. This study also confirmed that those who are taking NSAIDs for 4–6 months duration are significantly 138% more likely to have the epigastric or gastric pain as compared to 4 months and below of NSAID use. In connection to this, peptic ulcer among patients with upper bleeding is linked to the use of NSAIDs and found to be increased with the length of use [19,20]. Moreover, upper GI bleeding had more often been present in male seropositive RA patients [21]. In this study, however, GI bleeding occurs less likely in both gender as the study limits the investigation to patients with 6 months use of NSAIDs.

Several risk factors such as previous GI surgery, H-pylori infection, previous history of peptic ulcer, and concomitant use of other NSAIDs such as corticosteroids have been known for its associations to NSAIDs induced peptic ulcer disease. However, these confounding factors were excluded in the study analysis to specifically determine the prevalence of NSAIDs induced GI effects among RA patients. Thus, based on the result of the study, management recommendations are therefore not limited to RA patients with profile characteristics similar to study sample but for general RA patients’ population.

NSAIDs induced peptic ulcer involves a multipronged approach. Drug avoidance if possible and would be ideal. Other options include using the lowest effective dose, changing to NSAIDs with a safer GI risk profile, and avoiding concurrent use with other NSAIDs. Proton pump inhibitors are the mainstay of therapy for symptom relief, healing of erosive esophagitis, resolution of peptic ulceration, reduction of the risk for NSAID-induced mucosal damage, and prevention of disease recurrence. In contrast to NSAID-induced gastrointestinal ulcers, a well-tolerated histamine H2-receptor antagonist is reportedly effective in the prevention of gastrointestinal ulcers. Topical NSAID formulations deliver effective doses of analgesics directly to the affected joints, thereby limiting systemic exposure and potentially the risk of systemic adverse events, such as gastropathy.

Endoscopy remains the “gold standard” for the identification of mucosal disease such as peptic ulcer and should be performed in all RA patients with “new-onset” or persistent symptoms who are >45 years of age, as well as in individuals of any age who present with alarm symptoms, such as weight loss, vomiting, anemia, dysphagia, or evidence of GI bleeding. GI effects are shown to be more common among RA patients although they are mostly aware of its association with NSAIDs use. This will yield for the need for further awareness of patients on another aspect such as avoidance of its predisposing factors and understand the precautionary measures in taking NSAIDs, and another treatment regimen to prevent GI effects and further prevent peptic ulcer disease and development of high-risk gastrointestinal problems.


Conclusion

This study showed that patients with RA taking NSAIDs were at high risk of peptic ulcer disease as evidence of persistence of GI symptoms, particularly the older ones. Use of NSAIDs even for less than 6 months is associated with gastrointestinal effects. RA patients experiencing persistent GI symptoms must undergo endoscopy to identify the exact location of GI injury which is necessary for effective management and to prevent the occurrence of high-risk GI problems. Therefore, prevention of NSAIDs-induced GI effects should be based on accurate patients’ profile assessment, GI profile, monitoring, and patients’ follow-up.


List of abbreviations

GI Gastrointestinal
GMBF Gastric mucosal blood flow
NSAIDs Non-steroidal anti-inflammatory drugs
RA Rheumatoid arthritis

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this article.


Funding

None.


Consent for publication

Informed consent was obtained from the participants.


Ethical approval

Ethical approval was obtained from Ibn Sina National College, Jeddah, Saudi Arabia date: 4/2/2018 via letter no. ISNC-RC Reg. No.: RC-14-09012018.


Author details

Yaman Mazen Almerstani1, Abdulkader Aljuhani1, Sara Abdullah Alsaad1, Bashaer Mahboub Alalwani1, Ahmed Mohammad Alsahlawi1, Turky Mehssen Alyamy1, Razan Mohammad Aljohani1, Ameera Mishal Alosaimi1

  1. Ibn Sina National College, Jeddah, Saudi Arabia

References

  1. Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochr Database Syst Rev. 2002;(4):CD002296. https://doi.org/10.1002/14651858.CD002296
  2. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet. 2002;359(9300):14–22. https://doi.org/10.1016/S0140-6736(02)07273-2
  3. Henry D, Dobson A, Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs. Gastroenterology. 1993;105(4):1078–88. https://doi.org/10.1016/0016-5085(93)90952-9
  4. Evans JM, McMahon AD, McGilchrist MM, White G, Murray FE, McDevitt DG, et al. Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case-control study. BMJ. 1995;311(6996):22–6. https://doi.org/10.1136/bmj.311.6996.22
  5. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 1999;56:18–24.
  6. Crofford LJ, Lipsky PE, Brooks P, Abramson SB, Simon LS, van de Putte LB. Basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 2000;43(1):4–13. https://doi.org/10.1002/1529-0131(200001)43:1<4::AID-ANR2>3.0.CO;2-V
  7. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999;340(24):1888–99. https://doi.org/10.1056/NEJM199906173402407
  8. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology. 2001;120(3):594–606. https://doi.org/10.1053/gast.2001.21907
  9. Graham DY, Agrawal NM, Campbell DR, Haber MM, Collis C, Lukasik NL, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med. 2002;162(2):169–75. https://doi.org/10.1001/archinte.162.2.169
  10. Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology. 1999;117(4):776–83. https://doi.org/10.1016/S0016-5085(99)70334-3
  11. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 1999;282(20):1921–8. https://doi.org/10.1001/jama.282.20.1921
  12. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343(21):1520–8.
  13. Statistics at Square One, 11th Edition [Internet]. Wiley.com [cited 2019 Jan 30]. Available from: https://www.wiley.com/en-eg/Statistics+at+Square+One%2C+11th+Edition-p-9781405191005
  14. Nonsteroidal anti-inflammatory drugs: add an anti-ulcer drug for patients at high risk only. Always limit the dose and duration of treatment with NSAIDs. Prescrire Int. 2011;20(119):216–9.
  15. Tomita T, Mori S, Tozawa K, Arai E, Tano N, Oka H, et al. Are the symptoms of an NSAID-induced ulcer truly milder than those of an ordinary ulcer? Gastroenterol Res Pract. 2017;2017:4653250.
  16. Al-Dalaan A, Al Ballaa S, Bahabri S, Biyari T, Al Sukait M, Mousa M. The prevalence of rheumatoid arthritis in the Qassim region of Saudi Arabia. Ann Saudi Med. 1998;18(5):396–7. https://doi.org/10.5144/0256-4947.1998.396
  17. Alballa SR. The expression of rheumatoid arthritis in Saudi Arabia. Clin Rheumatol. 1995;14(6):641–5. https://doi.org/10.1007/BF02207929
  18. Ohtsuka E. Upper gastrointestinal endoscopic findings and gastric mucosal blood flow in patients with rheumatoid arthritis. Fukuoka Igaku Zasshi. 1992;83(2):62–71.
  19. Minakari M, Badihian S, Jalalpour P, Sebghatollahi V. Etiology and outcome in patients with upper gastrointestinal bleeding: study on 4747 patients in the central region of Iran. J Gastroenterol Hepatol. 2017;32(4):789–96. https://doi.org/10.1111/jgh.13617
  20. Lee SP, Sung I-K, Kim JH, Lee S-Y, Park HS, Shim CS. Risk factors for the presence of symptoms in peptic ulcer disease. Clin Endosc. 2017;50(6):578–84. https://doi.org/10.5946/ce.2016.129
  21. Janssen M, Dijkmans BA, van der Sluys FA, van der Wielen JG, Havenga K, Vandenbroucke JP, et al. Upper gastrointestinal complaints and complications in chronic rheumatic patients in comparison with other chronic diseases. Br J Rheumatol. 1992;31(11):747–52. https://doi.org/10.1093/rheumatology/31.11.747


How to Cite this Article
Pubmed Style

Almerstani YM, Aljuhani A, Alsaad SA, Alalwani BM, Alsahlawi AM, Alyamy TM, Aljohani RM, Alosaimi AM. NSAID associated with an increased risk of peptic ulcer among patient with arthritis. IJMDC. 2019; 3(7): 597-600. doi:10.24911/IJMDC.51-1548203278


Web Style

Almerstani YM, Aljuhani A, Alsaad SA, Alalwani BM, Alsahlawi AM, Alyamy TM, Aljohani RM, Alosaimi AM. NSAID associated with an increased risk of peptic ulcer among patient with arthritis. http://www.ijmdc.com/?mno=27568 [Access: May 27, 2019]. doi:10.24911/IJMDC.51-1548203278


AMA (American Medical Association) Style

Almerstani YM, Aljuhani A, Alsaad SA, Alalwani BM, Alsahlawi AM, Alyamy TM, Aljohani RM, Alosaimi AM. NSAID associated with an increased risk of peptic ulcer among patient with arthritis. IJMDC. 2019; 3(7): 597-600. doi:10.24911/IJMDC.51-1548203278



Vancouver/ICMJE Style

Almerstani YM, Aljuhani A, Alsaad SA, Alalwani BM, Alsahlawi AM, Alyamy TM, Aljohani RM, Alosaimi AM. NSAID associated with an increased risk of peptic ulcer among patient with arthritis. IJMDC. (2019), [cited May 27, 2019]; 3(7): 597-600. doi:10.24911/IJMDC.51-1548203278



Harvard Style

Almerstani, Y. M., Aljuhani, . A., Alsaad, . S. A., Alalwani, . B. M., Alsahlawi, . A. M., Alyamy, . T. M., Aljohani, . R. M. & Alosaimi, . A. M. (2019) NSAID associated with an increased risk of peptic ulcer among patient with arthritis. IJMDC, 3 (7), 597-600. doi:10.24911/IJMDC.51-1548203278



Turabian Style

Almerstani, Yaman Mazen, Abdulkader Aljuhani, Sara Abdullah Alsaad, Bashaer Mahboub Alalwani, Ahmed Mohammad Alsahlawi, Turky Mehssen Alyamy, Razan Mohammad Aljohani, and Ameera Mishal Alosaimi. 2019. NSAID associated with an increased risk of peptic ulcer among patient with arthritis. International Journal of Medicine in Developing Countries, 3 (7), 597-600. doi:10.24911/IJMDC.51-1548203278



Chicago Style

Almerstani, Yaman Mazen, Abdulkader Aljuhani, Sara Abdullah Alsaad, Bashaer Mahboub Alalwani, Ahmed Mohammad Alsahlawi, Turky Mehssen Alyamy, Razan Mohammad Aljohani, and Ameera Mishal Alosaimi. "NSAID associated with an increased risk of peptic ulcer among patient with arthritis." International Journal of Medicine in Developing Countries 3 (2019), 597-600. doi:10.24911/IJMDC.51-1548203278



MLA (The Modern Language Association) Style

Almerstani, Yaman Mazen, Abdulkader Aljuhani, Sara Abdullah Alsaad, Bashaer Mahboub Alalwani, Ahmed Mohammad Alsahlawi, Turky Mehssen Alyamy, Razan Mohammad Aljohani, and Ameera Mishal Alosaimi. "NSAID associated with an increased risk of peptic ulcer among patient with arthritis." International Journal of Medicine in Developing Countries 3.7 (2019), 597-600. Print. doi:10.24911/IJMDC.51-1548203278



APA (American Psychological Association) Style

Almerstani, Y. M., Aljuhani, . A., Alsaad, . S. A., Alalwani, . B. M., Alsahlawi, . A. M., Alyamy, . T. M., Aljohani, . R. M. & Alosaimi, . A. M. (2019) NSAID associated with an increased risk of peptic ulcer among patient with arthritis. International Journal of Medicine in Developing Countries, 3 (7), 597-600. doi:10.24911/IJMDC.51-1548203278