Address for correspondence:
Dr.Vinu M Jose
Senior Lecturer in Pharmacology
Government Medical College,Thrissur
E-Mail:vishnujose@hotmail.com


Abstract

Studies claiming misuse of anti-acidity drugs and questioning efficacy and safety of highly selective cycloxygenase 2 inhibitors, encouraged us to conduct a drug utilisation study to evaluate the extend of patients on NSAID who are provided gastro-protection. Use of highly selective cyclooxygenase 2 inhibitors and co-administration of NSAID with anti-acidity drugs were considered as gastro-protective agent usages. 
Materials and Methods A pharmacy based, retrospective, bill audit was performed. Classification was done for NSAID according to cycloxygenase selectivity and for anti-acidity drugs according to mechanism of action. Chi-square test, Fischer’s exact test and chi-square test for trend were performed for analysis. 
Results Among NSAID users 31% in 2000, 35% in 2001 and 48% in 2002 were provided gastro-protection. Usage of gastro-protective agents is advised only in high risk individuals who include elderly, those already receiving gastro-toxic agents and those with history of gastro-intestinal diseases. Prevalance of peptic ulcer disease in the community is 10-12%. 
Conclusions: we conclude a trend towards increasing use of gastro-protection among NSAID prescribers.

Keywords

Anti-ulcer, COX-2, gastro-protection, NSAID, Rationality

Introduction

Prevalence of peptic ulcer disease in the community is 10-12%[1]. Non-steroidal anti-inflammatory drug (NSAID) use is an important predisposing factor[1-3], warranting its cautious use in high risk individuals. Available alternatives are gastro-protective NSAID’s and co-administration of NSAID with anti-ulcer drugs[4]. 

There are reports questioning the efficacy and safety of highly selective COX2 inhibitors[5-7]. There are studies concluding irrational use of anti-ulcer drugs especially ranitidine8. Hence we conducted a drug utilization study (DUS) to evaluate the use of gastro-protective NSAID and co-administration of NSAID with anti-ulcer drugs to determine the rationality. Availability of NSAID and anti-ulcer drugs for self medication over the counter[1],[3] exaggerates its misuse. Similar studies evaluating the rationality of use of drugs from Calicut are few. Further this study will help us in determining the need of a program on promotion of rational use of drugs.



Materials and Methods

Drugs prescribed from our 2500 bed tertiary care hospital are bought from the attached low cost pharmacy. Other drug sources are; free hospital supply, which is restricted the few financially poor people and neighbouring approximately 10 private pharmacies.

Drugs sold from the store are entered in bill books and stored for annual audit. Randomly selected 50% of the bill books of July 2000,2001 and 2002 were collected and bill book number, dates of sale, bill numbers and NSAIDs and anti-ulcer drugs sold out were recorded in to a proforma by a trained medical personnel. All types of NSAIDs and anti-ulcer drugs were available in the store though same drug from all the manufacturers were not available. 6 randomly selected books were re-tabulated to cross check the correctness of the initial audit.

Classification of NSAID
According to COX enzyme selectivity, NSAID’s are classified[9] to COX1 selective group-1 which include low dose aspirin, non-selective group-2 which includes high dose aspirin, diclofenac, ibuprofen, indomethacin, mefenamic acid, naproxen, paracetamol and piroxicam, COX2 selective group-3 which include ketorolac, meloxicam, nabumetone and nimuselide and COX2 highly selective group-4 which includes celicoxib and rofecoxib. Since adverse drug reactions (ADR) and clinical use mostly correlate with COX selectivity, this classification pattern was followed. Group-1&2 separations were not done since it was not expected to provide any other valid outcome. 

Classification of Anti-ulcer drugs
Anti-ulcer drugs are classified[3],[10] according to mechanism of action to antacids, Histamine2 receptor (H2) blockers, proton pump inhibitors (PPI) and others. H2 blockers included ranitidine, famotidine and roxatidine, and PPI included omeprazole, lansoprazole and pantoprazole. 

The number of highly selective COX2 agents used along with combined NSAID and anti-ulcer agents used constituted usage of gastro-protective agent. Though a prospective study conducted at the pharmacy would have been ideal, since it requires huge manpower and more financial support it was not attempted.

Statistical evaluation
Drugs sold out over the years were compared by Chi-squared test and Fischer’s exact test. Trend over the years for the combined sale of gastro-protective agents were compared by Chi-squared test for trend. P value of <0.05 was considered significant. ‘Graph pad instat’ program was used for statistical evaluation. Values are expressed as numbers and percentages. 



Results

90, 98 and 88 bill books were utilised for drug sale in the month of July in the years 2000, 2001 and 2002 respectively. 50% of these were scrutinised and all NSAID’s and anti-ulcer agents prescribed were tabulated in to a proforma. 

Significant difference was observed in the usage of COX1 selective and non-selective COX agents combined, COX2 selective agents and highly selective COX2 agents. Among anti-ulcer agents significant difference was observed in the usage of antacids, H2 blockers and PPI (Fig.1).

Figure1- Pattern of NSAID and  anti-ulcer drug use over the years [Click to Enlarge]

Significant difference in the usage of anti-ulcer drugs, NSAID’s, highly selective COX2 agents, combined NSAID and anti-ulcer agents (with respect to both NSAID and anti-ulcer agents separately) and gastro protective agent use (with respect to NSAID use) were also observed (Tab.1). There was increasing trend (p<0.01) in the usage of gastro protective agents over the 3 years. 

Discussion

COX1 selective and non-selective agents combined were the most commonly used NSAID. There was increased use of highly selective COX2 inhibitors at the expense of other NSAID’s. This is observed amidst the controversy regarding the safety and efficacy of these highly selective COX2 agents[5],[6],[7]. 

H2 blockers were the most used anti-ulcer agent followed by PPI. Antacids were not much used. Antacid is indicated only for symptomatic relief of pain[3] and its use is associated with a number of drug interactions3 thereby restricting its rational indication. Sucralfate due to high incidence of associated drug interactions[3],[4] is not a preferred drug though rarely used in our study. Misoprostol was not available during the period of the study even though it is indicated for prophylaxis of high risk individuals[3]. Though PPI produce more complete acid suppression compared to H2 blockers[10], it was used to a lesser extend. 

There was increased co-administration of NSAID with anti-ulcer drugs and use of highly selective COX2 inhibitors. Gastro protective agent use thus showed an increasing trend. Physicians are over using highly selective COX2 inhibitors and NSAID with anti-ulcer drug combinations. Aggressive marketing strategies adopted by pharmaceutical companies and fear of peptic ulcer disease seem the reasons behind this attitude.

Prevalence of peptic ulcer disease in the community is 10-12%[1]. Incidence of gastrointestinal complications in long term NSAID users is 4%[2]. Usage of gastro-protective agents is advised for only three high risk groups of people; the elderly, those already receiving gastro-toxic drugs, and those with history of gastro-intestinal diseases[2],[4]. In high risk individuals, highly selective COX2 Inhibitors or co-administration of NSAID with omeprazole, misoprostol and H2 blockers are advised. Dyspepsia and other mild ADR’s following NSAID use in those not at high risk, are managed by co-administering milk, taking the drug with food[4] and if still not controlled by judicious use of antacids. The usage of 30.94%, 34.72% and 47.74% gastro-protective agents in the years 2000, 2001 and 2002, seems gross over use and trend towards irrational use. Hence a training program for rational use of drugs seems necessary in the present scenario.


Abbreviations used

NSAID- Non-steroidal anti-inflammatory drug 
COX- Cyclooxygenase
DUS- Drug utilisation study
ADR-Adverse drug reactions 
H2- Histamine2 receptor 
PPI- Proton pump inhibitors

References

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