The Different Patterns of Over-the-Counter Nonsteroidal Anti-Inflammatory Drugs or Analgesics Use in Patients with Chronic Kidney Disease and the General Population

Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs worldwide and their availability over-the-counter is increasing. The aim of this study was to examine the frequency of their use as well as the awareness of the associated risk of side effects in patients with chronic kidney disease (CKD) compared to the patients at general practice (GP) offices. We found that 88.5% of the CKD and 97.1% of the GP group used NSAIDs and/or analgesics (p < 0.0001). Paracetamol was chosen the most often by both study groups, but the proportion of patients taking paracetamol was significantly higher in the CKD group (p < 0.006). On the contrary, the proportion of patients taking ibuprofen was significantly higher in GP group (p < 0.0001). Furthermore, almost 37% of CKD and 60% of GP patients never consult with their doctor before taking NSAIDs or analgesics. The influence of advertisements on the decision to take these drugs was found to be marginal in both groups. In conclusion, the NSAIDs and/or analgesics use is very common. The differences between the studied cohorts in self-decision making and the type of drugs used between the studied cohorts warrant tailored educational approaches.


Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs worldwide and their availability over-the-counter (OTC) is increasing. For example, in the United States, the sales of these drugs are growing yearly, reaching the annual value of approximately 16 billion USD in 2019. Moreover, its further dynamic growth is estimated to 24.7 billion USD in 2027 [1]. Their availability and excessive advertisement may give the illusion that they can be taken without repercussions. This is a worrying phenomenon as most people consider OTC drugs safe [2,3]. We previously reported that the frequency of NSAIDs and analgesics self-use is very high even in a such high risk patient populations such as kidney and liver transplant recipients [4,5]. However, using them against recommendations or unintentionally taking the same substances sold under different trade names may cause serious health consequences. The NSAIDs and analgesics might have the detrimental impact on the function of the heart, central nervous system, gastrointestinal (GI) tract, kidneys and liver [6]. Furthermore, they may cause tachyphylaxis, which would require patients to take higher or more frequent doses to achieve expected relief, leading to addiction [7].
The most common and well-described complication of NSAIDs usage is duodenal and gastric mucosal lesions, reported in at least one third of patients [6,8]. However, NSAIDs also impact lower GI tract causing enteropathy manifested as, for example, iron deficiency anemia, indigestion or abdominal pain [9]. The enteric lesions such as erosions  The GP patients were aged from 24 to 92 years old (median 47 years), 57.0% were females and 43.0% males. The majority were people with secondary (48.8%), followed by higher (24.1%) and primary (16.9%) education. The smallest group was people with a vocational education (10.2%). Their demographic data is presented in Table 3. Clinical data were unavailable. The study cohorts were compared considering the available demographic data, comparison is presented in Table 4.

Comparison between CKD and GP Cohort
As many as 88.5% of the CKD and 97.1% of GP patients used NSAIDs and/or analgesics and the difference between the study groups was significant (p < 0.0001; Figure 1). b Fisher's exact test.

Comparison between CKD and GP Cohort
As many as 88.5% of the CKD and 97.1% of GP patients used NSAIDs and/or analgesics and the difference between the study groups was significant (p < 0.0001; Figure  1). We decided to divide the study participants into the three subgroups, regarding their OTC NSAIDs and/or analgesics frequency of use (A-most often, B-occasionally, Crarely). Paracetamol was chosen the most often by patients from both study groups, but the proportion of patients taking paracetamol was significantly higher in CKD group (p < 0.006; Figure 2A). Interestingly, we found that the less frequently the NSAIDs or analgesics were taken (2B, 2C vs. 2A), the lower the proportion of paracetamol (34.09%, 31.34% vs. 71.57% for CKD and 41.44%, 25.68 vs. 59.60% for GP) and the higher the proportion of ibuprofen (30.30%, 22.39% vs. 7.84% for CKD and 44.49%, 54,92% and 33.33% for GP) was reported. This indicated to us that CKD patients who reach for these drugs less frequently prefer ibuprofen, acetylsalicylic acid or metamizol, whereas GP patients use mostly ibuprofen. Accordingly, the proportion of patients taking ibuprofen was significantly higher in GP group in all 3 categories of the frequency of the drug use (p < 0.0001; p = 0.006; p < 0.0001; Figure 2A-C). The statistical calculations are presented in Table 5. We decided to divide the study participants into the three subgroups, regarding their OTC NSAIDs and/or analgesics frequency of use (A-most often, B-occasionally, Crarely). Paracetamol was chosen the most often by patients from both study groups, but the proportion of patients taking paracetamol was significantly higher in CKD group (p < 0.006; Figure 2A). Interestingly, we found that the less frequently the NSAIDs or analgesics were taken ( Figure 2B, Figure 2C vs. Figure 2A), the lower the proportion of paracetamol (34.09%, 31.34% vs. 71.57% for CKD and 41.44%, 25.68 vs. 59.60% for GP) and the higher the proportion of ibuprofen (30.30%, 22.39% vs. 7.84% for CKD and 44.49%, 54,92% and 33.33% for GP) was reported. This indicated to us that CKD patients who reach for these drugs less frequently prefer ibuprofen, acetylsalicylic acid or metamizol, whereas GP patients use mostly ibuprofen. Accordingly, the proportion of patients taking ibuprofen was significantly higher in GP group in all 3 categories of the frequency of the drug use (p < 0.0001; p = 0.006; p < 0.0001; Figure 2A-C). The statistical calculations are presented in Table 5. Such significant differences in ibuprofen use between CKD and GP patients may be partially explained by the differences in indications for therapy. The most popular cause of NSAIDs or analgesics use in CKD patients was joint and muscle pain, which was reported almost twice as often as an indication for use in CKD compared to GP patients. Similarly, spinal pain was significantly more often the reason to take these drugs in CKD than in GP patients. In contrast, infection or fever was a more common indications for use of NSAIDs or analgesics in GP patients, in whom they were significantly more often indicated than in CKD patients. Toothache was an indication for NSAIDs and/or analgesics use in twice as many GP patients compared to the CKD group ( Figure 3).
Patient gender was found to be associated with acetylsalicylic acid use in CKD patients only. Most probably because of the higher frequency of cardiovascular indications in the CKD group. Other drug use was not linked to gender (Table 6).
We also found a significantly higher frequency of NSAIDs or analgesics use in GP compared to CKD patients ( Figure 4). As many as 33% of the GP group took NSAIDs or analgesics on the day or the day preceding the survey. In contrast, 28% and 24% of CKD group took these drugs a month or 6 months prior to survey, respectively. No significant differences (Chi 2 = 0.69, p-value = 0.4) were found between the number of CKD and GP patients who read the drug information in the leaflet. Importantly, in both study groups as many as one fourth of patients does not read it at all (26.6 and 23.5% for CKD and GP group, respectively). The awareness of the potential side effects of NSAIDs or painkillers was not significantly different in CKD and GP patients ( Figure 5). It is worth to mentioning that the patients' awareness of the potential side effects of NSAIDs or analgesics is highly satisfactory. Interestingly, as many as 84% of GP respondents stated that they had never observed side effects after taking these drugs.    Such significant differences in ibuprofen use between CKD and GP patients may partially explained by the differences in indications for therapy. The most popular ca of NSAIDs or analgesics use in CKD patients was joint and muscle pain, which reported almost twice as often as an indication for use in CKD compared to GP patie Similarly, spinal pain was significantly more often the reason to take these drugs in C than in GP patients. In contrast, infection or fever was a more common indications for of NSAIDs or analgesics in GP patients, in whom they were significantly more o indicated than in CKD patients. Toothache was an indication for NSAIDs and analgesics use in twice as many GP patients compared to the CKD group ( Figure 3). Patient gender was found to be associated with acetylsalicylic acid use in C patients only. Most probably because of the higher frequency of cardiovasc indications in the CKD group. Other drug use was not linked to gender (Table 6).  The influence of advertisements on the decision to take NSAIDs or analgesics was found to be marginal in both studied groups. As many as 63.7% of CKD patients stated that their decision to choose NSAIDs or analgesics was never advertisement-driven ( Figure 6). Moreover, 51.6% of GP patients graded their belief that advertisement is important decision factor as very weak ( Figure 6).
Almost 60% of GP patients and 37% of CKD patients never go to see a doctor to consult taking NSAIDs or analgesics (Figure 7). Only this difference between the groups is statistically significant. We also found a significantly higher frequency of NSAIDs or analgesics use in GP compared to CKD patients ( Figure 4). As many as 33% of the GP group took NSAIDs or analgesics on the day or the day preceding the survey. In contrast, 28% and 24% of CKD group took these drugs a month or 6 months prior to survey, respectively. No significant differences (Chi 2 = 0.69, p-value = 0.4) were found between the number of CKD and GP patients who read the drug information in the leaflet. Importantly, in both study groups as many as one fourth of patients does not read it at all (26.6 and 23.5% for CKD and GP group, respectively). The awareness of the potential side effects of NSAIDs or painkillers was not significantly different in CKD and GP patients ( Figure 5). It is worth to mentioning that the patients' awareness of the potential side effects of NSAIDs or analgesics is highly satisfactory. Interestingly, as many as 84% of GP respondents stated that they had never observed side effects after taking these drugs. The influence of advertisements on the decision to take NSAIDs or analgesics was found to be marginal in both studied groups. As many as 63.7% of CKD patients stated that their decision to choose NSAIDs or analgesics was never advertisement-driven  The influence of advertisements on the decision to take NSAIDs or analgesics was found to be marginal in both studied groups. As many as 63.7% of CKD patients stated that their decision to choose NSAIDs or analgesics was never advertisement-driven ( Figure 6). Moreover, 51.6% of GP patients graded their belief that advertisement is important decision factor as very weak ( Figure 6). Almost 60% of GP patients and 37% of CKD patients never go to see a doctor to consult taking NSAIDs or analgesics (Figure 7). Only this difference between the groups is statistically significant.

Discussion
The results of our study confirmed that NSAIDs and/or analgesics use is very common both in the nephrological and the primary care patient populations: 89 and 97% of patients, respectively. These very high proportions in combination with the age ranges of our populations suggest that patients using OTC painkillers are people of all ages. The elderly were previously reported to be particularly prone to take these drugs for multiple complaints. They are also at higher risk of adverse events [19]. However, young individuals were also reported to use NSAIDs and/or analgesics excessively. In a British study, over two thirds of the university student population took these drugs, and one sixth of them exceeded the maximum dose [2].
Interestingly, patients visiting their GP used NSAIDs and analgesics significantly more often than CKD patients. The differences in analgesics and antipyretics consumption between different patient populations are known from the literature. For example, according to the Swedish registry, 34% of elderly people with intellectual disabilities use these drugs, in comparison to 44% of the general population [20]. We previously reported that 64% of liver [4] and 63% of kidney transplant recipients use NSAIDs and/or analgesics [4,5]. In contrast, analgesics and antipyretics were recorded only in 6.6% of patients hospitalized in the internal medicine wards [21]. Such cohort-related discrepancies may be explained by the differences in the indications, population-specific comorbidities, pain burden and medical advice, age, drug education, patients' beliefs and study methodologies.

Discussion
The results of our study confirmed that NSAIDs and/or analgesics use is very common both in the nephrological and the primary care patient populations: 89 and 97% of patients, respectively. These very high proportions in combination with the age ranges of our populations suggest that patients using OTC painkillers are people of all ages. The elderly were previously reported to be particularly prone to take these drugs for multiple complaints. They are also at higher risk of adverse events [19]. However, young individuals were also reported to use NSAIDs and/or analgesics excessively. In a British study, over two thirds of the university student population took these drugs, and one sixth of them exceeded the maximum dose [2].
Interestingly, patients visiting their GP used NSAIDs and analgesics significantly more often than CKD patients. The differences in analgesics and antipyretics consumption between different patient populations are known from the literature. For example, according to the Swedish registry, 34% of elderly people with intellectual disabilities use these drugs, in comparison to 44% of the general population [20]. We previously reported that 64% of liver [4] and 63% of kidney transplant recipients use NSAIDs and/or analgesics [4,5]. In contrast, analgesics and antipyretics were recorded only in 6.6% of patients hospitalized in the internal medicine wards [21]. Such cohort-related discrepancies may be explained by the differences in the indications, population-specific comorbidities, pain burden and medical advice, age, drug education, patients' beliefs and study methodologies.
We found paracetamol to be the most frequently used drug in both study groups. However, the proportion of ibuprofen use, the most popular NSAID, was significantly higher in GP than in CKD patients. This observation is in line with previous reports. People with intellectual disabilities were more likely than those in the general population cohort to be prescribed paracetamol for all investigated types of pain, and were less likely to have a prescription for NSAIDs [20]. Paracetamol was also the most frequent among analgesics and antipyretics recorded in patients hospitalized in the internal medicine ward [21]. We hypothesize, that CKD patients pay more attention to their kidney function and are better educated about NSAIDs nephrotoxicity. In fact, the awareness of the adverse events risk associated with NSAIDs and/or analgesics use seems relatively high in our study (86% of CKD respondents). Nevertheless, almost 60% of GP patients and 37% of CKD patients never go to see a doctor to consult taking NSAIDs or analgesics. The better education of CKD patients could explain such difference; they probably know that paracetamol is less harmful than NSAID for their kidneys and make a self-decision to take OTC medications instead of waiting for the consultation. However, previous reports suggests that such analgesics self-use dependence on the type of studied cohort [22]. This is puzzling as it is known that 88% of patients consider doctors to be the most reliable source of information about these drugs [4]. Moreover, in one of the surveys as many as 30% of the respondents reported at least one case of NSAIDs or analgesics misuse [23]. Perhaps another explanation for the high self-decision rate is the fact that only 16% of our GP respondents experienced side effects and thus have a sense of drug safety. According to the available data, the frequency of side effects varies depending on the damaged organ and may be as high as 70% in the case of gastrointestinal diseases [9,10]. However, it should be taken into the account that patients may not experience all of the NSAIDs and/or analgesics side effects. It seems that their asymptomatic course was responsible for the low percentage of reported side effects in our study.
Another very important observation is the fact that advertising had little influence on the drug choice. It might seem that it is their availability and excessive advertisement builds the common belief that their use is safe. Meanwhile, according to our survey, the most important factors motivating the purchase of a particular drug were the previous experience with the drug, dosing method, and to a lesser extent the price of the drug, but not its advertising. These results seem to be an important voice in the discussion of the advantage of patient education over advertising bans in order to reduce the related complications and their consequences.
Our study has some limitations. Firstly, the number of completed questionnaires is not equal in CKD and GP groups for the reason we explained previously. Secondly, the GP group was younger and that might influence the reasons, the frequencies and the type of the OTC taken by both groups. Unfortunately, the surveys in each group were performed in different time points and the questions were in part non-identical. However, the statistical analysis was based on the identical questions only and remained unbiased. Finally, the clinical data from GP group were unavailable and many of the CKD patients are currently lost to follow-up. So, we cannot fully estimate the risk factors of NSAIDs intake entirely.

Conclusions
As many as 89% of CKD and 97% of GP patients of all ages use NSAIDs and/or analgesics.
Almost 37% of CKD and 60% of GP patients (!) never go to a doctor to consult taking NSAIDs or analgesics The awareness of the potential side effects of NSAIDs or painkillers is satisfactory (more than 85% in both groups).
The most popular reason of NSAIDs or analgesics use differ between cohorts. Almost 70% of CKD pointed joint and muscle pain, whereas 69% of GP chose infection or fever as a main reason.
Previous patient experience rather than drug advertising drives the decision on NSAIDs and/or analgesics choice, implying educational approaches. (Mark one answer, please) a. today b. yesterday c. this week d. this month e. during the last 6 months f. I didn't take analgesic drugs in the last 6 months g. hard to say, I don't remember 8. Do you read the leaflets attached to the over-the counter painkillers before use? (Mark one answer, please) a. yes, always b. yes, sometimes c. occasionally d. no, never 9. How much on average do you spend on drugs per month?
(Mark one answer, please) a. less than 10 PLN b. 10 When did you take over-the counter painkiller for the last time? (Mark one answer, please) a. today b. yesterday c. this week d. this month e. during the last 6 months f. I didn't take analgesic drugs in the last 6 months g. hard to say, I don't remember * answer 'g' was not included in calculations When was the last time you took over-the-counter painkiller?
a. today b. yesterday c. this week d. in the last month e. during the last 6 months f. I didn't take analgesic drugs in the last 6 months Do you think that the painkillers may cause side effects? (Mark one answer, please) * do not need any explanation, this is information from author about how the questionnaires were interpreted.