Efficacy and Safety of Pharmacist-Managed NSAIDs Deprescribing: A Jordanian Outpatient Study

,


Introduction
Nonsteroidal anti-infammatory drugs (NSAIDs) are often prescribed as frst-line treatment for a number of illnesses, including the management of various acute and chronic pain conditions, including osteoarthritis, rheumatoid arthritis, and other musculoskeletal disorders [1].Tey are among the most widely used drugs in the world.Tese medications are sold over-the-counter (i.e., without a prescription) and prescribed in clinics and hospitals across the globe because it is thought that their use is safe even when taken for extended periods of time [2].Furthermore, compared to going to the ER or scheduling an appointment to see a general practitioner, many members of the public believe that getting an analgesic over-the-counter will save time and money and provide speedier pain relief [3].Teir widespread use can be attributed to their efcacy in alleviating pain and reducing infammation [4].However, the therapeutic benefts of NSAIDs often come with a price, as their prolonged use has been associated with a spectrum of adverse efects, raising concerns regarding their long-term safety, especially in outpatient settings [5,6].
One of the most prominent risks of NSAIDs usage is gastrointestinal (GI) bleeding, which can encompass conditions such as stomach ulcers, heartburn, and even lifethreatening GI hemorrhage [7].Te mechanism underlying this risk involves the inhibition of cyclooxygenase enzymes by NSAIDs, leading to the suppression of prostaglandin synthesis [8].Prostaglandins are essential for the maintenance of the gastric mucosal barrier and blood fow regulation within the GI tract [9].NSAIDs-induced reduction in prostaglandins can compromise the mucosal integrity, making the stomach and intestines more susceptible to damage, irritation, and ulceration [5,9].Te severity of GI bleeding events is often dose-dependent and durationrelated, with continuous NSAIDs use being a critical risk factor [10].
Additionally, NSAIDs have been associated with adverse renal efects, including acute kidney injury and increased blood pressure [11].NSAIDs exert their impact on renal function by constriction of the aferent arterioles, leading to reduced renal perfusion and potential nephron injury [12].Te reduction in renal blood fow can cause electrolyte imbalances, fuid retention, and increased blood pressure, particularly in patients with preexisting hypertension [13].
Consumers may be more likely to accidentally exceed the recommended NSAIDs dosage, which could result in potentially dangerous adverse efects, due to the availability of several products containing NSAIDs as well as a lack of awareness and understanding of NSAIDs [14].
To address the potential risks of prolonged NSAIDs use, deprescribing programs have emerged as a viable strategy to minimize harm in patients requiring pain management [15][16][17].Pharmacist-led deprescribing programs have gained recognition for their role in optimizing medication use and reducing the risks associated with long-term drug therapy [18][19][20].Such programs aim to assess the necessity and appropriateness of ongoing drug therapy, gradually taper drug doses, explore alternative treatment options, and ultimately discontinue medications when the potential harms outweigh the benefts [21,22].
According to the Department of General Statistics in Jordan (2018), the elderly make up around 5% of the country's total population [23].Older patients are particularly afected, with a higher frequency of chronic diseases than people in other age groups [24][25][26].Prior reports have documented the high frequency of polypharmacy among elderly patients in Jordan and the irrational and unethical prescribing practices [27].At Jordan, NSAIDs are among the most widely available over-the-counter medications found at community pharmacies [28].Approximately one-third of older Jordanian patients experienced polypharmacy, with NSAIDs prescriptions being written for individuals at least once every three prescriptions [23].
Deprescribing is the process of stopping an inefective medicine under the supervision of a medical professional in order to manage polypharmacy and enhance efcacy, safety, and fnancial outcomes [29,30].An interdisciplinary approach is used in the deprescribing of NSAIDs to support the appropriate and efcient use of pharmacological and nonpharmacological pain management therapies.Patients using NSAIDs for various forms of pain are given evidence-based therapies by the clinical pharmacists.Te process of deprescribing and optimizing medicine for pain management has a favorable impact on every aspect of patients' lives, including social interactions, physical activity, mood, and sleep quality [17].Efective NSAIDs deprescribing in different settings and for various high-risk patients would improve NSAIDs safety.Te current study ensured the direct engagement with patients to enhance safety outcomes of NSAIDs deprescribing and especially appropriate deprescribing of OTC NSAIDs use since these drugs are sold without prescription.
In Jordan, where the utilization of NSAIDs is common for pain management, and the population demographics include a signifcant portion of elderly individuals, there is an imperative need to explore the efcacy and safety of pharmacist-managed deprescribing programs in outpatient settings [23].Tis study was designed to address this need and to evaluate the impact of a pharmacist-led deprescribing program on NSAIDs-related adverse events, with a particular focus on GI events such as bleeding, heartburn, ulcer, and fuctuation in blood pressure readings.By investigating the efectiveness of this intervention, our aim is to contribute to the advancement of safer pain management practices for patients in Jordan and, potentially, in other similar healthcare settings.

Study Design and
Participants.Tis study employed a prospective interventional design to evaluate the efectiveness and safety of a pharmacist-managed deprescribing program for NSAIDs among the Jordanian outpatient population.Participants were recruited from July to November 2022.In order to be eligible for the current study on the deprescribing of NSAIDs, the sample was made up of any patient over 18 who have been taken NSAIDs both by prescription or OTC and with an adequate intelligence level to respond to the questionnaire as a structured interview and after comprehensive assessment of their medical condition and suitability for deprescribing interventions.Te used NSAIDs could control acute pain (lasting less than four weeks), subacute pain (lasting four to twelve weeks), or chronic pain (lasting more than twelve weeks).Among the NSAIDs were cyclooxygenase-2 inhibitors, oxicam derivatives, acetic acid derivatives, and propionic acid derivatives.Patients who qualifed for the deprescribing program between July and November of 2022 were included in the trial cohort.After that, the recruited participants were chosen during the initial doctor appointment.
Te following variables were gathered as follows: (1) sociodemographic data including gender, age, job title, educational level, marital status, health insurance, and smoking status, (2) medical condition variables including chronic illnesses, chronic illnesses associated with chronic pain, acute illnesses with acute pain, regular medication usage, and the length of chronic medication usage, (3) questions are related to the used NSAIDs including duration of NSAIDs usage, sources of information for NSAIDs usage, side efects due to NSAIDs usage, sensitivity to NSAIDs medication usage, and (4) type of deprescribing intervention by pharmacist after consulting a doctor including stop using it for the patient and give suitable alternatives, reducing the dose by 25%-50%, reducing the duration of medication use, giving an alternative from within the NSAID group, frequency reduction, and using when needed.Finally, there was assessment of diferent variables before and after the 2 Journal of Clinical Pharmacy and Terapeutics deprescribing intervention in regards to safety outcomes evaluation and whether pharmacist intervention was accepted by the responsible physician.
2.2.Deprescribing Procedure.Although pharmacists are not authorized by Jordanian law to start, stop, or modify medications directly with patients, they still maintain essential pharmacy services.Te current investigation was therefore carried out under the guidance of physicians specializing in orthopedics, internal medicine, and general practice.After obtaining approval and consulting with the responsible physician and initiating face-to-face discussions with the patients in the clinic and based on the inclusion criteria, medical fles were screened to fnd patients who met the requirements.Following the identifcation of eligible patients, the clinical pharmacist assessed each patient's condition to ascertain whether the patient would beneft from deprescribing interventions.Te clinical pharmacist and the responsible physician discussed the best deprescribing intervention based on the patient's demographic information, presence of comorbidities, pain type, medication schedule, preferred and updated evidence-based interventions, and patient's lifestyle.Medication reviews for gaps and duplication of therapy, patient education regarding medication self-administration and monitoring, and therapy optimization recommendations in accordance with the updated guidelines and drug-drug interactions were all included in the scheduled deprescribing.Te deprescribing approach included various options, such as discontinuation of NSAIDs use, dose reduction, and ofering alternative medications or treatment strategies.During the deprescribing process, self-reported questionnaires were administered to participants to assess multiple aspects.Te patient's fle contains records of the conversations and decisions made by the patient, physician, and pharmacist.Lastly, a follow-up appointment is usually set up four months after the original visit, and in the interim, the clinical pharmacist can be reached by phone for weekly check-ins.Tis allowed for ongoing progress monitoring of the patient, as well as planned follow-up monitoring for pain management and evaluation of the deprescribing plan's efcacy.

Efectiveness Outcomes.
Te clinical pharmacist assessed all existing NSAIDs, selected medications to be targeted for discontinuation, created a deprescribing schedule, and planned depending on patient's needs and responsible physician consultation.
Tis study investigated the rate of (1) new onset GI events, such as GI bleeding (stool color change and/or blood through vomiting like cofee color), heartburn, or stomach ulcers and (2) variations in blood pressure for hypertensive patients in order to assess the efcacy of the pharmacistmanaged NSAIDs deprescribing program.

Safety Outcome.
In the current study, the rate of ER visits or hospitalization due to pain exacerbation or use of preexisting pain as a proxy for the safety result was defned as the safety outcome.By following up patients through clinic visits, preventing pain from getting worse by giving alternatives to other medications from natural sources to remove infammation and/or giving alternative analgesics that are less harmful like paracetamol for mild pain.Te recruited participants in the current study monitored to report any change in pain intensity and any increase or decrease in pain exacerbation after the deprescribing intervention.
2.5.Sample Size.Te sample size calculation was determined based on the number of patients visiting the pharmacy daily.Te Raosoft ® software [31] was employed to estimate the minimal sample size required, which was 100 participants.A convenience sampling approach was utilized to select the 100 participants who met the inclusion criteria for the study.

Ethical Considerations.
Tis study meticulously followed ethical principles to safeguard the rights and wellbeing of participants.Approval was obtained from the Institutional Review Board at Zarqa University (no.2023/ 2022/71) ensuring that the research design aligns with ethical principles and regulations.Informed consents were secured from participants, emphasizing the voluntary nature of participation and confdentiality.Privacy and data security measures were strictly upheld, with personal information anonymized.

Data Analysis. Data analysis was conducted using the
Statistical Package for the Social Sciences, version 26 (SPSS ® , IBM Corp, USA).Descriptive statistics were generated to summarize key study variables.Diferences among groups were assessed using the chi-square test for categorical variables, aiming to identify signifcant diferences in the levels of NSAIDs usage and awareness among participants.A p value of less than 0.05 was considered statistically signifcant.Te study data were collected, analyzed, and presented in a comprehensive manner to provide meaningful insights into the efectiveness and safety of the pharmacist-led deprescribing program for NSAIDs among the Jordanian outpatient population.

Results
One hundred participants were recruited for the study, and their sociodemographic characteristics are summarized in Table 1.Te majority of participants were females (77%), and most were aged over 60 years old (62%).Approximately twothirds of the participants had public insurance (61%), while one-third had noninsured coverage (37%).Te highest level of education among the participants predominantly consisted of those with a high school or lower (96%).In terms of occupation, a large majority were not engaged in any occupation (87%).
Chronic diseases among the participants were prevalent, with hypertension (21%) being the most frequently reported, while psychiatry disorders (1%) were the least common (Table 2).Most participants used 1-3 medications (91%), and analgesics (84%) were the most commonly used group of medications.
Chronic diseases that cause pain were also reported among participants, with rheumatoid arthritis pain (24%) and osteoarthritis pain (22%) being the most frequent (Table 3).Chronic low back pain (9%) was the least reported among the participants.
Participants in the study reported various NSAIDs usage patterns, with ibuprofen (28%) and diclofenac (22%) being the most widely used nonselective NSAIDs (Table 4).Notably, 72% of the participants reported using NSAIDs for chronic pain management, with only 3% referring to NSAIDs usage for subacute pain (4-12 weeks).Surprisingly, a substantial portion of participants reported having no specifc information sources for NSAIDs usage (66%) or relied on family and relatives (21%), while a smaller number sought advice from healthcare professionals (13%).
Te implementation of the pharmacist-managed deprescribing program was associated with several positive outcomes.Table 5 illustrates the types of NSAIDs deprescribing initiated by the clinical pharmacist researcher in consultation with the responsible doctors.Te most common deprescribing approach was "stop using it for the patient and give suitable alternatives" (52%).Among the efectiveness outcomes, the data revealed that heartburn (81%), stomach ulcer (24%), and renal problems (28%) were the most frequently reported side efects before deprescribing.After deprescribing, almost complete disappearance of these side efects was observed (p < 0.001).A signifcant reduction in heartburn and stomach ulcer was observed.Table 6 shows detailed efectiveness outcomes before and after deprescribing.However, there was no signifcant change in the occurrence of GI bleeding events (p � 0.20), heart palpitations (p � 0.33), sore throat (p � 0.08), dry cough (p � 0.22), and pallor (p � 0.35).Fluctuations in blood pressure had a signifcant decrease after deprescribing (p � 0.038).Moreover and as safety outcome measurement, participants reported a decrease in pain exacerbation from 40% to 20% after the deprescribing intervention (p � 0.003).

Discussion
To our knowledge, this is the frst study to examine the efcacy and safety results of a deprescribing program for NSAIDs in patients with various pain types in the Middle East area and in Jordan specifcally.NSAIDs are essential for treating a wide range of painful and infammatory disorders.Unfortunately, there are signifcant side efects associated with using NSAIDs.Tese include bleeding and ulceration of the gastrointestinal tract, toxicities to the liver and kidneys, and a rise in thromboembolic events [2].Finding a balance between gastrointestinal and cardiovascular safety is necessary for the safe use of NSAIDs.Te risk rankings are based on epidemiologic data and are not absolute; conversely, NSAIDs that are the safest for the heart often have higher gastrointestinal toxicity.Te fndings of the current study underscore the efectiveness and safety of a pharmacist-managed deprescribing program for NSAIDs in an outpatient population.Tis primary goal was to address the potential health risks associated with prolonged NSAIDs   4 Journal of Clinical Pharmacy and Terapeutics use, particularly the risks of GI bleeding events and kidney problems.Although the absolute reduction in the occurrence of these adverse events was relatively modest, the results have important implications for the feasibility of implementing pharmacist-led deprescribing initiatives to enhance the safety of chronic pain management in outpatient settings.Tis study showed that the majority of NSAIDs users were nonsmoker females and more than 60 years old.Also, a number of earlier research studies have noted that women use NSAIDs more frequently than males [32,33].Tis is noteworthy due to the potential infuence of age on pain experience, comorbidities, and consequently NSAIDs usage [34,35].Smoking status is another crucial variable, revealing that nonsmokers constituted a substantial portion of the sample compared to smokers.Te recent study found that 79% of NSAIDs users were not smokers.Smoking is thought to raise pain thresholds and tolerance levels [36,37], which would reduce the need for analgesics.We also discovered that NSAIDs users accounted for about 37% of those in our community without health insurance.When people lack health insurance, they may fnd it diffcult to see doctors or receive follow-up care, which could increase their use of self-medication [38].Tis disparity could potentially infuence pain perception and NSAIDsrelated health risks [39].Te distribution of health insurance coverage indicated that around two-thirds of the participants had public insurance, which may impact healthcare accessibility and the ability to seek medical advice on medication usage.Occupation status ofers insights into daily activities that might contribute to pain and NSAIDs usage, highlighting the need for a multidisciplinary approach to pain management.
Te prevalence of chronic pain conditions in the study population was substantial, with rheumatoid arthritis and osteoarthritis being the most common causes of pain.Tis aligns with previous research emphasizing the burden of chronic pain on individuals' daily lives and the signifcance of efective pain management strategies [40].NSAIDs are frequently used for pain management, but their long-term use raises concerns about adverse efects, especially GI bleeding and kidney problems [41].Understanding the range of chronic pain conditions allows healthcare providers to provide more personalized and comprehensive pain management solutions.
Remarkably, the study found that none of the participants reported allergies or sensitivity to NSAIDs.Tis observation is consistent with a high tolerance for NSAIDs within the study population [42].According to our statistics, 13% of users received NSAIDs prescriptions from doctors or pharmacists.Nonetheless, 21% of respondents self-prescribed NSAIDs based on recommendations from friends and family, or even 66% relied on no information at all, indicating an overuse of these drugs in the public health system [43].Te prominence of no source of information for NSAIDs usage raises concerns about the potential lack of awareness and education among the users.Tese fndings underscore the importance of tailored deprescribing programs that consider the specifc needs of patients, their overall health, and the educational requirements, particularly for individuals with chronic pain conditions.Tey also highlight the crucial role of pharmacists collaborating with physicians to ensure safe and efective deprescribing.Te most prevalent forms of interventions utilized by the clinical pharmacist when deprescribing NSAIDs were to substitute the used medicine with a safer alternative (52%), reduce the dosage by 25-50% (12%), cut down on the length and frequency of needless pharmaceutical usage (15%), and only use the NSAIDs when necessary to treat acute pain (6%).Tis indicates the necessity for clinical pharmacists in a particular portion of the prison population as well as the wide range of services provided by pharmacy practice, including advising on healthy living choices and prescription knowledge.Consequently, the pharmacist's role in the deprescribing process is crucial, and it has been researched in the context of NSAIDs and other drugs, including the deprescribing of oral antidiabetics, proton pump inhibitors, antihistamines, hypnotics, and others [44][45][46].Physicians' positive assessment of the role of clinical pharmacists within the health care team is demonstrated by the 100% physician acceptance rate for pharmacist interventions.Selecting the best medication to treat pain, lower cardiovascular risks, and safeguard the gastrointestinal mucosa is a challenging process that requires skilled pharmacists and the application of appropriate techniques.Community-based pharmacists are becoming more and more involved in the ongoing management of patients with multiple chronic conditions [47,48].Based on the type of intervention, the roles of clinical pharmacists were divided into two categories: interventions involving drug review, consultation, or therapy management, and educational interventions.Pharmacist interventions have been shown to lower healthcare costs, support the safe and efcient use of pharmaceuticals, improve adherence, and have a favorable impact on disease control [47,48].
Te efectiveness of the pharmacist-managed deprescribing program was evident in the reduction of GI bleeding events.Although the absolute reduction was 5%, it is important to note that the occurrence of GI bleeding events is often dose-dependent and linearly related to continuous NSAIDs use over time [10].Tus, even a modest decrease in these events indicates a promising reduction in risk.Moreover, as most NSAIDs users often require long-term pain management, this reduction becomes even more signifcant in the context of extended NSAIDs use [5].Te most signifcant outcome was observed in the case of stomach ulcers, with a notable decline from 24% before deprescribing to only 1% after deprescribing, with highly statistical signifcance.Tis fnding underscores the program's efectiveness in preventing one of the most severe adverse events associated with NSAIDs use.
Heartburn problems saw substantial improvement as well.Heartburn dropped signifcantly from 81% before deprescribing to 0% after deprescribing, with signifcant p value <0.001.Tese results strongly indicate that the deprescribing program efectively mitigated severe and potentially life-threatening complications tied to NSAIDs use [49].
Tis study also addressed pain exacerbation, with participants reporting a decrease in pain exacerbation following the deprescribing intervention.Te alternative therapies utilized, such as collagen therapy and selective serotonin reuptake inhibitors (SSRIs), suggest efective pain management strategies in the absence of chronic NSAIDs use.While collagen therapy has shown limited impact on pain and joint infammation in some studies [50], SSRIs have long been considered for chronic pain treatment due to their role in managing pain states associated with depression [51].Tis suggests that alternative therapies may provide efective pain management strategies in the absence of chronic NSAIDs use.Te recruited participants in the current study reported a decrease in pain exacerbation from 40% to 20% after the deprescribing intervention (p � 0.003).One study reported lower pain levels among older adults who reduced NSAIDs as part of a pharmacist review program [16].
While this study demonstrates the feasibility and effectiveness of a pharmacist-managed deprescribing program, it is important to acknowledge its limitations.Te study design, limited sample size, and short follow-up time are among the constraints that may restrict the generalizability of the fndings to a broader population.Unobserved factors, including lifestyle, dietary habits, and the use of over-the-counter NSAIDs or aspirin, may have infuenced the results but were not accounted for in this study.Moreover, the study did not collect data on other relevant outcomes, such as the frequency of physician visits or the use of other opioid drugs that might impact the results.Information on other relevant outcomes, such as the economic result or the frequency of doctor visits, was not gathered for the current study.Nonetheless, this study has shed Additionally, it is impossible to predict the recurrence of a condition by short-term symptom monitoring after stopping the usage of prescription drugs intended as preventive measures.Removing the long-term advantages of preventative medicine prescriptions means deprescribing them will likely increase death.Te hazards of continuing outweigh the long-term benefts, therefore quitting the medicine should, and in theory, they have a net positive efect if it is determined to be inappropriate and designated for deprescribing.Making educated decisions about appropriateness (and hence the possibility of deprescribing) in older persons is, at best, challenging because the advantages and drawbacks of many preventive drugs are not well understood.Furthermore, the regional focus in Jordan may not fully represent the diversity of patient populations found in other countries, highlighting the need for more extensive, multinational research to better understand the applicability of deprescribing programs.
Finally, since the main focus of patient treatment has been shifting around physician competency and skills, the current study is the frst in to assess the role of pharmacist in deprescribing NSAIDs, which is a relatively new concept in Jordan and the MENA region.In actuality, clinical pharmacists do not yet have a well-defned role or actively participate in patient treatments in Jordan.Tis may be mostly related to a lack of trust and inadequate communication between doctors and their pharmacist colleagues.Unfortunately, the majority of the Middle East and North African nations witness the same depressing relationship between pharmacists and doctors.To make matters more complicated, in Jordan and the surrounding nations, nonprescription purchases are permitted for all NSAIDs.Terefore, it is essential to have community and clinical pharmacists play a recognized role in the selection and monitoring of medications in order to enhance patient clinical outcomes.In order to maximize patient therapy and establish a more positive role for the pharmacist, deprescribing procedures are crucial.

Conclusion
In conclusion, the results of this study suggest that a pharmacist-managed deprescribing program for NSAIDs in outpatient settings can efectively reduce the risks associated with prolonged NSAIDs use.Te observed improvements in GI safety profle, as well as the reduction in pain exacerbation, are particularly promising.Despite the study's limitations, these fndings provide valuable insights into the potential benefts of deprescribing initiatives for enhancing pain management safety in outpatient populations.Longterm investigations are essential to confrm the sustainability of these improvements over extended durations and to further evaluate the clinical benefts of such programs.Te study highlights the importance of collaborative eforts among healthcare professionals to optimize pain management while minimizing the risks associated with NSAIDs use in patients with chronic pain.Te pharmacist-managed deprescribing program for NSAIDs demonstrated its potential to signifcantly reduce the risk of gastrointestinal adverse events among patients with chronic pain without causing harm in the short-term follow-up.Tese fndings suggest a viable strategy for enhancing the safety of pain management in outpatient settings.Long-term investigations are essential to validate the sustainability of these improvements and explore their impact on the overall health and well-being of patients.Tis study contributes to the growing body of evidence supporting the value of collaborative healthcare eforts, involving pharmacists and physicians, in optimizing pain management while minimizing the risks associated with prolonged NSAIDs use.
* Public (Ministry of Health, military, universities, and other ministries).

Table 2 :
Chronic disease among participants, number of medications used, and groups of medications used (N � 100).
* Psychiatry disorders were depression and anxiety.* * Respiratory disorders were asthma and COPD.

Table 3 :
Chronic diseases that cause chronic pain among participants (N � 100).

Table 5 :
Types of NSAIDs deprescribing by the pharmacist after consulting the responsible doctor (N � 100).

Table 6 :
Efectiveness outcomes (before and after deprescribing) (N � 100).important light on how deprescribing NSAIDs afects individuals who use them for a variety of pain conditions.Te researchers intend to keep informing diverse stakeholders about the fndings and recommended courses of action.Subsequently, larger sample sizes and longer follow-up times are required for further investigations, as some NSAIDs side efects can become more apparent over time.