Assessment of the effectiveness and safety of nonsteroidal anti-inflammatory drugs use in real-world clinical practice: an analysis of dosing regimens and drug-drug interactions

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) occupy a key position in the structure of analgesic therapy in both surgical and therapeutic practice [1–3]. Despite their efficacy, the use of drugs in this class is associated with the risk of developing significant complications—NSAID-induced gastropathy [4–7], cardiovascular events [8, 9], and acute kidney injury [10, 11]—making adherence to safety protocols critically important [7, 12, 13].

Data from international systematic audits indicate that the rate of potentially hazardous or inappropriate NSAID prescribing in real-world clinical practice reaches 27.7–34% [14, 15]. A preliminary analysis of local practice, conducted as a process audit, revealed comparable deficiencies and served as the rationale for conducting the present study.

Objective — to assess the frequency and structure of violations of NSAID prescribing protocols in a surgical hospital, including compliance with dosing limitations, duration of use, correctness of medical documentation, and potentially dangerous pharmacological combinations.

Object of the study — actual prescribing practice of NSAIDs in a surgical hospital.

Subject of the study — structure and frequency of violations of prescribing requirements.

Research hypothesis — that in real-world clinical practice of a surgical hospital, clinically significant deviations from NSAID prescribing protocols occur and are distributed unevenly across individual drugs and types of violations.

Materials and Methods

Study design. A retrospective process audit of NSAID prescribing was conducted in a surgical hospital. Since the study was a retrospective audit of routine clinical practice and used exclusively de-identified data, formal approval by a local ethics committee was not required. The study is a retrospective audit of de-identified data conducted as part of an assessment of the quality of medical care (Order No. 785n of the Ministry of Health of the Russian Federation). According to regulatory requirements, informed consent and special ethics committee review are not required for this type of work [16].

Population: 149 medical records of patients hospitalized in the departments of maxillofacial surgery, coloproctology, traumatology, and vascular surgery with NSAID prescriptions during the period from January 1, 2025, to October 1, 2025.

Methodology. The study methodology was based on international approaches to clinical audits. For the classification of violations, the principles of nonconformity management and process monitoring described in ISO 9001:2015 (clauses 8.7 and 9.1.1) were used. These provisions are applicable to healthcare organizations and allow identified deviations to be formally interpreted as nonconformities with established requirements. Inappropriate NSAID prescribing is one of the key preventable adverse drug events. The approach to evaluating medical records corresponds to the structure of clinical audit outlined in the WHO Handbook for National Quality Policy and Strategy (2020): defining criteria, data collection, comparison with standards, and formulation of improvement directions. The format of audit criteria follows the principles of the NICE Clinical Audit Tools (UK): each criterion is linked to a specific regulatory source, predefined, and quantifiable. The clinical audit process did not interfere with the delivery of medical care and did not modify prescriptions in real time.

Sample selection. Using simple random sampling, 149 medical records meeting the inclusion criteria were selected from all available cases. The data collection period (January 1 – October 1, 2025) spans three quarters and ensures representativeness considering seasonal fluctuations in surgical profiles. The observation period was limited by the availability of complete prescription sheet archives. The selection of medical records was performed by simple random sampling using a random number generator applied to the complete list of available cases meeting the inclusion criteria. The formation of the final sample from the initial pool (n=180) is shown in Figure 1. Data extraction was performed by a resident physician (clinical pharmacologist). To minimize systematic errors, a double-check mechanism was applied: each identified pharmacotherapy defect underwent expert verification jointly with the head of the clinical pharmacology department. The final decision on inclusion of a case in the analysis was made collegially.

Fig. 1. Flowchart: final sample selection (n=149)

Sample size justification. An a priori calculation was performed using the formula for estimating a proportion. Assuming an expected violation rate of 30%, a permissible error of ±8%, and a 95% confidence interval, the minimum sample size was 126 observations. The actual sample size (N=149) exceeded the calculated value. The chosen level of permissible error corresponds to the range recommended for healthcare quality audits (5–10%).

Inclusion criteria

1. Hospitalization in one of the surgical departments (maxillofacial surgery, coloproctology, traumatology, vascular surgery, etc.)

2. Presence of at least one NSAID prescription (oral or parenteral) during the period from January 1, 2025, to October 1, 2025.

Exclusion criteria

1. Medical records with incomplete prescription sheets.

Outcome measures
The following were assessed:

1. Correctness of single and daily dosages.

2. Compliance with duration of therapy.

3. Presence of a prescribing regimen (fixed / PRN [pro re nata; as needed]).

4. Potentially hazardous drug interactions.

5. Compliance with age restrictions.

6. Formal documentation defects.

7. Compliance with the prescribing protocol for parenteral ketorolac (≤2 days; ≤60 mg/day in patients ≥65 years).

Statistical analysis. The study design corresponded to the criteria of a retrospective pharmacoepidemiological analysis (Drug Utilization Review). The primary objective was to identify potentially inappropriate prescribing (PIP) and dosing errors that pose a risk to patients. Results of descriptive statistics for categorical variables are presented as absolute numbers and proportions with 95% confidence intervals. The integral indicator of critical deviations (Critical Deviation Rate, CDR), which included exceeding maximum permitted NSAID doses, exceeding treatment duration, non-compliance with age restrictions, potentially hazardous drug interactions, and NSAID prescription in children, was 20.8% (31 out of 149 patients; 95% CI 15.1–28.0%).

Results and Discussion

The analysis included 149 medical records of patients receiving NSAIDs in a surgical hospital. The frequency of identified violations is presented in Table 1.

Table 1. Frequency of pharmacotherapy defects in patients receiving NSAIDs (n=149)

Analysis of the structure of NSAID consumption in the study sample (n=149) demonstrated a marked imbalance toward the use of non‑selective cyclooxygenase inhibitors. The dominant drug was ketorolac — 90 prescriptions (60.7%). The second most frequently used drug was the selective COX-2 inhibitor etoricoxib — 30 cases (19.9%), used primarily as part of multimodal analgesia or in step‑down therapy. The proportions of nimesulide and diclofenac were 15 (9.8%) and 7 (4.9%) prescriptions, respectively (see Fig. 2).

Fig. 2. Analysis of the structure of NSAID consumption in the study sample (n=149)

Ketorolac was the dominant drug in the structure of clinically significant violations of NSAID prescribing protocols. All cases of exceeding the duration of therapy related to ketorolac; in some records, the course reached 6–9 days. Dosing violations also primarily concerned ketorolac: in 52% of episodes in patients ≥65 years, the daily dose exceeded the established limit of 60 mg. The violations are presented in Table 2.

Table 2. Distribution of violations by drug (ketorolac vs. other NSAIDs)

The criteria for ketorolac were based on the summary of product characteristics (SmPC) (LP‑003693). The following control limits were considered: maximum daily dose 90 mg (<65 years) and 60 mg (≥65 years; in renal impairment), as well as the maximum duration of parenteral therapy according to the SmPC.

Given the consumption structure, interpretation of violation frequency requires analysis of relative measures (number of violations per 100 prescriptions of each drug), which will allow differentiation between the effect of high prevalence of use and true predisposition to dosing errors.

The integral indicator of critical deviations (Critical Deviation Rate), which included exceeding dosage, age restrictions, hazardous interactions, and NSAID prescription in children, was 20.8% (31 out of 149 patients). Thus, nearly every fifth patient received a prescription accompanied by potentially clinically significant risk.

Dosing violations were also predominantly associated with ketorolac: 52% (13/25) represented exceeding the age limit of ≤60 mg/day in patients ≥65 years; the maximum recorded daily dose reached 120 mg.

The combination of ketorolac with acetylsalicylic acid at cardioprotective doses was documented in 3 patients, posing an additional risk of bleeding.

In the structure of dosing violations (n=25), the majority of episodes were associated with ketorolac: 20 cases (80.0%; 95% CI 60.9–91.1%) versus 5 (20.0%) for other NSAIDs. Testing the hypothesis of uniform distribution of dosing violations between ketorolac and other NSAIDs (p=0.5) revealed a statistically significant predominance of ketorolac (χ²=9.0; p=0.0027). This indicates a disproportionate contribution of ketorolac to dosing discrepancies in pain management at the study hospital. For PRN prescriptions without specification of maximum daily dose (n=33), no differences in distribution between ketorolac (18 cases) and other NSAIDs (15 cases) were found (χ²=0.27; p=0.60) (Fig. 3).

Fig. 3. Differentiation of the etiology of iatrogenic risk: drug‑specific nature of dose‑related disturbances in comparison with the systemic nature of PRN regimen defects

The present study constitutes a process audit of NSAID prescribing. The identified defects indicate systematic violations of NSAID prescribing protocols. The most likely causes include:

1. Inertia of clinical practice, particularly regarding ketorolac [17].

2. High physician workload, lack of automated restrictions on duration and dose.

3. Insufficient standardization of prescription documentation, as reflected by the high frequency of formal defects.

4. Lack of educational interventions focused on safe analgesic therapy.

The audit results demonstrate a high frequency of violations of NSAID prescribing protocols. The obtained data are consistent with Russian pharmacoepidemiological studies, which also report a high frequency of NSAID prescribing protocol violations, especially for ketorolac [17–20]. This confirms the systemic nature of the identified deviations.

The study results can be used to revise local pain management protocols and implement automated restrictions on NSAID dose and duration of use.

A root cause analysis of the identified nonconformities was performed in accordance with ISO 9001:2015:

1. Absence of automated restrictions in the medical information system.

2. Insufficient standardization of prescription sheets.

3. High proportion of manual documentation.

The particular prominence of ketorolac in the structure of identified violations is likely due to the combination of its pronounced analgesic effect and persistent clinical habit of its use in inpatient practice. Short-term ketorolac prescription is often perceived as relatively safe, which reduces vigilance regarding dose and time limits. However, precisely in elderly patients, this risk perception bias is accompanied by an increased frequency of NSAID‑associated bleeding and acute kidney injury, underscoring the clinical significance of the identified nonconformities.

Of particular concern is the high frequency of ketorolac prescription to patients over 65 years of age without dose adjustment (52% of cases). From a clinical pharmacology perspective, this creates preconditions for renal injury. In geriatric patients, renal blood flow becomes prostaglandin‑dependent. Blockade of COX‑1 and COX‑2 by high doses of ketorolac (up to 120 mg/day) leads to critical vasoconstriction of the afferent arteriole. In the context of age‑related renal involution (decline in glomerular filtration rate (GFR)) and postoperative hypovolemia, this transforms subclinical dysfunction into overt acute kidney injury. The dosing pattern we identified ignores the exponential increase in nephrotoxicity risk when exceeding the threshold of 60 mg/day in elderly individuals (Fig. 4).

Fig. 4. Simulation of the dose stacking effect in a geriatric patient

Although the frequency of the ketorolac + acetylsalicylic acid combination was only 2.0%, the clinical significance of this defect falls into the life‑threatening category. Concurrent use of a non‑selective NSAID (ketorolac) and an antiplatelet agent (ASA) produces a synergistic ulcerogenic effect. Ketorolac depletes cytoprotective gastric mucosal prostaglandins, while ASA irreversibly inhibits platelet COX‑1. Under surgical stress, this creates a therapeutic window for massive gastrointestinal bleeding. The fact that these prescriptions were not blocked at the physician decision stage indicates the absence of automated drug interaction checking systems in the hospital.

The practice of prescribing NSAIDs on an "as needed" basis without specifying the maximum daily frequency, identified in 22.1% of cases, is a predictor of uncontrolled drug accumulation. In the absence of a restrictive protocol (e.g., "no more than 3 times daily"), the dosing interval is determined by the patient's subjective pain perception rather than the drug's half‑life. This leads to overlapping concentration curves (stacking effect), where a repeat dose is administered before the elimination of the previous one, causing peak plasma concentrations to rise above the toxic threshold. For ketorolac, with its narrow therapeutic index, this practice is unacceptable.

Based on the identified risk patterns, the implementation of an NSAID prescribing control system is proposed:

1. Administrative level: introduction into medical information systems (MIS) of hard blocks on parenteral ketorolac prescription at doses >60 mg/day for individuals over 65 years and a prohibition on extending NSAID therapy beyond 5 days without re‑authorization.

2. Clinical level: revision of PRN ("as needed") protocols. The prescription must include a mandatory limiting interval (time‑lock interval) calculated based on the drug's half‑life in patients with reduced GFR to avoid the dose‑stacking effect.

The identified heterogeneity of violations necessitates a shift in scientific paradigm: from discrete error auditing to integral mathematical risk modeling. Future research may focus on the development of in silico predictive models capable of quantifying individual drug burden.

Study Limitations

1. Age was recorded only when required to verify age‑related treatment restrictions, which is consistent with first‑level audit methodology.

2. The study did not include an analysis of clinical outcomes.

3. Analysis of actual adverse drug reactions was not within the objectives of this study design, which focused on a process audit of prescribing quality.

The retrospective design eliminated investigator influence on the prescribing process and enabled the study of real, unbiased practice. Data analysis did not involve detailed collection of demographic variables, which is consistent with its objectives and does not hinder the achievement of the primary goal of the process audit — identifying and quantifying regulatory nonconformities at the level of the treatment process. These features are consistent with process optimization objectives and do not affect the validity of nonconformity identification.

Conclusion

Analysis of medical record data revealed a significant frequency of violations of NSAID prescribing protocols in the surgical hospital. The most significant violations concerned ketorolac: 100% of exceeding course duration and 80% of dose exceedances were associated with this drug; 52% of dosing violations in elderly patients reflected non‑compliance with the age limit of ≤60 mg/day. The skew in violation frequency toward ketorolac reflects its predominant use in the hospital departments during the analyzed period.

The obtained data can serve as a basis for the development of a local clinical pain management protocol and the implementation of automated control tools in prescription sheets. Domestic studies also show that standardization of NSAID use reduces the likelihood of adverse pharmacotherapy reactions [21]. The concentration of critical violations in ketorolac prescribing allows this drug to be considered a sensitive indicator of the quality and safety of the pain management process in a surgical hospital. A focused intervention aimed at standardizing its use could potentially lead to a disproportionately large reduction in the total number of clinically significant violations.

The obtained data indicate that the potential of simple algorithmic checks (checklists) has been exhausted. The solution to the problem of personalized safety lies in the mathematical objectification of risk. A transition is needed toward tools that allow real‑time assessment of cumulative therapy toxicity and prediction of individual patient vulnerability before clinical complications develop. This approach will transform pharmacotherapy safety control from a reactive discipline (error recording) into a predictive one (risk prevention based on forecasting).