An Up-to-Date Description of the Use of Non-steroidal Anti-inflammatory Drugs (NSAIDs) in Italy: Evidence from Real Clinical Practice

Abstract

Introduction

The prescription of non-steroidal anti-inflammatory drugs (NSAIDs) covered by the Italian National Health Service is limited to certain pathologies defined in the 2018 update of Note 66 of the Italian Medicines Agency (AIFA), meant to ensure appropriate use of NSAIDs. This analysis was conducted in real clinical practice to describe NSAID utilization from 2019 to 2022 with respect to Note 66 update.

Methods

For this real-world analysis, data were extracted from the administrative databases of healthcare institutions covering ~ 9.1 million citizens. From 2019 to 2022, all subjects with ≥ 1 NSAID prescription were identified. Demographic and clinical characteristics, the proportion of NSAID-treated patients over time, the most prescribed molecules, and drug consumption defined as daily dose (DDD) per 1000 inhabitants/day were recorded.

Results

The percentage NSAID-treated patients showed a slight increase over time (1.9–3.0%). The most prescribed active ingredients were diclofenac, ketoprofen, nimesulide, etoricoxib, and ibuprofen. NSAID consumption increased from 15.5 to 16.8 DDD/1000 inhabitants/day over 2020–2022, especially in older patients (65–74 years group: 36.2–39.3 DDD/1000 inhabitants/day). From 2019 to 2022, 2,811,910 patients with NSAID prescription(s) in Note 66 were identified, whose average age was 59.7 years. Among them, 0.1–1.0% received NSAIDs for rheumatic diseases and 11.9% in the oncological setting. While diclofenac, etoricoxib, and ketoprofen were commonly prescribed at medium–low dosage as recommended, ibuprofen was used at high dosage (600 mg) in 80% of cases.

Conclusion

The analysis showed that patients prescribed with NSAIDs were relatively young (~ 60 years), in contrast with the pathologies covered by Note 66, which typically affect elderly people. Moreover, rheumatic and oncological diseases were poorly represented, thus it is possible that NSAIDs might have been prescribed for indications outside the note. These findings suggest that the use of NSAIDs for pain management in Italy should be optimized, properly weighting their risks and benefits.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03153-3.

Key Summary Points

This real-world analysis described the use of non-steroidal anti-inflammatory drugs (NSAIDs) in Italy from 2019 to 2022, with respect to the latest update of Note 66 released by the Italian Medicines Agency (AIFA) in 2028, indicating a list of the conditions under which NSAIDs are reimbursed by the Italian National Health Service.

During the 3-year period 2019–2022, over 2.8 million within a catchment area of 9.1 million Italian citizens received at least one prescription of NSAID, with a tendential increase over time in the proportion NSAID-treated patients (1.9–3.0%).

The patients with NSAIDs prescriptions were aged around 60 years, so younger than expected, considering that the pathologies mentioned in the note predominantly affect older people (over 75 years). In addition, rheumatic and oncological diseases were poorly represented, in 0.1–1.0% and 11.9%, respectively, of the patients prescribed with NSAIDs.

Taken together, these findings suggest a possible suboptimal appropriateness of NSAID prescription and the necessity to optimize pain management in Italy.

Introduction

Pain is a common symptom reported by patients in both medical and surgical settings [1, 2]. Given the multidimensional and subjective nature of pain, together with the large variability in response to medications, many prescribers are guided in their therapeutic choices essentially by pain severity scores [1]. The World Health Organization (WHO) has developed a pain ladder, conceived for patients with cancer, based on three steps where the degree of pain divided into (1) mild, (2) mild-to-moderate, and (3) moderate-to-severe, corresponds with the matching therapeutic recommendations.

Pain management involves a comprehensive approach, including pharmacological, non-pharmacological, and interventional therapies [4, 5]. In patients with mild pain, non-opioid drugs such as paracetamol, aspirin, or alternatively non-steroidal anti-inflammatory drugs (NSAIDs) are considered as adequate. In patients with moderately severe pain, if adequate relief is not achieved with non-opioids administered on a regular basis, codeine is suggested as an alternative weak opioid. In patients with severe pain, morphine is the drug of choice, with proper dose adjustment, although opioids are now used cautiously due to addiction concerns [3, 6].

However, it has been reported that, in more the half of the cases (52.6%), pain medications are administered with a possible prescription appropriateness [1, 7]. In particular, the possible misuse of NSAIDs, especially in the older and frail population [7], still represents an open issue in the assessment of potentially inappropriate prescribing, and suggests the need for the re-evaluation of pain management strategies. In this context, one point to be noted is that paracetamol, the analgesic of choice for tolerability and manageability, especially in patients with non-neoplastic pain, is less commonly utilized in Italy than in other European countries: the international comparison of the top 20 active ingredients revealed that paracetamol occupies the eighth rank in Italy, with respect to the first rank in Belgium, France, Portugal, Spain and Sweden, and the second rank in UK and the whole of Europe [8]. In addition, the increased use of NSAIDs might also be related to some cultural barriers for opioid drugs in Mediterranean countries [9, 10], together with a suboptimal awareness and insufficient patient education on the safety profile of NSAIDs [11]. In a nutshell, while NSAIDs offer significant benefits in pain and inflammation management, it is crucial to balance these advantages against the potential risks, in terms of possible cardiovascular, gastrointestinal, hepatic, and renal side effects. Healthcare providers should conduct thorough assessments to ensure the safe and effective use of NSAIDs, tailoring treatment plans to individual patient needs and risk profiles [12–14].

The use of NSAIDs to treat both acute and chronic pain has grown significantly over the last years in Italy. The OsMed report of the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) on the national drug utilization in 2022 revealed that approximately 16 out of 100 citizens received at least one prescription of NSAIDs, with higher exposure levels in females (18.1%) than in males (13.7%) [15]. Moreover, based on the epidemiology of certain clinical conditions such as arthritis and osteoarthritis, for which these drugs are used, consumption increases with age reaching the maximum value of defined daily dose (DDD) in the 75–84 age group, up to 53.3 DDD/1000 people in women and 37.6 DDD/1000 people in men [15]. These rising trends have been confirmed in the most recent OsMed report (released on November 12, 2024) which showed a delta increase between 2022 and 2023 of 2.8% for DDD of NSAIDs and 8% delta for the expenses per capita [16].

During the last decade, Italy emerged as the European country with the highest consumption of NSAIDs with a markedly larger proportion of pain symptoms controlled through the administration of an NSAID compared to other nations [17].

This poses the question of whether NSAIDs are prescribed without a proper assessment of the origin of the pain and of the actual need for an anti-inflammatory drug, also resulting in incorrect dosage and duration of treatment [18, 19]. According to the scientific literature and the indications of the regulatory authorities, the use of NSAIDs should be limited to the minimum effective dosage and the shortest possible time because of the cardiovascular, gastrointestinal, hepatic, and renal side effects that chronic use can induce [12–14].

An even more extensive utilization of NSAIDs was observed during the pandemic period, most probably due to the recommendations for use in the symptomatic treatment of patients with COVID-19 at home [20]. This trend has remained constant in the subsequent period, with a 7.1% increase of NSAID prescriptions in Italy during 2021 [5].

The prescription of NSAIDs covered by the Italian National Health Service (NHS) is limited to the list of pathologies defined in last update of the Note 66 released by AIFA in 2018, which includes arthropathy, osteoarthritis, neoplastic pain, and acute gout attack. The rationale of AIFA Note 66 is to ensure the appropriate use of NSAIDs, with the ultimate goal of encouraging clinicians to weigh the risks and benefits of these medications. This approach is meant to reduce unnecessary drug use, to ensure that NSAIDs are prescribed only when needed, and to minimize adverse health outcomes related to inappropriate use [22].

With the exception of the above-mentioned conditions, all the other indications included in the summary of product characteristics are not reimbursed by the NHS and therefore are paid by the patient (out-of-pocket).

This analysis was conducted in normal Italian clinical practice to describe the use of NSAIDs with respect to the latest update of the AIFA Note 66, focusing on the following objectives: (1) describing the main characteristics of patients treated with NSAIDs, namely age, sex distribution and conditions for which NSAIDs were prescribed; (2) assessing NSAID consumption in the period 2019–2023, in terms of main active ingredients prescribed, number of patients treated, and dosage (DDD/1000 inhabitants); and (3) defining the therapeutic pathways and drug utilization in patients treated with NSAIDs, with a focus on the most prescribed molecules, duration of treatment, sequence of treatments, combinations, and dosages.

Methods

Data Source

An observational retrospective analysis was carried out through data extrapolated from the administrative databases of a pool of Italian entities covering about 9.1 million health-assisted individuals. In detail, the following databases were used: beneficiaries’ database for data on patients' demographics; pharmaceutical database for data on medications reimbursed by the Italian NHS, including: the Anatomical-Therapeutic Chemical (ATC) code, and prescription date; hospitalization database, for information on discharge diagnoses at any level classified according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and date of diagnosis; and outpatient diagnostic tests and specialist visits database, for information on the type and date of delivered tests/procedures.

Ethical Approval

The dataset used consists solely of anonymized data. Approval has been obtained from the ethics committees of the participating healthcare entities, provided in Table S1 of the Supplementary Materials. authorization of the Ethics Committee “BAT (Barletta-Andria-Trani) Comitato etico interprovinciale Area I” (protocol number 68/CE/20, approval date 3/12/2020); authorization of the Ethics Committee “Berica Comitato Etico per le Sperimentazioni Cliniche (CESC) della Provincia di Vicenza” (protocol number 1627, approval date 28/10/2020); authorization of the Ethics Committee of Bergamo (protocol number 330, approval date 6/4/2023); authorization of the Ethics Committee “Brindisi Comitato Indipendente di Etica Medica” (protocol number 48148, approval date 28/05/2021); authorization of the “Regional Ethics Committee Liguria” (protocol number 797/2021, approval date 14/03/2022); authorization of the Ethics Committee “Frosinone Comitato Etico Lazio 2” (protocol number 0179046/2020, approval date 28/10/2020); authorization of the Ethics Committee “Napoli 3 Comitato Etico Interaziendale Campania Sud” (protocol number 51, approval date 02/09/2020); authorization of the Ethics Committee “Comitato Etico Palermo 1” (protocol number 02/2021, approval date 24/02/2021); authorization of the Ethics Committee “Pedemontana Comitato Etico per le Sperimentazioni Cliniche (CESC) della Provincia di Vicenza” (protocol number 0036999, approval date 28/04/2021); authorization of the Ethics Committee “Roma 3 Comitato Etico Lazio 2” (protocol number 0031200/2021, approval date 10/02/2021); authorization of the Ethics Committee “Roma 4 Comitato Etico Lazio 1” (protocol number 1079/CE Lazio 1, approval date 23/09/2020); authorization of the Ethics Committee “Roma 5 Comitato Etico Lazio 1” (protocol number 1166/CE Lazio 1, approval date 12/10/2020); authorization of the Ethics Committee “Roma 6 Comitato Etico Lazio 2” (protocol number 0216084/2020, approval date 16/12/2020); authorization of the Ethics Committee “Serenissima Comitato Etico per la Sperimentazione Clinica della provincia di Venezia e IRCCS S. Camillo” (28/07/2020); authorization of the Ethics Committee “Umbria 2 Comitato Etico Regionale Umbria” (protocol number 19414/20/ON, approval date 16/09/2020); authorization of the Ethics Committee “Vercelli Comitato Etico Interaziendale A.O. SS. Antonio e Biagio e Cesare Arrigo – Alessandria” (protocol number 0008668, approval date 20/04/2021).

Study Population and Design

From January 2019 to December 2023, the analysis included all the patients with at least one prescription for NSAIDs listed in the Note 66 (Table S2 of the Supplementary Materials). The index-date was the date of the first prescription of an NSAID; all the patients included were investigated in the year before the index-date (characterization period) and followed for at least 1 year after the index-date.

Patients’ Characteristics

For all patients included in the study, demographic characteristics, namely age and sex distribution, were collected at index-date. Patient’s clinical status was evaluated during the characterization period by the presence of drug prescriptions searched in the year preceding the index-date and the most frequent causes of hospitalization during the whole period of data availability before the index-date. The conditions for which NSAIDs are indicated by the Note 66 were investigated in the entire period before and after the index-date by means of the criteria used as diagnosis proxy listed below.

Rheumatic diseases. Rheumatoid arthritis (RA): identified by ICD-9-CM codes: 714.0 or exemption code: 006.714.0; ankylosing spondylitis (AS): identified by ICD-9-CM codes: 720.0, exemption code: 054.720.0; osteoarthritis: identified by ICD-9-CM codes: 715; acute gouty arthritis: identified by ICD-9-CM codes: 274.0.

Oncological diseases. At least one of the following conditions: exemption for neoplasm, identified by code 048 searched in the entire period before and after the index-date; diagnosis (principal or secondary) of malignant neoplasm, identified by ICD-9-CM codes: 140–209 searched throughout the period before and after the index-date; treatment with antineoplastic agents, identified by at least one prescription with ATC code L01 searched in the year preceding and the entire period following the index-date.

Renal disease. At least one of the following conditions: exemption for chronic renal insufficiency, identified by code 023 searched throughout the period preceding and following the index-date; diagnosis (principal or secondary) of chronic renal failure, identified by ICD-9-CM code: 585 searched throughout the period before and after the index-date.

Drug Utilization

Drug utilization was analyzed during the first year of follow-up on patients with at least 1 year of data availability after the index-date. Dosage was evaluated for the prescribed drug at the index-date. Combinations were determined by the presence of NSAIDs other than the one prescribed at the index-date and the main combinations found were then reported. The duration of index treatment was calculated as the sum of the days of treatment from the index-date (first prescription) to the date of the last prescription of the index-drug plus the coverage of the last prescription.

Statistical Analysis

A descriptive statistical analysis was conducted on continuous variables, reported as mean ± standard deviation (SD) and categorical variables expressed as numbers and percentages. According to "Opinion 05/2014 on Anonymization Techniques" drafted by the "European Commission Article 29 Working Party", the results of subgroups consisting of less than 3 patients were not disclosed, as potentially attributable to single individuals and reported as NI (not issuable). All the analyses have been performed using STATA SE version 17.0 (StataCorp, College Station, TX, USA).

Results

During the period of the analysis, 2019–2023, a total of 3,078,513 patients with at least one prescription of NSAIDs included in the Note 66 were identified. As shown in Table 1, there was a slight predominance of women (55.7%), and the mean age was 59.4 years. The largest majority of NSAIDs were aged 45–74 years, specifically 19.0% in the range 45–54 years and 21.7% in the range 55–64 years. NSAIDs were prescribed in the oncology setting in 12.1% of the cases, for rheumatic diseases in 4.9%, and for renal disease in 1.9%. The largest majority of the patients (99.0%) received one single active ingredient at index-date.

Table 1.

Main demographic and clinical characteristics of the patients with at least one prescription of NSAIDs included in the Note 66 between 2019 and 2023

	Patients with at least one prescription of NSAIDs (n = 3,078,513)
Male sex, n (%)	1,362,379 (44.3%)
Age (years), mean ± SD	59.4 ± 16.7
Age groups
Age < 15 years, n (%)	5337 (0.2%)
Age 15–44 years, n (%)	569,756 (18.5%)
Age 45–54 years, n (%)	585,672 (19.0%)
Age 55–64 years, n (%)	667,820 (21.7%)
Age 65–74 years, n (%)	641,425 (20.8%)
Age > 74 years, n (%)	608,503 (19.8%)
Rheumatic diseases	152,262 (4.9%)
Ankylosing spondylitis, n (%)	3762 (0.1%)
Rheumatoid arthritis, n (%)	29,169 (0.9%)
Acute gouty arthritis, n (%)	861 (0.0%)
Osteoarthritis, n (%)	121,818 (4.0%)
Oncological diseases, n (%)	373,322 (12.1%)
Renal disease, n (%)	58,561 (1.9%)
Number of active ingredients at index-date
1, n (%)	3,048,354 (99.0%)
> 1, n (%)	30,130 (1.0%)

NSAIDs non-steroidal anti-inflammatory drugs, SD standard deviation

The proportion of patients treated with NSAIDs during the study period ranged from 1.9% (April 2020) to 3.0% (January and May 2019) (Fig. 1A). The same analysis stratified by geographical area showed the largest consumption in South Italy, followed by central and with northern regions (Fig. 1B).

Fig. 1.

Trends of NSAID consumption during the study period (2019–2023) in A overall sample and B stratified by geographic area. NSAIDs non-steroidal anti-inflammatory drugs

During the observation period (2019–2023), the most widely prescribed active ingredients were diclofenac and ketoprofen, followed by ibuprofen, etoricoxib, and nimesulide; an increasing trend over time was observed regarding the use of ibuprofen (Fig. 2).

Fig. 2.

Most prescribed active ingredients per year from 2019 to 2023

In recent years, the consumption of NSAIDs increased from 15.5 to 16.8 DDD/1000 people, between 2020 and 2022, then declined to 15.1 DDD/1000 people in 2023 (Fig. 3A). In the population stratified by age classes (Fig. 3B), the highest consumption of NSAIDs was found in the patients aged 65–74 years, immediately followed by the group of over 75 years, larger than the half values of DDD/1000 people in the subjects between 45 and 64 years of age.

Fig. 3.

Yearly consumption of NSAIDs A in the overall sample, B by age classes, and C by geographic area. DDD defined daily dose, NSAIDs non-steroidal anti-inflammatory drugs

The same analysis by geographical area (Fig. 3C) confirmed that NSAID consumption was tendentially higher in southern regions, than in central and northern ones.

An analysis of NSAID drug utilization in terms of dosages, combinations, and duration of treatment was then performed. Among the most frequent NSAIDs, diclofenac, etoricoxib and ketoprofen were commonly prescribed at a low to medium dosage as recommended, while ibuprofen was used at high dosage (600 mg) in 81% of the cases (Table 2).

Table 2.

Dosages of the most frequently used NSAIDs; the most commonly prescribed dosages are highlighted in bold

Index-molecule	mg	No. of patients (%)
Diclofenac (n = 751,295)	25	22 (0.002%)
	50	80,616 (10.7%)
	75	365,420 (48.6%)
	100	83,370 (11.1%)
	150	213,267 (28.4%)
	100 mL–50 mg/mL	8600 (1.1%)
Etoricoxib (n = 359,929)	30	< 4
	60	219,439 (61.0%)
	90	128,710 (35.8%)
	120	11,778 (3.3%)
Ibuprofen (n = 477,328)	100	< 4
	125	< 4
	200	129 (0.02%)
	400	68,749 (12.7%)
	500	738 (0.1%)
	600	439,431 (81.0%)
	800	30,124 (6.1%)
	Oral suspensiona	110 (0.02%)
Ketoprofen (n = 574,302)	25	54 (0.01%)
	50	446,585 (77.8%)
	80	70 (0.01%)
	100	89,561 (15.6%)
	160	< 4
	200	34,280 (6.0%)
	320	3745 (0.7%)
	Dropsb	6 (0.001%)

^a150 mL 100 mg/5 mL, 100 mL 200 mg/5 mL, 120 mL 20 mg/mL

^b20 mL–25 mg/mL, 30 mL–80 mg/mL

As shown in Table 3, about 20% of the patients received at least one other NSAID in combination with the one prescribed at index-date during the first year of observation.

Table 3.

Combinations of NSAIDs during the first year of follow-up

Index-molecule	Patients with at least another NSAID in combination, n (%)	Most common combinations, n (%)
Diclofenac (n = 666,329)	128,253 (19.2%)	Ketoprofen, 43,181 (33.7%)
		Ibuprofen, 29,224 (22.8%)
		Etoricoxib, 27,759 (21.6%)
Etoricoxib (n = 319,152)	128,253 (20.7%)	Diclofenac, 24,871 (37.7%)
		Ketoprofen, 16,263 (24.6%)
		Ibuprofen, 13,551 (20.5%)
Ibuprofen (n = 452,930)	84,110 (18.6%)	Diclofenac, 33,051 (39.3%)
		Ketoprofen, 18,926 (22.5%)
		Etoricoxib, 15,887 (18.9%)
Ketoprofen (n = 525,808)	113,723 (21.6%)	Diclofenac, 50,886 (45.1%)
		Ibuprofen, ,693 (22.6%)
		Etoricoxib, 18,402 (16.2%)

NSAIDs non-steroidal anti-inflammatory drugs

Focusing once again only on the most commonly prescribed NSAIDs, the average duration of treatment in the first year of observation was about 2.4 and 3.7 months (Table 4).

Table 4.

Duration of treatment for the most commonly prescribed NSAIDs during the first year of observation

Index-molecule	Mean (± SD) duration of treatment in months
Diclofenac (n = 666,329)	2.4 (± 3.3)
Etoricoxib (n = 319,152)	2.9 (± 3.4)
Ibuprofen (n = 452,930)	2.9 (± 3.2)
Ketoprofen (n = 525,808)	3.7 (± 3.7)

NSAIDs non-steroidal anti-inflammatory drugs, SD standard deviation

Discussion

The management of pain represent a key component of patients’ care in all healthcare settings. However, several aspects might contribute to the inadequate treatment of pain and inappropriate prescribing behaviors [19].

This real-world analysis was focused on the utilization of NSAIDs to treat both acute and chronic pain in Italy, which is the European country with the highest consumption of NSAIDs [10]. There might be multiple underlying reasons behind these data. One possible explanation might the lower use of paracetamol in Italy compared to other European countries, although this analgesic is recommended in the non-oncological setting for tolerability and manageability [17]. Another reason might be the fear of opioid addiction, also due to the alarming opioid crisis in US and the issue of illegal drug trafficking. This scenario might have led to further underprescription of opioids in Italy and other countries of Southern Europe [10].

Consistent with the data of the OsMed reports, in the present analysis, the pattern of the most prescribed NSAIDs was fairly consistent with the latest OsMed report, which confirmed diclofenac as the molecule associated with the highest consumption and costs, followed by etoricoxib and ibuprofen [15, 16]. Moreover, the proportion of patients treated with NSAIDs showed a rising trend over time [15, 16]. The larger use in the southern regions compared to central and with northern regions should be contextualized considering the purely descriptive nature of the analysis. The variability of NSAIDs consumption alone cannot fully explain a higher or lower level of appropriateness, and this aspect prevents us from drawing firm conclusions on possible differences in prescriptive attitudes across the Italian geographical areas. When analyzing the DDD, the consumption of NSAIDs rose between 2020 and 2022, but dropped during 2023. Such a course might partly be explained by the effect of the COVID-19 pandemic, since NSAIDs were recommended for home-treatment of COVID-19 symptoms [20, 21].

The assessment of prescriptions is an essential process to evaluate the appropriateness of drug utilization and a crucial aspect for healthcare systems. In an effort is to best meet the care needs of patients through the appropriate use of drugs, the AIFA Notes were introduced in 1993 to define the therapeutic indications for which certain drugs are reimbursable by the NHS. They have become a regulatory tool aimed at ensuring their appropriate use, directing the prescribing activity of doctors on the basis of the best evidence of efficacy described in the literature. The process of revising and updating the Notes takes place on an ongoing basis according to the availability of new scientific evidence, making this regulatory instrument flexible in response to the needs of daily medical practice throughout the country. The changes are aimed at simpler and more direct management of the patient by the physician, at a better correspondence between indications of proven efficacy and those eligible for reimbursement by the NHS, and at the prevention of improper use [7].

The NSAIDs reimbursed by the Italian National NHS are limited to specific pathologies reported in the 2018 update of the AIFA Note 66, namely arthropathy, osteoarthritis, neoplastic pain, and acute gout attack [22]. In our analysis, the rate of prescription of NSAIDs in the presence of the conditions indicated by Note 66 was 12.1% in the oncology setting, 4.9% for pain related to rheumatic diseases, and 1.9% for renal disease, but the numbers might be underrated due to the use of diagnosis proxies (hospitalization codes, exemption codes, and drug prescriptions) to identify the pathologies in the administrative databases. Nevertheless, the epidemiology of the pathologies indicated in the Note, which are most frequently found in older patients, together to the relatively young population (about one-third of the patients aged < 54 years) suggest that NSAIDs were also prescribed for indications not covered by Note 66, and therefore not reimbursable.

Regarding the length of therapy, scientific evidence and guidelines recommend the use of NSAIDs at the most effective dose and for the shortest duration of time, which was defined as 10 days or fewer. In patients without contraindications, short-term therapy with NSAIDs is relatively safe [23, 24]. In our analysis, only a minority of patients received NSAIDs in the rheumatic, oncological, and renal setting, suggesting that most patients were treated for other conditions not mentioned in Note 66. Thus, the observed duration of therapy of about 3–4 months raises some concerns. It is known that, even when prescribed for the pathologies of Note 66, the risk and benefits of long-term treatment with NSAIDs should be carefully evaluated. In the oncology area, a Cochrane review highlighted the paucity of high-quality evidence for the use of NSAIDS for cancer pain. In particular, the review emphasized that, while retrospective data seem to suggest a contribution of NSAIDs to a improve pain control in hospitalized patients with cancer, in older subjects in the last weeks of life, the reduction in NSAID prescribing had no implications for pain relief [25]. In the rheumatology setting, a recent study on the long-term impact of NSAIDs on the progression of symptoms and structural deterioration of the joint in knee osteoarthritis, showed that compared to non-users, individuals using long-term NSAIDs had a significantly increased likelihood of experiencing severe complications, including pain, disability, and stiffness, alongside a higher requirement of total knee replacement [26]. In a nutshell, in the patients matching the indications of Note 66, continued use of NSAIDs should also be decided on a case by case basis, taking into account the patient's likely prognosis. The misuse or overuse of NSAIDs, as well as the duration of therapy, can pose serious health risks. Gastrointestinal complications, such as ulcers, bleeding, and perforation, are common, particularly with prolonged use of NSAIDs; moreover, the long-lasting coadministration of proton pump inhibitors to prevent these complications might expose the patients to additional adverse events (i.e., renal disorders, cardiovascular risks, fractures, infections) [12, 14, 27, 28]. NSAIDs have also been reported to increase cardiovascular risks, including heart attacks and strokes, especially in high doses or long-term use [29]. Renal impairment is another concern, as NSAIDs reduce renal blood flow, potentially causing acute kidney injury [30].

These results should be evaluated in the context of some limitations. First, its retrospective nature and of use of administrative databases that might lack some information, including the pain severity scores that might have potentially driven the therapeutic choices. Given that the databases are conceived to tack the economic flows from the NHS to the healthcare providers, only the reimbursable services or medications are traceable, and this might have led to an underestimation of certain diagnoses in the event of untreated or non-hospitalized patients. Moreover, the conditions mentioned in 2018 update of Note 66 are not traceable within the databases. Lastly, the findings of the current analysis derive from data of a subset of health-assisted individuals representing a sample of the Italian population, which limits the generalizability of our results on a larger scale.

Conclusion

The results emerged from this analysis conducted in real clinical practice in Italy showed an increasing trend in NSAID consumption between 2019 and 2023, with some differences across geographical areas, and to a greater extent in southern regions, in older subjects, and for the active ingredient ibuprofen, which was also used at high dosages in 81% of the patients. Moreover, notwithstanding the indications of Note 66, the analysis highlights some aspects to be improved in the use of NSAIDs for pain management. Firstly, the relatively young age of the patients prescribed with NSAIDs, in contrast to the type of pathologies covered by the Note, which are more common in elderly people, seem to indicate a probable inappropriate use of NSAIDs. In addition, the relatively small proportion of subjects with the diseases covered by the note (rheumatic, oncological), although potentially underestimated due to the use of administrative databases to identify the diagnoses, suggest that these drugs might have been prescribed in other pathological settings.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Conceptualization: Valentina Perrone, Maria Ciappetta, Domenico Lucatelli, Luca Degli Esposti; Methodology: Valentina Perrone, Chiara Veronesi; Formal analysis and investigation: Valentina Perrone, Chiara Veronesi, Andrea Cinti Luciani; Review and editing: Valentina Perrone; Supervision: Valentina Perrone, Maria Ciappetta, Domenico Lucatelli, Andrea Cinti Luciani, Luca Degli Esposti. All authors read and approved the final manuscript for publication.

Funding

Angelini Pharma funded the study report, Rapid Service and the Open Access Fee.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Maria Ciappetta and Domenico Lucatelli are employees of Angelini Pharma S.p.A, Italy. Valentina Perrone, Chiara Veronesi, Andrea Cinti Luciani, Luca Degli Esposti have no conflicts of interest.

Ethical Approval

Approval has been obtained from the following ethics committees of the involved: authorization of the Ethics Committee “BAT (Barletta-Andria-Trani) Comitato etico interprovinciale Area I” (protocol number 68/CE/20, approval date 3/12/2020); authorization of the Ethics Committee “Berica Comitato Etico per le Sperimentazioni Cliniche (CESC) della Provincia di Vicenza” (protocol number 1627, approval date 28/10/2020); authorization of the Ethics Committee of Bergamo (protocol number 330, approval date 6/4/2023); authorization of the Ethics Committee “Brindisi Comitato Indipendente di Etica Medica” (protocol number 48148, approval date 28/05/2021); authorization of the “Regional Ethics Committee Liguria” (protocol number 797/2021, approval date 14/03/2022); authorization of the Ethics Committee “Frosinone Comitato Etico Lazio 2” (protocol number 0179046/2020, approval date 28/10/2020); authorization of the Ethics Committee “Napoli 3 Comitato Etico Interaziendale Campania Sud” (protocol number 51, approval date 02/09/2020); authorization of the Ethics Committee “Comitato Etico Palermo 1” (protocol number 02/2021, approval date 24/02/2021); authorization of the Ethics Committee “Pedemontana Comitato Etico per le Sperimentazioni Cliniche (CESC) della Provincia di Vicenza” (protocol number 0036999, approval date 28/04/2021); authorization of the Ethics Committee “Roma 3 Comitato Etico Lazio 2” (protocol number 0031200/2021, approval date 10/02/2021); authorization of the Ethics Committee “Roma 4 Comitato Etico Lazio 1” (protocol number 1079/CE Lazio 1, approval date 23/09/2020); authorization of the Ethics Committee “Roma 5 Comitato Etico Lazio 1” (protocol number 1166/CE Lazio 1, approval date 12/10/2020); authorization of the Ethics Committee “Roma 6 Comitato Etico Lazio 2” (protocol number 0216084/2020, approval date 16/12/2020); authorization of the Ethics Committee “Serenissima Comitato Etico per la Sperimentazione Clinica della provincia di Venezia Comitato Etico per la Sperimentazione Clinica della provincia di Venezia (protocol number 05.08, approval date 08/10/2020); authorization of the Ethics Committee “Umbria 2 Comitato Etico Regionale Umbria” (protocol number 19414/20/ON, approval date 16/09/2020); authorization of the Ethics Committee “Vercelli Comitato Etico Interaziendale A.O. SS. Antonio e Biagio e Cesare Arrigo – Alessandria” (protocol number 0008668, approval date 20/04/2021).