Intravenous Opioid Dose Titration for Refractory Cancer Pain: A Comparative Analysis of Switching from Transdermal Fentanyl to Morphine or Methadone

Abstract

Introduction

Switching from transdermal fentanyl (TDF) to other opioids is clinically challenging because of the subcutaneous reservoir that delays drug elimination. This study compares the efficacy and safety of intravenous (IV) dose titration with morphine (MO) versus methadone (ME) as a “bridging” strategy to overcome this pharmacological lag.

Methods

In this secondary analysis of an observational cohort study, patients who required an opioid switching from TDF (≥ 50 µg/h) to IV morphine or IV methadone were selected. As per protocol of the original study, patients were titrated with IV boluses of MO (n = 17) or ME (n = 22) until analgesia was achieved, followed by continuous infusion and subsequent oral conversion. The primary outcome was clinical stabilization; secondary outcomes included the comparison of final oral morphine equivalents (OME).

Results

Both groups achieved analgesia rapidly. The median IV dose required for stabilization was 10 mg for MO and 15 mg for ME (p = 0.152). Methadone demonstrated a significant “opioid-sparing” effect, allowing stabilization with equianalgesic doses (OME) significantly lower than those used in the morphine group and compared to baseline TDF.

Conclusion

IV opioid dose titration is a safe and effective method for managing TDF switching effectively eliminating the “waiting period” associated with patch removal. While both drugs are effective, methadone stands out for its ability to significantly lower the total daily opioid requirement.

Key Summary Points

Why carry out this study?

Opioid switching from transdermal fentanyl (TDF) is frequently required in patients with refractory cancer pain, but the subcutaneous drug depot causes a pharmacological lag that delays effective rotation and prolongs patient suffering.

Traditional rotation strategies (e.g., the 3-day switch) impose a hazardous waiting period; it was unclear whether an aggressive, bedside-monitored intravenous (IV) titration protocol could safely eliminate this lag when switching from TDF to morphine or methadone.

What was learned from the study?

Both IV morphine and IV methadone titration achieved rapid analgesia and a significant improvement in the Maddalena Opioid Switching Score (MOSS), with methadone associated with a highly significant 44.4% median reduction in oral morphine equivalents (OME) from baseline.

IV dose titration is a practical, reproducible bridging strategy that can be adopted in acute palliative care units to shorten the time to pain stabilization during TDF rotation; methadone in particular may offer a meaningful opioid-sparing benefit that warrants confirmation in larger, randomized studies.

Introduction

Cancer pain is the primary reason for referral to palliative care [1]. Opioid agonists remain the preferred treatment for cancer-related pain [2], with the majority of patients experiencing significant relief within 14 days if they can tolerate the prescribed dose [3]. Despite these established protocols, there is no single opioid of choice as first-line therapy [4]. The response to an initially administered opioid may be suboptimal in a subset of patients as a result of intolerable adverse effects, poor analgesic response, or an unfavorable balance between the two [5].

Major clinical challenges arising from these limitations may be mitigated by opioid switching (OS), a strategy where one opioid is substituted for another to improve the therapeutic index. There is a growing body of literature documenting the effects of OS on pain and other patient-related outcomes, as well as the development of equianalgesic dosing conversions to help clinicians determine an appropriate starting dose once a new agent is selected [6,7]. Various OS modalities have been reported, ranging from more aggressive to more conservative approaches depending on the clinical setting [8,9].

However, for patients hospitalized with severe pain intensity and high levels of distress, the time required to achieve a positive response is of paramount importance. Most existing studies have not focused on this temporal aspect, often reporting outcomes at an indefinite time of dose stabilization based on subjective evaluations. Moreover, calculating the dose of the second opioid can be particularly complicated in difficult clinical contexts [10]. Traditional “stop and go” strategies, 3-day transition methods, or “as-needed” dosing using ratios calculated on a variable percentage of the previous opioid dose have been invariably reported in the literature. Yet, these methods present evident limitations due to the lack of a pragmatic, standardized approach applicable to daily clinical settings [8, 11–16]. Indeed, in most cases, the truly effective dose is the result of an individual response based on numerous, often unpredictable factors.

In recent years, intravenous (IV) opioid dose titration has been introduced to expedite the achievement of optimal analgesia with the best analgesia/adverse effect ratio, while simultaneously testing the effectiveness of the intervention. The rationale for IV titration is rooted in the concept of minimum effective concentration, where a sufficient loading dose of opioid must be administered before starting a continuous infusion to reach steady-state more rapidly [14, 17–19].

Finding the effective dose through titration may allow clinicians to foresee the subsequent daily dose necessary to maintain effective plasma concentrations without referring to complex, and often inaccurate, conversion ratios—particularly when using methadone for OS. A preliminary observation reported that switching to IV methadone and titrating the doses could be considered a viable option for patients who failed a previous dose titration with IV morphine [20]. Furthermore, retrospective analyses have shown that IV methadone titration followed by IV infusion allowed for rapid pain control within minutes, facilitating successful conversion to the oral route and home discharge [21].

The objective of this secondary analysis of this observational cohort study was to investigate an IV opioid dose titration protocol for OS, based on the principle of individualizing the dose of the second opioid according to the specific clinical response of each patient.

Methods

This is a planned secondary analysis of a non-randomized cohort study of a consecutive number of patients admitted to an acute palliative care unit (APCU) for uncontrolled pain and/or opioid-induced adverse effects. Patients were recruited over a 2-year period (2014–2015). Inclusion criteria were patients with advanced cancer who required an OS because of an unfavorable pain/adverse effect balance or uncontrolled pain of severe intensity (7/10 on a numerical scale). Exclusion criteria were cognitive failure not due to opioids, language barriers, and an expected survival of less than 2 weeks. Patients who were re-titrated with the same drug, those switched to oral drugs, or those who did not receive an IV titration dose process were also excluded. This study was conducted in accordance with the Declaration of Helsinki (1964) and its later amendments. The original clinical protocol under which these patients were treated and prospectively followed (2014–2015) was conducted as part of routine departmental practice; the present secondary analysis of the anonymized dataset was specifically reviewed and approved by the Ethics Committee of Palermo (Comitato Etico Provinciale di Palermo 1, Verbale n. 14, 06/06/2024). Written informed consent to participate in the original clinical protocol, and for the subsequent use of anonymized data for research and publication purposes, was obtained from all participants prior to their inclusion. No identifiable personal information is included in this article; therefore, separate consent to publish was not required.

Patients’ Assessment

The baseline TDF dose (inclusion threshold ≥ 50 µg/h) was 75 µg/h (IQR 50–125) in the morphine group and 100 µg/h (IQR 50–125) in the methadone group; no significant between-group difference in baseline TDF dose was observed, consistent with the comparable baseline OME reported in Table 1.

Table 1.

Demographic and clinical characteristics of two patient groups switched to morphine or methadone

Variable	Morphine	Methadone	p
Gender N° (%)			0.461
M/F	5 (33.3%)/9 (66.7%)	11 (55%)/9 (45%)
Age (years)	67.5 (62.2–76)	63 (54.5–71)	0.326
Karnofsky	50 (47.5–50)	50 (40–50)	0.889
Anticancer treatments N° (%)			0.772
On	6 (42.8%)	10 (50.0%)
Off	3 (21.4%)	4 (20.0%)
Uncertain	5 (35.7%)	5 (25.0%)
Follow-up	0 (0%)	1 (5.0%)
Reason to switch N° (%)			0.667
Pain	12 (85.7%)	16 (80.0%)
Pain and adverse effects	2(14.3%)	4 (20.0%)
Mean dose for IV dose titration
Median (IQR)	10 (6.5–15)	15 (10–19)	0.152
Pain intensity 15 min after titration, median (IQR)	5 (5–5)	5 (4–5.5)	0.389
Basal OME (mg/day)	180 (120–300)	240 (120–290)	0.795

Demographics and clinical characteristics in Table 1 reflect the cohort of patients who successfully completed the initial titration and stabilization phase (N = 34). Initial recruitment included 39 patients (17 in the morphine group and 22 in the methadone group); reasons for early attrition prior to complete baseline analysis details (1 death in the morphine group and 4 titration failures) are fully detailed in the CONSORT flow diagram (Fig. 1)

IQR interquartile range, OME oral morphine equivalent

^aIntergroup difference

Epidemiologic data, Karnofsky status, and anticancer treatment status (classified as “on therapy”, “off therapy”, or “uncertain”) were recorded. Information regarding patient characteristics, pain scores on the Edmonton Symptom Assessment Scale (ESAS), Memorial Delirium Assessment Scale (MDAS), and opioid routes and doses expressed as OME were collected. The ESAS is a tool widely used to assess the most common physical and psychological symptoms (numerical scale rated 0–10) [22]. The MDAS is a validated tool used to measure the severity of delirium [23]. The Maddalena Opioid Switching Score (MOSS) was calculated from pain intensity, advance effects intensity, and MDAS. This integrated score turned out to be a sensitive instrument for measuring the clinical improvement produced by OS, such as in patients with cancer pain [24]. Data were recorded at admission (T0), 24 h later (T1), 48 h later (T2), 72 h later (T3), and after 1 week of comprehensive palliative care (T7). Pain intensity was also measured 15 min after the boluses of IV opioid dose titration used for OS.

Procedures

OS was defined as a switch from one opioid to another in patients with an unfavorable response to a previous opioid due to poor pain control, adverse effects, or both. The reasons for OS were recorded. This was a pragmatic study reflecting daily activity; therefore, treatment allocation was based on clinical judgment to maintain a flexible protocol in the patients’ best interest. The choice of opioid for OS was made by the attending physician.

IV opioid dose titration was used according to local department policies. After the initial assessment, consecutive IV boluses of 2–10 mg were administered, depending on the previous level of opioid tolerance (previous OME). Strict bedside monitoring of clinical signs of pain relief guided the administration of further boluses at 2–5 min intervals. Titration was stopped when the patient reported meaningful analgesia. The effective dose, measured as a meaningful reduction of pain intensity, was multiplied by 6 in patients switched to IV morphine (IV MO) [25,26], by 3 in patients switched to IV methadone (IV ME) [21], and by 12 in patients switched to IV fentanyl (IV-FE) [27]. The calculated daily dose was then prescribed as a continuous IV infusion. A dose of 15–20% was used for breakthrough pain episodes. For example, an effective total dose of 10 mg of IV ME corresponded to an IV infusion of 30 mg/day, while 10 mg of IV MO corresponded to 60 mg/day. Infusion rates were adjusted according to clinical needs, with frequent reassessment. The calculated daily dose was then prescribed as a continuous IV infusion. A rescue dose equivalent to 15–20% of the daily infusion was used for breakthrough pain episodes. For instance, an effective titration dose of 10 mg of IV methadone (MET) corresponded to a daily IV infusion of 30 mg/day, whereas an effective dose of 10 mg of IV morphine (MO) corresponded to an infusion of 60 mg/day. The IV infusion rate was adjusted according to clinical needs in the subsequent hours. Finally, careful observation and frequent reassessments were provided during the following days. During the initial 12–24 h after patch removal, when residual fentanyl release from the subcutaneous depot could still contribute to analgesia, patients were monitored at the bedside at least every 2–4 h; if pain recurred or breakthrough analgesic requirements exceeded the pre-set 15–20% threshold, the continuous infusion rate was increased in increments of approximately 20–30%, with a further re-titration bolus considered in case of a pain crisis. This close monitoring window allowed the infusion rate to be progressively adjusted as the fentanyl depot was cleared, rather than being fixed at the initial calculated dose.

Once stabilized (adequate analgesia with ≤ 3 breakthrough pain episodes and acceptable adverse effects), the IV dose was converted to a non-parenteral route using an initial ratio of 1:1.2 for methadone and 1:3 for morphine. For TDF, a similar dose was used initially. Final doses and routes were recorded at T7. For instance, once a stable daily IV dose of 30 mg/day was achieved, the corresponding oral methadone dose was calculated at 36 mg/day (applying the 1:1.2 ratio). In the case of morphine, the daily infusion dose was multiplied by 3 to determine the oral equivalent, based on a 1:3 IV-to-oral ratio [15, 25,26, 28,29]. For fentanyl, an equivalent initial dose was administered transdermally. Subsequently, patients could be switched to equianalgesic transdermal doses of other opioids, such as buprenorphine, for clinical convenience. Thereafter, oral opioid doses were adjusted according to the clinical evolution to meet individual patient needs, aiming to achieve the optimal balance between pain relief and opioid-related symptoms. The final opioid dose and route of administration were recorded at T7.

As summarized in Table 2, clinical stabilization was achieved progressively over the 7-day observation period in both groups: pain intensity and MOSS scores decreased significantly from T0 to T1 (within the first 24 h) and continued to improve through T7 (MOSS p < 0.0005 for both sequences), while the opioid-sparing effect in the methadone group became statistically significant from T3 onward (p = 0.002), indicating that meaningful clinical stabilization was generally attained within the first 24–48 h, with further optimization of opioid dosing occurring over the subsequent days.

Table 2.

Longitudinal variations of clinical variables and opioid doses over time

Variable	T0 Mo	T0 Met	T0 p	T1 Mo	T1 Met	T1 p	T2 Mo	T2 Met	T2 p	T3 Mo	T3 Met	T3 p	T7 Mo	T7 Met	T7 p	P intragroup Mo/Me	Post hoc
OME	180 (112–195)	270 (145–320)	0.09	127 (64–202)	180 (114–260)	0.15	120 (82–220)	180 (127–237)	0.24	120 (60–161)	165 (112–225)	0.11	105 (43–125)	150 (87–232)	0.12	0.39/0.002	T0 vs T3, T7
MDAS	2.5 (2–4)	3 (1.5–5)	0.88	3.5 (2–4)	5 (3–5.5)	0.27	4 (2.7–5.2)	5 (1.5–6)	0.69	4 (2–5.2)	5 (1.5–5.5)	0.54	4 (2.7–5)	5 (1.5–5.5)	0.54	0.32/0.97	–
MOSS	22 (16–26)	24 (15–26)	0.74	17 (12–21)	18 (12–21)	0.85	14 (10–18)	13 (9–17)	0.78	11 (7–15)	11 (6.5–15)	0.91	8 (5–12)	7 (4–11)	0.66	< 0.0005/ < 0.0005	T0 vs all epochs
Pain (median)a	10 (9–10)	8 (7–9.5)	0.024	6 (5–7)	6 (5–7)	0.94	5 (4–6)	5 (4–6)	0.97	4 (3.5–5.2)	4 (3–5)	0.67	3 (2–4)	3 (2–4)	0.95	< 0.0005/0.21	Mo: T0 vs all epochs

Data are presented as median (IQR)

OME oral morphine equivalents, MDAS Memorial Delirium Assessment Scale, Met methadone, Mo morphine, MOSS Maddalena Opioid Switching Score

^aPain values are presented clearly as median to reflect the non-parametric nature of the statistical analysis, addressing the mismatch with previous text versions

Expert physicians provided comprehensive pain and symptom management, and all patients were strictly monitored by a multidisciplinary team of doctors and nurses. No patient received anticancer therapy during the study period. A successful OS was defined on the basis of clinical judgment, typically indicated by a clear improvement in the balance between pain intensity and adverse effects. Following a pragmatic approach, patients could discontinue the treatment to undergo a further OS if necessary. In cases of poor response, alternative treatments were considered. Study reporting followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational studies.

Statistics

Statistical analysis of quantitative and qualitative data, including descriptive statistics, was performed for all items. Continuous variables were assessed for normality using the Shapiro–Wilk test within each patient group. Since most variables were not normally distributed, continuous data are presented as median and interquartile range (IQR). Between-group comparisons were performed using the Mann–Whitney U test. Categorical variables, when present, were compared using the chi-square test or Fisher’s exact test, as appropriate. For intragroup longitudinal analysis across repeated time points, the Friedman test was used for non-parametric repeated measures. When the Friedman test showed statistical significance, post hoc pairwise comparisons were performed using Wilcoxon’s test with Bonferroni correction for multiple comparisons. Data were analyzed by IBM SPSS Software 24 version (IBM Corp., Armonk, NY, USA). All p values were two-sided and p ≤ 0.05 was considered statistically significant.

Results

Of 1100 admitted to APCU during the period taken into consideration, 123 patients underwent IV dose titration: 35 were re-titrated with the same opioid and excluded. Ninety-one OS were performed in 88 patients in the period taken into consideration. Five patients died as a result of rapid deterioration, and nine failed OS based on physician’s judgement of an unfavorable analgesia/adverse effect balance. One of these patients, who had been switched from oral methadone to IV fentanyl, subsequently underwent intrathecal therapy. Complete data for the 74 subjects who completed the 7-day observation period were recorded (see CONSORT flow diagram in Fig. 1).

Fig. 1.

CONSORT-style flow diagram of patient selection for the transdermal fentanyl (TDF)-to-morphine/methadone switching sub-analysis. Of the 39 patients who underwent intravenous dose titration during opioid switching from TDF (22 to methadone, 17 to morphine), 5 were excluded from the analysis (1 death in a patient switched to morphine; 4 failed opioid switching, 2 in each arm), leaving 34 patients (20 methadone, 14 morphine) whose data are presented in Tables 1 and 2. Of these 34 patients, 3 were subsequently switched to transdermal buprenorphine for clinical convenience during follow-up (2 originally from the morphine arm, 1 from the methadone arm), as noted in the figure

Thirty-four OS procedures from TDF to either morphine or methadone were analyzed. Epidemiological characteristics are shown in Table 1. No significant differences were found between the two groups regarding age (p = 0.326), Karnofsky status (p = 0.889), or basal OME (p = 0.795), ensuring a fair starting point for comparison.

Pain Intensity

Both groups achieved analgesia quickly. The median IV dose needed to stabilize patients was 10 mg for morphine and 15 mg for methadone (p = 0.152).

The morphine group showed a highly significant reduction in pain from T0 to T7 (p < 0.0005). In the methadone group, the mean pain score dropped from 8 to 3, though the statistical significant within this specific subgroup was lower (p = 0.21), likely as a result of the smaller sample size (Table 2).

MOSS

MOSS improved significantly in both groups (p < 0.0005), confirming the success of the switch in balancing analgesia and adverse effects. Both sequences (TDF to morphine, TDF to methadone) led to a significant improvement in overall symptom burden.

OME Reduction

In the methadone group, the median OME dropped from 270 mg (T0) to 150 mg (T7), a median reduction of 120 mg (44.4%). This reduction was highly significant over time (p = 0.002), with post hoc analysis confirming significance at T3 and T7. In the morphine group the median OME dropped from 180 mg (T0) to 105 mg (T7), a reduction of 75 mg (41.6%), but this did not reach statistical significance (p = 0.39). At the individual patient level, the magnitude of OME reduction from baseline was variable, as reflected by the interquartile ranges reported in Table 2; nonetheless, the majority of patients in the methadone group showed a consistent downward trend in daily opioid requirement across all time points, supporting a genuine opioid-sparing effect rather than one driven by a small number of outliers.

Discussion

This pragmatic clinical study compared two different switching sequences in patients for whom TDF therapy had failed, addressing a significant gap in the current literature. The results of this sub-analysis highlight the clinical effectiveness of using IV opioid titration as a pharmacological “bridge” during the transition from TDF to either morphine or methadone. A key observation lies in the distinct behavior of the two groups regarding their daily medication requirements: patients switched to methadone experienced a substantial reduction in their total OME by the end of the first week. In contrast, while the morphine group also showed a decrease in dosage, this reduction was less pronounced and exhibited greater intersubject variability. Despite these diverging dosing trends, both strategies were equally successful in stabilizing pain levels and improving the overall symptomatic burden shortly after the switch.

Switching from TDF is widely considered a clinical challenge because of the drug’s persistent release from the subcutaneous depot even after patch removal, which can complicate the introduction of a second opioid. Literature on TDF switching is often limited by protocols requiring long stabilization periods—up to 72 h—due to the slow elimination kinetics of the drug. In some instances, previous studies reported initiating oral methadone 8–24 h after TDF withdrawal, with timing dependent on the patient’s prior doses (ranging from < 100 µg/h to > 300 µg/h). [18]. A rapid switching (“stop and go”) strategy using an initial fixed TDF-to-methadone ratio of 1:20 has been reported as an effective method to expedite the balance between analgesia and adverse effects in patients with cancer who had a poor response to previous opioids [14]. The IV dose titration approach departs from these traditional methods, such as the “3-day switch,” and aligns with more recent research [21] demonstrating that immediate analgesia can be achieved without waiting for a complete TDF washout. Our findings support the use of an aggressive IV titration protocol to overcome this “pharmacological lag.” The marked “opioid-sparing effect” observed in the methadone group is consistent with established literature regarding methadone’s unique pharmacodynamics. Unlike morphine, which acts as a pure mu-receptor agonist, methadone’s additional activity as an NMDA receptor antagonist allows it to manage pain more efficiently, often at a fraction of the expected equianalgesic dose [30]. This explains why the methadone group achieved similar analgesic success with a significantly lower overall chemical load, effectively resetting the opioid response in patients with tolerance or opioid-induced hyperalgesia [31]. This suggests that methadone may be more effective than morphine at resetting the opioid response in patients who have developed tolerance or hyperalgesia under TDF treatment. Alternatively, the trend toward a reducing methadone dose requirement over time may also be attributed to its accumulation due to complex pharmacokinetics [32]. On the other hand, genetic polymorphisms in CYP450 genes, along with factors such as age, sex, and concomitant treatments, contribute to the significant interindividual variability in methadone response [33]. The individualized dosing approach provided by IV titration may effectively mitigate these issues by tailoring the dose to the specific clinical response of each patient.

Limitations and Strengths

The present study has some limitations that warrant consideration. First, as a post hoc analysis, the sample size of the two cohorts selected by an observational study was relatively small, which may have limited the statistical power of some observations. Second, treatment allocation was based on clinician expertise rather than random assignment; therefore, it is possible that methadone was selectively chosen for patients with more complex pain profiles, potentially introducing selection bias. Finally, the study was conducted in a highly specialized APCU, where intensive monitoring facilitates rapid IV maneuvers that might be difficult to replicate in less specialized clinical settings.

Despite these limitations, this study possesses several significant strengths. First, its pragmatic design provides a realistic reflection of clinical practice within an APCU setting, thereby offering high ecological validity. Second, the implementation of a standardized IV dose titration protocol allowed for a direct and objective comparison between morphine and methadone, minimizing the confounding variables often associated with slower, less controlled oral rotations. Another major strength lies in the granularity of the data collected, particularly through the use of validated tools such as MOSS and ESAS. These instruments allowed us to capture not only the reduction in pain intensity but also the broader improvement in the patients’ global symptomatic burden and the clinical success of the switch itself. Finally, this work contributes to a relatively scarce body of literature specifically focused on TDF rotation, providing practical evidence for a strategy that significantly reduces the time required to achieve clinical stability in patients with refractory pain.

Conclusions

IV opioid dose titration is a safe and effective method for managing the transition from TDF to morphine or methadone. Both drugs are effective, but methadone stands out for its ability to significantly lower total daily opioid requirement. This protocol eliminates the “waiting period” typically associated with transdermal rotations, providing immediate relief for patients in pain crisis and also suggesting that methadone is a particularly efficient choice for those requiring high-dose TDF rotation.

Further large-scale randomized controlled trials (RCTs) are warranted to confirm if methadone should be prioritized over morphine as a second-line agent. Additionally, future research should explore the feasibility and safety of implementing this IV dose titration protocol in less specialized settings, such as home care or general oncology wards, to broaden its clinical impact.

Developing simplified guidelines for rapid switching could significantly broaden the clinical impact of this strategy, ensuring that a larger population of patients with cancer can benefit from timely and effective pain stabilization. Implementation of such protocols may reduce the burden of refractory pain and improve overall quality of life in advanced oncology settings.

Author Contributions

Sebastiano Mercadante: conceptualization, study supervision, writing—original draft. Yasmine Grassi and Flavia Sanzo: investigation and data curation. Giorgio Sapienza: investigation. Alessandra Casuccio: formal statistical analysis. Alessio Lo Cascio: data curation and writing—review and editing. All authors: writing—review and editing. All authors read and approved the final manuscript and meet the ICMJE authorship criteria.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

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

Declarations

Conflict of Interest

Yasmine Grassi, Alessio Lo Cascio, Giorgio Sapienza, Flavia Sanzo, and Alessandra Casuccio have nothing to disclose. Sebastiano Mercadante has nothing to disclose. Sebastiano Mercadante is an Editorial Board member of Pain and Therapy. Sebastiano Mercadante was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki (1964) and its later amendments. The original clinical protocol under which these patients were treated and prospectively followed (2014–2015) was conducted as part of routine departmental practice; the present secondary analysis of the anonymized dataset was specifically reviewed and approved by the Ethics Committee of Palermo (Comitato Etico Provinciale di Palermo 1, Verbale n. 14, 06/06/2024). Written informed consent to participate in the original clinical protocol, and for the subsequent use of anonymized data for research and publication purposes, was obtained from all participants prior to their inclusion. No identifiable personal information is included in this article; therefore, separate consent to publish was not required.