Abstract
In Japan, a low-dose transdermal fentanyl (TDF; 0.5 mg) has been approved to address pain in opioid-naïve patients with cancer; however, efficacy and safety data are lacking. To determine the efficacy and safety of TDF, patients with opioid-naïve cancer pain prescribed TDF (0.5 mg/d) and oral oxycodone sustained-release formulation (OXY) 10 mg/d were extracted from electronic medical and nursing records. Overall, 40 and 101 subjects were analyzed in the TDF and OXY groups, respectively. Compared with baseline (median [minimum, maximum]) values, changes in the Numerical Rating Scale (NRS) score on days 1, 3, and 7 post-administration were as follows: TDF (0 [−5, 4]) and OXY (−1.0 [−8, 3]); TDF (−1.5 [−6, 3]) and OXY (−2.0 [−8, 4]); and TDF (−2.0[−6, 3]) and OXY (−3.0[−8, 5]), respectively. No significant difference was observed between the groups on days 1 and 3; however, the change in the NRS on day 7 was significantly higher in the OXY group than that in the TDF group. Regarding adverse events, nausea occurred in 12.5 and 13.9% of patients in the TDF and OXY groups, respectively, while 12.5% of TDF- and 10.9% of OXY-treated patients experienced somnolence, revealing similar occurrence in both groups. However, constipation was more common in the OXY group (TDF: 50.0%, OXY: 71.3%). No serious adverse events (e.g., respiratory depression) were observed in either group. Low-dose TDF (0.5 mg), available only in Japan, showed comparable efficacy and safety to OXY (10 mg/d) and can be a first choice for opioid-naïve patients with cancer pain.
INTRODUCTION
Fentos® (transdermal fentanyl formulation, TDF), administered every 24 h, can be valuable in patients who experience difficulty taking oral formulations. The TDF is available in six dosage formulations, i.e., 0.5, 1, 2, 4, 6, and 8 mg, with only 0.5 mg TDF (estimated mean absorption 6.25 µg/h) indicated for opioid-naïve patients with cancer pain. With the TDF, the blood fentanyl concentration increases gradually after application, taking approximately 5 d to achieve a steady state. Therefore, in Japan, it is stipulated that the dose should not be increased for at least 2 d after the initial application. The ESMO2018 cancer pain guidelines recommend the use of the TDF in patients with chronic renal impairment (estimate glomerular filtration (eGFR) ≤ 30 mL/min)1); however, several serious side effects, including respiratory depression, have been reported.2–5) According to an analysis using the Japanese Adverse Drug Event Report database, fentanyl has more reported cases of respiratory depression than other opioid analgesics, including morphine and oxycodone.6) A phase III clinical trial was conducted to assess the TDF formulation (0.5 mg) in opioid-naïve patients with cancer pain, and its use in Japan became possible in 2020; however, this clinical trial was conducted in an uncontrolled manner. Moreover, there are no reports comparing the analgesic effects and adverse events of the TDF with those of oral opioid analgesics.
Accordingly, the purpose of the present study was to clarify the analgesic effect and adverse events of TDF 0.5 mg/d when compared with those of an oral oxycodone sustained-release formulation (OXY; 10 mg/d) in opioid-naïve patients with cancer pain.
PATIENTS AND METHODS
Study DesignThe present multicenter, open-label, active-control, retrospective study was primarily performed at Kameda General Hospital, and the Japanese Society for Pharmaceutical Palliative Care and Sciences publicly recruited and selected 12 facilities as joint research institutes. The clinical trial design was approved by the Clinical Research Review Board of Kameda General Hospital (Approval Number: 21-080, Chiba, Japan) and complied with the institutional code of ethics, as well as the Declaration of Helsinki.
SubjectsThe study subjects were opioid-naïve inpatients who were prescribed TDF (6.25 µg/h; 0.5 mg every 24 h) or OXY (5 mg orally twice daily) to manage cancer pain. Data of patients prescribed the above drugs between February 1, 2021 and January 31, 2022, were extracted from medical and nursing records. Patients with opioid-naïve cancer pain were defined as those who had not used tramadol, codeine, morphine, oxycodone, fentanyl, methadone, hydromorphone, tapentadol, or buprenorphine during the 30-d period prior to initiating the study drug. Exclusion criteria were any deviations from the study drug-approved dosage and administration, use of multiple opioid analgesics (excluding rescue medications), missing data on pain intensity, and under the age of 20. In addition, periods during which neither TDF nor OXY could be prescribed were excluded.
Research MethodsThe charts of patients who fulfilled the eligibility criteria were reviewed, and their medical and nursing records were closely evaluated. Within 24 h prior to study drug initiation, patient background (age, sex, weight, cancer type, presence or absence of metastasis, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)), blood laboratory data (eGFR, serum creatinine level (SCr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin level (T-Bil), serum albumin (Alb)), pain site, and pain intensity were extracted from the chart. If blood laboratory data within 24 h prior to study drug initiation were unavailable, the closest data within one week before initiation were used. In addition, on day 1 (approx. 24 h after the start), day 3 (48–72 h), and day 7 (144–168 h) after study drug initiation, the dosage of the around-the-clock opioid analgesics, use of rescue analgesics, pain intensity, concomitant medications (drugs other than opioid analgesics and medications to treat adverse events), nausea, vomiting, constipation, somnolence, number of breaths per minute, delirium, difficulty urinating, and urinary retention were investigated. Pain intensity was evaluated using the Numerical Rating Scale (NRS). If the visual analog scale (VAS) was used, the numerical value obtained after rounding up the decimal point was used as the NRS value; if the face scale (Wong–Baker’s facial pain rating scale) was used, the number listed under the facial expression was used as the NRS value (Supplementary Material 1). In addition, if pain intensity was assessed several times a day, the mean value was calculated, and the numerical value obtained after rounding up the decimal point was used as the NRS value.
OutcomesThe primary endpoint was the change in NRS score from baseline to that on days 1, 3, and 7 after study drug initiation. The exploratory endpoints were changes in NRS from baseline on days 1, 3, and 7 after study drug initiation for patients with a baseline NRS >3. The efficacy rate (NRS2 or less) was evaluated on days 1, 3, and 7 after study drug initiation. In addition, we analyzed factors affecting the TDF and OXY groups. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.07) daily for one week after study drug initiation.
Statistical AnalysisStatistical analyses were performed using EZR (Jichi Medical University Saitama Medical Center, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).8) Considering the patient backgrounds of the two groups, nominal variables were compared using Fisher’s exact test, and normal distribution of continuous variables was performed using the Shapiro–Wilk test, Mann–Whitney U test, or Student’s t-test. “NRS change from baseline on days 1, 3 and 7 after study drug initiation” and “NRS change from baseline on days 1, 3, and 7 after study drug initiation in patients with baseline NRS >3” were assessed using the Mann–Whitney U test. Fisher’s exact test was used to evaluate the “efficacy rate (NRS2 or less) on days 1, 3, and 7 after study drug initiation.” In addition, a multivariate logistic regression analysis was performed to identify factors influencing the two groups. The multicollinearity of independent variables confirmed that the variance inflation factor was ˂4. A p-value <0.05 was considered significant.
RESULTS
Patient CharacteristicsAt 12 hospitals, 96 opioid-naïve patients were prescribed TDF 0.5 mg/d and 224 were prescribed OXY (10 mg/d) to treat cancer pain. Patients who lacked data on pain assessment (TDF: 45 patients, OXY: 108 patients), those who died (TDF: 6 patients, OXY: 6 patients), had no pain improvement (TDF: 2 patients), experienced insufficient effects (TDF: 2 patients, OXY: 1 patient), had side effects (OXY 1 patient), fever (TDF: 1 patient), or those who had difficulty taking medication (OXY: 7 patients) were excluded. Subsequently, we included 40 patients in the TDF group and 101 in the OXY group for analysis (Table 1). There were no differences between the two groups in terms of age, sex, body weight, metastases, PS, or laboratory test values. However, baseline NRS values and concomitant analgesics significantly differed between the two groups. The OXY group had higher baseline NRS values and concomitant analgesic use than the TDF group.
Table 1. Baseline Demographics
| Transdermal fentanyl | CR oral oxycodone | p-Value |
|---|
| Percentage or mean ± S.D. or median [minimum, maximum](Number of patients) |
|---|
| Age | 70.7 ± 12.1 (40) | 69.3 ± 12.3 (101) | 0.633c) |
| Sex |
| Male | 70.0% (28) | 64.4% (65) | 0.561d) |
| Female | 30.0% (12) | 35.6% (36) | |
| BW (kg) | 52.6± 13.2 (40) | 56.1 ± 14.3 (97) | 0.090c) |
| Laboratory data |
| eGFR (mL/min/1.73 m2) | 62.0 ± 27.4 (39) | 73.1 ± 33.2 (99) | 0.066e) |
| SCr (mg/dL) | 1.1 ± 0.8 (39) | 1.0 ± 1.1 (99) | 0.078c) |
| AST (IU/L) | 41.5 ± 77.7 (39) | 43.9 ± 71.9 (99) | 0.833c) |
| ALT (IU/L) | 33.8 ± 76.2 (39) | 35.6 ± 49.8 (99) | 0.570c) |
| T-Bil (mg/dL) | 1.0 ± 0.9 (38) | 1.0 ± 1.9 (98) | 0.092c) |
| Alb (g/dL) | 2.9 ± 0.8 (37) | 3.1 ± 0.8 (98) | 0.144c) |
| PS 0–4 | 2 [0, 4] (38) | 2 [0, 4] (97) | 0.058c) |
| PS 0 | 7.5% (3) | 17.8% (18) | |
| PS 1 | 20.0% (8) | 24.8% (25) | |
| PS 2 | 27.5% (11) | 22.8% (23) | |
| PS 3 | 27.5% (11) | 26.7% (27) | |
| PS 4 | 12.5% (5) | 3.9% (4) | |
| Unknown | 5.0% (2) | 3.9% (4) | |
| Baseline NRS | 3 [0, 8] (40) | 5 [0, 10] (101) | 0.018c) |
| Baseline NRS (NRS > 3) | 6 [4, 8] (19) | 6 [4, 10] (66) | 0.390c) |
| Analgesic use (Yes) | 65.0% (26) | 83.2% (84) | 0.025d) |
| Metastasis (Yes) | 70.0% (28) | 82.2% (83) | 0.117d) |
| Primary cancer site |
| Lung | 2.5% (1) | 17.8% (18) | |
| Esophagus/stomach | 20.0% (8) | 9.9% (10) | |
| Head and neck | 12.5% (5) | 9.9% (10) | |
| Bowel | 12.5% (5) | 7.9% (8) | |
| Pancreas | 10.0% (4) | 8.9% (9) | |
| Lymphoid | 5.0% (2) | 7.9% (8) | |
| Billary tract | 7.5% (3) | 5.0% (5) | |
| Prostate | 0 | 7.9% (8) | |
| Othera) | 30.0% (12) | 24.8% (25) | |
| Anatomical pain siteb) |
| Abdomen | 55.0% (22) | 36.6% (37) | |
| Lower back | 17.5% (7) | 29.7% (30) | |
| Head and neck | 22.5% (9) | 10.9% (11) | |
| Breech | 2.5% (1) | 10.9% (11) | |
| Lower extremity | 5.0% (2) | 7.9% (8) | |
| Chest | 5.0% (2) | 4.0% (4) | |
| Upper extremity | 0 | 3.0% (3) | |
| Ear, vagina, esophagus, head | 0 | 4.0% (4) | |
S.D.; standard deviation, BW; body weight, eGFR; estimated glomerular filtration rate, SCr; serum creatinine, AST; aspartate aminotransferase, ALT; alanine aminotransferase, T-Bil; total bilirubin, Alb; serum albumin, PS; performance status, NRS; numerical rating scale, a) Kidney, Uterus, Liver, Breast, Bladder/Urinary Tract, Ovary/Fallopian Tube, Thyroid, Pleura, Soft Tissue, Cervix, Vulva/Vagina, Skin, Unknown Primary, Germ Cell Tumor, b) Multiple responses were possible, c) Mann–Whitney U-test, d) Fisher-test, e) Student t-test.
The change in the NRS score (median [minimum, maximum]) from baseline to that on days 1, 3, and 7 after study drug initiation was as follows: TDF group (0 [−5, 4]) and OXY group (−1.0 [−8, 3]) on day 1; TDF group −1.5 [−6, 3]) and OXY group (−2.0 [−8, 4]) on day 3; and TDF group (-2.0 [−6, 3]) and OXY group (−3.0 [−8, 5]) on day 7. No significant difference in the NRS score was observed between the two groups on days 1 and 3 after the study drug initiation. However, on day 7, the NRS score was significantly altered in the OXY group when compared with that of the TDF group (Fig. 1). Considering patients whose baseline NRS was >3, the change in the NRS score from baseline to that recorded on days 1, 3, and 7 after study drug initiation was as follows: TDF group (−1.0 [−5, 1]) and OXY group (−1.5 [−8, 2]) on day 1, TDF group (−3.0 [−6, 1]) and OXY group (−3.0 [−8, 4]) on day 3; and TDF group (−3.0 [−6, 2]) and OXY group (−4.0 [−8, 2]) on day 7; there were no significant differences between the two groups (Fig. 2). In addition, the analgesic efficacy rate (NRS2 or less) after study drug initiation was 37.5% for the TDF group and 31.7% for the OXY group on day 1; 31.7% for the TDF group and 50.0% for the OXY group on day 3; and 49.5% for the TDF group and 60.0% for the OXY group 65.3% on day 7; there were no significant differences between the two groups (p = 0.56, p = 1.00, and p = 0.57, respectively). On days 1, 3, and 7 after study drug initiation, the percentage of patients using rescue and adjuvant analgesics was significantly lower in the TDF group than that in the OXY group (Table 2).
Table 2. Time Course of Treatment from Baseline to Day 7
| Transdermal fentanyl (n = 40) | CR oral oxycodone (n = 101) |
|---|
| Base line | Day 1 | Day 3 | Day 7 | Base line | Day 1 | Day 3 | Day 7 |
|---|
| Dosage (mg/d, mean ± S.D.) | none | 0.5 | 0.59 ± 0.36 | 0.71 ± 0.41 | none | 10 | 10.99 ± 2.83 | 13.56 ± 6.49 |
| Dosage (mg/d, median [minimum, maximum]) | none | 0.5 [0.5, 0.5] | 0.5 [0.5, 2.5] | 0.5 [0.5, 2.0] | none | 10 [10, 20] | 10 [10, 20] | 10 [10, 40] |
| Pain intensity (NRS, median [minimum, maximum]) | 3 [0, 8] | 3 [0, 8] | 2.5 [0, 6] | 2 [0, 7] | 5 [0, 10] | 3 [0, 10] | 3 [0, 10] | 2 [0, 7] |
| Pain intensity (NRS > 3, median [minimum, maximum]) | 6 [4, 8] (n = 19) | 4 [4, 8] (n = 16) | 4 [4, 6] (n = 11) | 5 [4, 7] (n = 8) | 6 [4, 10] (n = 66) | 5 [4, 10] (n = 47) | 5.5 [4, 10] (n = 30) | 5 [4, 7] (n = 19) |
| Percentage of adjuvant analgesic use |
| NSAIDs (%) | 15.0 | 17.5 | 17.5 | 22.5 | 41.6 | 41.6 | 43.6 | 43.6 |
| Acetaminophen (%) | 37.5 | 47.5 | 42.5 | 47.5 | 44.6 | 50.5 | 48.5 | 48.5 |
| Othersa) (%) | 7.5 | 7.5 | 7.5 | 7.5 | 5.9 | 6.9 | 7.9 | 8.9 |
| Percentage of patients using rescue analgesics (%) | none | 27.5 | 35.0 | 40.0 | none | 46.5 | 53.5 | 40.6 |
| Percentage of patients with adverse events |
| Nausea (%) | none | 7.5 | 10.0 | 2.5 | none | 7.9 | 8.9 | 7.9 |
| Vomiting (%) | none | 0.0 | 0.0 | 0.0 | none | 1.0 | 1.0 | 1.0 |
| Constipation (%) | none | 40.0 | 45.0 | 45.0 | none | 46.5 | 58.4 | 62.4 |
| Somnolence (%) | none | 7.5 | 7.5 | 7.5 | none | 5.9 | 6.9 | 4.0 |
| Delirium (%) | none | 0.0 | 0.0 | 0.0 | none | 0.0 | 3.0 | 6.9 |
| Difficulty urinating (%) | none | 0.0 | 0.0 | 2.5 | none | 0.0 | 0.0 | 0.0 |
| Urinary retention (%) | none | 2.5 | 2.5 | 5.0 | none | 1.0 | 1.0 | 2.0 |
| Respiratory rate (times/minute, mean ± S.D.) | - | 16.8 ± 1.5 (n = 12) | 16.3 ± 1.2 (n = 12) | 16.9 ± 2.3 (n = 12) | - | 16.8 ± 1.4 (n = 52) | 16.7 ± 1.6 (n = 52) | 16.4 ± 1.2 (n = 51) |
| Medication for adverse events | | | | | none | | | |
| Laxative (%) | none | 37.5 | 35.5 | 42.5 | none | 63.4 | 72.3 | 76.2 |
| Antiemetic (%) | none | 15.0 | 12.5 | 12.5 | none | 45.5 | 45.5 | 42.6 |
a) Others; anticonvulsants, steroids, an extract from inflamed cutaneous tissue of rabbits inoculated with vaccinia virus.
Adverse events with an incidence of ≥10% during the study period included nausea, constipation, and somnolence (Fig. 3). The incidence of nausea in the TDF and OXY groups was 12.5 and 13.9%, respectively, whereas that of somnolence was 12.5 and 10.9%, thereby demonstrating the similar incidences between the two groups. Conversely, constipation occurred in 50.0 and 71.3% of patients in the TDF and OXY groups, respectively. Grade 3 urinary retention (1 case) was observed in the TDF group, and Grade 3 constipation (2 cases) was observed in the OXY group; however, all other adverse events were Grade 2 or lower. No patient experienced respiratory depression at <10 breaths/min. The use of laxatives and antiemetics for adverse events was higher in the OXY group than that in the TDF group on days 1, 3, and 7 after study drug initiation (Table 2).
Analysis of Factors Affecting GroupsAfter adjusting for baseline NRS and analgesic use, which showed significant differences (Table 1), factors influencing TDF and OXY groups were extracted by performing multivariate logistic regression analysis. Using “whether or not the dose of opioid analgesics was increased,” “whether or not rescue analgesics were used” and “whether or not additional other analgesics were used” as independent variables, the rate of use of rescue analgesics was 47.5 and 72.3% in the TDF and OXY groups, respectively, with a significantly higher use rate in OXY group (Table 3).
Table 3. Multivariate Logistic Regression Analysis of Factors That Affect between the Two Groups
| TDF (%, n = 40) | OXY (%, n = 101) | Odds ratio | 95%CI | p-Value |
|---|
| Increased dose of opioid analgesics (Yes) | 27.5 (n = 11) | 30.7 (n = 31) | 0.92 | 0.39–2.16 | 0.845 |
| Using rescue dose (Yes) | 47.5 (n = 19) | 72.3 (n = 73) | 2.52 | 1.14–5.56 | 0.022 |
| Additional concomitant use of other analgesics (Yes) | 12.5 (n = 5) | 5.1 (n = 5) | 0.34 | 0.05–2.24 | 0.260 |
※Adjusted for baseline NRS and baseline analgesic use. Rescue use explanatory variables were analyzed as the proportion of patients using rescue on either day 1, 3, or 7. CI, Confidence interval; TDF, transdermal fentanyl formulation; OXY, oral oxycodone sustained-release formulation.
DISCUSSION
Selecting opioids for cancer pain management should be determined after considering the pharmacokinetics, contraindications, and adverse events associated with each opioid analgesic.9) Fentanyl is considered to exert relatively few adverse gastrointestinal symptoms, such as constipation, owing to its limited action on intestinal peristalsis. However, fentanyl has been associated with a higher risk of respiratory depression than other opioid analgesics. Notably, TDF can be administered even when oral intake is obstructed, affording a unique advantage, although it requires approximately 5 d to achieve a steady state10); therefore, disadvantages such as insufficient efficacy in the early stages of administration and difficulty in dose adjustment need to be considered. Since 2020, 0.5 mg TDF has been available in Japan for patients with opioid-naïve cancer pain. However, concerns regarding the risk of respiratory depression and weak analgesic effects during the early stages of the administration persist. Moreover, comparative assessments with other opioid analgesics are lacking. Accordingly, the present study compared the analgesic effects and safety of TDF 0.5 mg/d and OXY (10 mg/d) in opioid-naïve patients with cancer pain.
Considering the primary endpoint, i.e., change in the NRS score from baseline, there were no significant differences between the two groups on days 1 and 3 of administration; however, the change in NRS score was significantly greater in the OXY group than that in the TDF score on day 7. Constipation was more frequent in the OXY group, with no differences in other adverse events observed between the two groups; respiratory depression did not occur in either group. Based on these findings, it can be suggested that the analgesic effect during early administration was equivalent between the TDF 0.5 mg/d and OXY (10 mg/d) groups. In addition, the TDF (0.5 mg) was considered safe for use in opioid-naïve patients with cancer-related pain, with a low risk of respiratory depression. Conversely, the baseline NRS score was significantly higher in the OXY group than that in the TDF group, suggesting that more patients in the OXY group experienced severe pain. Furthermore, the frequency of concomitant use of adjunctive analgesics such as NSAIDs was higher in the OXY group than in the TDF group. These may explain why the change in the NRS score on day 7 was greater in the OXY group than that in the TDF group. The use of rescue analgesics was also higher in the OXY group than in the TDF group. Multivariate logistic analysis revealed that rescue analgesic use was significantly higher in the OXY group than that in the TDF group, which may explain the greater change in the day 7 NRS score in the OXY group. Furthermore, in patients with a baseline NRS score of >3, the change in the NRS score did not significantly differ between the groups on days 1, 3, and 7. On evaluating the analgesic efficacy rate (NRS2 or less), we detected no significant difference between the two groups on days 1, 3, and 7 after the study drug initiation, with the score increasing gradually. Accordingly, these results suggest that TDF 0.5 mg/d and OXY (10 mg/d) are equally effective regardless of the number of days after administration. Yamaguchi et al.11) have conducted a phase III clinical trial assessing TDF 0.5 mg/d in opioid-naïve patients with cancer pain, reporting that the analgesic efficacy rate was 181 out of 208 (87.0%), which was higher than that observed in our study (60.0%); however, this discrepancy could be this attributed to nearly half of the patients (82 out of 181) increasing their dose to ≥1.0 mg TDF. In a retrospective observational study by Kang et al.12) assessing 96 opioid-naive patients with cancer pain, TDF 12.5 µg/h significantly decreased the NRS score (median value) from 6.0 before administration to 3.0 at follow-up. This indicates a transition similar to that observed in our study. However, the smaller rate of NRS reduction in our study was likely due to the smaller dose employed; Kang et al. used 12.5 µg/h, which was double the dose assessed in our study. Furthermore, in a prospective observational study by Koizumi et al.13) assessing 20 opioid-naive patients with cancer pain, treatment with OXY 10 mg/d resulted in VAS values of 47.7 ± 26.4 mm before administration, 28.8 ± 22.3 mm after 24 h, and 15.7 ± 16.6 mm after 7 d, decreasing significantly, thereby indicating a transition similar to that observed in our study.
Regarding safety, adverse events were predominantly Grade 2 or lower, except for one Grade 3 urinary retention event in the TDF group and two Grade 3 constipation event in the OXY group; there were no serious adverse events reported. Adverse events with an incidence of ≥10% included nausea, constipation, and somnolence. Nausea and somnolence showed similar incidence in both groups, but the incidence of constipation was higher in the OXY group than that in the TDF group. Given that several patients in the OXY group used laxatives, constipation should be carefully considered when using OXY. In addition, respiratory depression was not observed in either group, which could be attributed to the low frequency of adverse events and the small number of cases in the present study. Yamaguchi et al.11) have reported the occurrence of nausea, constipation, and somnolence in 13.9, 15.4, and 18.3% of patients, respectively; respiratory depression occurred in one patient after the TDF was increased to 4.0 mg. Kang et al.12) have reported the occurrence of nausea (38%), vomiting (22%), dizziness (22%), and constipation (9%) in patients treated with TDF 12.5 µg/h. The authors reported less constipation and more nausea and vomiting than that in the present study; this discrepancy could be because antiemetics are usually administered concurrently with opioid analgesics in Japan, in addition to the effect of dosage. Koizumi et al.13) treated patients with OXY 10 mg/d and reported adverse events such as nausea, drowsiness, and constipation in 28, 50, and 32% of patients, respectively. Koizumi et al. targeted Japanese subjects, documenting the frequent occurrence of constipation, as observed in the present study, which differs from the report by Kang et al. This difference could be attributed to racial differences, and Japanese patients need to be careful when controlling constipation.
The present study evaluated the efficacy and safety of TDF 0.5 mg/d and OXY (10 mg/d) in opioid-naive patients with cancer pain. The analgesic effects of both formulations were considered equivalent, and there were no serious adverse events such as respiratory depression. In addition, given that TDF induced fewer constipation-related adverse events than OXY, it was considered an option for patients with constipation. In this study, there were differences between the two groups in baseline NRS and use of concomitant analgesics in patient background. In addition, there were differences between the two groups in the use of rescue analgesics. Therefore, we performed a complementary multiple regression analysis using the TDF group (vs. OXC group), baseline NRS, use of concomitant analgesics, and use of rescue analgesics as explanatory variables, with NRS change as the objective variable, and found that baseline NRS and presence of rescue use had a significant effect on NRS change (Supplementary Material 2). This was a retrospective study, and the differences between groups are a limitation of this study. Above, the TDF formulation (0.5 mg), available only in Japan, is useful for opioid-naïve patients with cancer pain and may become a first-line opioid analgesic. To the best of our knowledge, our study is the first to compare low-dose TDF and OXY, and prospective comparative studies assessing TDF and OXY should be undertaken in the future.
Acknowledgments
This study was supported by members of the Japanese Society of Pharmaceutical Palliative Care and Sciences, Research Support Committee.
Conflict of Interest
The authors declare no conflict of interest.
Supplementary Materials
This article contains supplementary materials.
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