FormalPara Key Summary Points

Why carry out this study?

Tapentadol has analgesic effects comparable to those of conventional opioids and is associated with fewer side effects than other opioids.

The safety of tapentadol in the Japanese population and the characteristics of patients likely to discontinue this treatment owing to adverse events remain unclear.

In particular, there have been no nationwide studies on the safety of tapentadol.

What was learned from this study?

This study showed that 17.4% of patients discontinued tapentadol owing to adverse events, the most common of which were nausea and drowsiness.

Patients were most likely to discontinue tapentadol owing to adverse events when they were prescribed by a palliative care physician, switching to tapentadol due to side effects from previous opioids, and when they were not taking naldemedine.

Concomitant use of naldemedine may reduce the risk of tapentadol discontinuation owing to side effects.

Introduction

Cancer pain is associated with multiple factors and mechanisms. Pain is mainly classified into nociceptive and neuropathic pain. The prevalence of neuropathic pain has been estimated to be 19–39% among patients with cancer when mixed pain is included [1]. The mechanism of descending noradrenergic modulation may be an important component of neuropathic pain. Tapentadol (TAP) has a noradrenaline reuptake inhibitory effect in addition to a μ-receptor agonist effect and may be effective in neuropathic pain management. TAP is used for moderate to severe chronic pain management in some countries. However, in Japan, it is indicated for cancer pain. Previous randomized controlled trials have reported that the analgesic effect of TAP is comparable to that of oxycodone and morphine [2, 3].

Opioid treatment is associated with side effects that stem from the action of opioid and non-analgesic receptors. In clinical practice, the onset of intolerable side effects may lead to dose reduction, which may result in inadequate analgesic relief, triggering treatment discontinuation in approximately 30% of patients. Side effects of opioids include constipation, nausea, vomiting, dry mouth, and sedation, of which constipation is the most common and persistent symptom [4, 5]. Controlling these symptoms is essential to the clinical application of opioids. Laxatives and antiemetics are often used along with opioids to control side effects. In clinical trials, naldemedine has been shown to improve opioid-induced constipation in patients without and with cancer [6]. It is a direct μ-receptor antagonist, known in basic research to improve intestinal hypoperistalsis [7].

TAP undergoes a predominantly glucuronic acid reaction rather than being metabolized by cytochrome P450, which makes it unlikely to trigger drug–drug interactions. TAP also has minimal serotonin effect, resulting in a relatively low risk of a serotonin syndrome [8]. Moreover, the combination of µ-opioid receptor activation and noradrenaline reuptake inhibition reduces the risk of adverse effects and improves TAP tolerability [9,10,11,12,13,14]. Previous studies have shown that TAP may cause fewer adverse events, such as constipation, nausea and vomiting, and drowsiness and dizziness, than other opioids [3, 15,16,17,18,19]. In fact, there is inadequate information on the side effects of TAP that could make its intake difficult for patients. The present study aimed to investigate the real-world safety of TAP treatment and the characteristics of patients likely to discontinue this treatment owing to adverse events.

Methods

This clinical study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the local ethics committees at nine institutions: Yokohama City University Hospital (B191200005 dated December 20, 2019), National Cancer Centre Hospital (2019-330 dated April 9, 2020), National Cancer Centre Hospital East (2019-330 dated April 9, 2020), Cancer Institute Hospital of Japanese Foundation for Cancer Research (2019-1247 dated April 6, 2020), Tohoku University Hospital (2019-1-978 dated March 23, 2020), Yamagata Prefectural Central Hospital (133 dated January 8, 2020), University of Yamanashi Hospital (2214 dated April 1, 2020), Yokohama Minami Kyousai Hospital (1-19-12-11 dated January 15, 2020), and Toranomon Hospital (2133 dated December 16, 2020). The study was registered as UMIN 000044282 (University Hospital Medical Information Network).

Participants

We enrolled patients with carcinoma who started taking TAP between August 18, 2014, the date of its launch in Japan, and October 31, 2019. Eligible patients were identified at nine institutions (Yokohama City University Hospital, National Cancer Centre Hospital, National Cancer Centre Hospital East, Cancer Institute Hospital of JFCR, Tohoku University Hospital, Yamagata Prefectural Central Hospital, University of Yamanashi Hospital, Yokohama Minami Kyousai Hospital, and Toranomon Hospital). All patients who took TAP during the study period were included, but patients who met the exclusion criteria described below or who did not wish to participate in the study were excluded. The exclusion criteria included patients whose date of starting TAP was not recorded and those who were unsuitable for the study on the basis of the judgment of the investigators. Data were extracted from electronic medical records, and the date of the first TAP prescription was defined as the study index date. Patients with an unknown date of TAP initiation were excluded.

Patients were eligible for this study regardless of age, sex, prescribing physician, or treatment setting (outpatient or inpatient).

Measurement and Evaluation Items

Data on age, sex, tumour site, comorbid treatment, survival time, TAP treatment setting and duration, concomitant medication, treatment dosage, pre-induction opioid use, type of rescue medication, reason for starting/stopping TAP, and outcomes were collected. In addition, data on the use of laxatives (such as naldemedine), antiemetics, and analgesic aids as concomitant medication were collected.

The primary outcome was the percentage of patients discontinuing TAP owing to adverse events. The secondary endpoints included the rates of TAP discontinuation owing to adverse events within 28 days of initiation, change in concomitant medication use, reason for TAP treatment initiation, treatment setting, duration of prescription, and incidence of adverse events.

Statistical Analysis

Continuous variables were expressed as median ± interquartile range (IQR). Patients’ characteristics were compared between a group that discontinued TAP owing to adverse events and one that continued to take TAP; comparisons were made with a two-sided chi-square test for categorical variables; p values of less than 0.05 were considered statistically significant.

Variables with p < 0.2 in the univariate analysis were included in the multivariate analysis using a logistic regression model, examining factors associated with discontinuation of TAP due to adverse events. Variables with a significance level of p < 0.05 in the multivariable model were retained. Analyses were performed using JMP 14.0 (SAS Institute Inc, Cary, North Carolina, USA).

Results

Demographic and Clinical Characteristics

Data from a total of 906 (48.8% women; median age, 64 years) patients who met the inclusion criteria were analysed. The patients’ demographic and clinical characteristics are presented in Table 1. Tumour sites were the head and neck (n = 36, 4.0%); gastrointestinal tract (n = 167, 18.4%); lung (n = 191, 21.1%); breast (n = 93, 10.3%); liver, biliary tract, or pancreas (n = 119, 13.1%); urologic tract (n = 62, 6.8%); female reproductive system (n = 83, 9.2%); haematologic tissue (n = 21, 2.3%); skin (n = 19, 2.1%), soft tissue (n = 60, 6.6%), and thyroid (n = 6, 0.7%). In addition, 463 (51.1%), 101 (11.1%), 225 (24.8%), and 117 (12.9%) patients were treated with chemotherapy, radiotherapy, palliative care only, and other therapies, respectively.

Table 1 Patients’ demographic and clinical characteristics (n = 906)
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Findings Before and After Tapentadol Use

At baseline, 277 (31.9%), 467 (53.9%), and 123 (14.2%) patients were opioid naïve, switched over from other opioids, and received TAP as an add-on treatment to other opioids, respectively. Among patients previously treated with opioids, the median oral morphine equivalent daily dose (OMEDD) before starting TAP was 40 mg/day. TAP was initiated in 259 (28.6%), 203 (22.4%), 33 (3.6%), and 411 (45.4%) palliative outpatients, general outpatients, inpatients in palliative beds, and inpatients in general beds, respectively. The median dose of TAP at initiation was 50 mg/day. TAP was prescribed to relieve nociceptive or neuropathic pain in 380 (42.0%) and 315 (34.8%) patients, respectively, and to manage side effects, such as nausea, constipation, drowsiness, and other side effects in 93 (10.3%), 21 (2.3%), 26 (2.9%), and 69 (7.6%) patients, respectively. Overall, 695 (83.2%) and 140 (16.8%) patients received TAP for pain and adverse event management, respectively (Table 2).

Table 2 Treatment setting, findings at baseline and after treatment with tapentadol (TAP)
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At baseline, 291 (32.6%) patients were opioid naïve. Meanwhile, 603 (67.4%) patients had used opioids before the initiation of TAP; among them, oxycodone was most used (n = 335, 37.5%). At baseline, tramadol, fentanyl, morphine, hydromorphone, and other opioids were used in 148 (16.6%), 53 (5.9%), 34 (3.8%), 12 (1.3%), and 21 (2.3%) patients, respectively. After treatment initiation, the median duration of TAP treatment was 28.5 days, including 451 (49.9%) and 452 (50.1%) patients that were prescribed TAP for at most 28 days and less than 29 days, respectively. While taking TAP, 715 (79%) patients were not taking concomitant opioids; in contrast, 191 (21%) patients were taking concomitant opioids, including oxycodone (n = 100, 11.0%), fentanyl (n = 33, 3.6%), morphine (n = 19, 2.1%), tramadol (n = 14, 1.5%), hydromorphone (n = 9, 1.0%), and other opioids (n = 16, 1.8%). The median daily dose of TAP during the prescription period was 200 mg/day; moreover, 797 (91%) patients took a TAP dose of less than 400 mg/day.

Reasons for Treatment Discontinuation

TAP was discontinued in 685 (75.6%) cases overall and in 119 (17.4%) cases owing to adverse events (Table 3). Among the cases, 153 (21.9%), 83 (12.1%), 8 (1.2%), 141 (20.6%), 90 (13.1%), 3 (0.4%), 30 (4.4%), and 23 (3.4%) cases of discontinuation were because of insufficient effect, pain relief, difficulty breathing, difficulty taking medication, hospital transfer, discharge home, death, and patient wishes, respectively. Among patients who discontinued TAP owing to adverse events, nausea, drowsiness, constipation, diarrhoea, delirium, cardiovascular symptoms, and other/unknown symptoms were reported in 32 (4.7%), 12 (1.8%), 1 (0.1%), 4 (0.6%), 8 (1.2%), 8 (1.2%), and 54 (44%) cases, respectively. A total of 311 (34.3%) patients discontinued TAP within 28 days of administration.

Table 3 Frequency and causes of tapentadol (TAP) discontinuation owing to adverse events (n = 906)
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Factors Associated with Treatment Discontinuation

Comparisons between the groups that did and did not discontinue treatment are presented in Table 4. The following variables were consistently associated with treatment discontinuation owing to adverse events: treatment with opioids at baseline (p = 0.038), use of TAP as a part of supportive care (p = 0.003), prescription received from a palliative care physician (p = 0.022), receiving at least two tablets per dose (p = 0.004), treatment with naldemedine (p < 0.0001), and side effects because of which TAP was prescribed (p = 0.04). Multivariate analysis showed that patients who were prescribed TAP by a palliative care physician (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.36–4.99, p = 0.004), those switching to TAP due to side effects from previous opioids (OR 2.19, 95% CI 1.05–4.56, p = 0.037), and those who did not use naldemedine (OR 5.06, 95% CI 2.47–10.37, p < 0.0001) were more likely than their counterparts to discontinue treatment owing to adverse events (Table 5).

Table 4 Factors likely to cause discontinuation of tapentadol in univariate analysis
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Table 5 Prediction models for the risk of discontinuation due to adverse events
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Discussion

In the present study, 17.4% of patients who were followed up until TAP cessation discontinued TAP owing to adverse events, of which the most common were nausea and drowsiness. There was only one case of discontinuation due to constipation, suggesting the safety of TAP for constipation.

In a retrospective, single-centre study of 84 patients, none of the patients had to discontinue TAP because of its side effects [20]. In another retrospective study on 38 patients, only one patient (2.6%) had an adverse event of grade 3 or higher [21]. Compared with previous reports, more patients discontinued medication because of side effects in the present study. It may be difficult to compare the present study with previous studies because of the differences in the institutions participating in this study, the study protocol, and the patients’ backgrounds.

Patients were most likely to discontinue TAP owing to adverse events when they were switching to TAP due to side effects from previous opioids, prescribed by a palliative care physician, and when they were not taking naldemedine. The switch to TAP due to side effects was found to be a risk factor for discontinuation of TAP. This may indicate that a certain number of patients are less tolerant not only to TAP but also to opioids in general.

In addition, palliative care physicians are effective at recognizing treatment-related adverse events and changing their approach to care, as required, which may have contributed to the rates of TAP discontinuation. Another factor is that patients who consult a palliative care physician may have more advanced cancer, poorer general health, and lower opioid tolerance despite having more severe pain.

The use of naldemedine was significantly associated with adverse event-related TAP discontinuation; however, discontinuation due to constipation was observed only in one case. Naldemedine may relieve gastrointestinal symptoms, such as nausea. A previous study has shown that naldemedine may help prevent opioid-induced nausea and vomiting in patients treated with morphine or oxycodone [22]. Whether a similar effect is observed in different contexts requires further research.

The size of a TAP tablet is 17 mm in length in all standards. A previous study reported that the most desirable tablet size for a frail older adult was 7–8 mm, given their capacity for swallowing and handling [23]. TAP comes in large tablets, which may be difficult to swallow. In addition, tablet size may have accounted for 20.6% of discontinuation cases in the present study, which were related to swallowing difficulties.

This study has several strengths. First, this study included a large sample. Second, three-quarters of participants were followed up until the end of their treatment and the reasons for treatment termination were investigated. Finally, the present study was a multicentre study; thus, the present findings are more generalizable than those of single-centre studies.

Nevertheless, there are several limitations to this study. First, this was a retrospective cross-sectional study, precluding meaningful conclusions regarding causality. Although we included a large sample of eligible patients, some bias may have remained. In addition, we could not evaluate pain management efficacy because of the lack of relevant data. Future prospective studies are required to fill this gap. Second, this was a single-arm study; thus, we did not compare the safety profile between groups; a study with treatment and control groups may help address this limitation. Third, this study may have been affected by selection bias, as the included patients were treated at several specialist medical institutions. Future studies should validate the present findings in general hospitals and among physicians that perform house calls. Fourth, the present findings may have been affected by rescue medication. Since the fast-release formulation of TAP is not available in Japan, other opioid types are used as the fast-release formulation. In this study, oxycodone accounted for 73% of the rescue drugs used, potentially affecting the present findings. Finally, the eligibility of the target population was not determined because this study was an all-cases survey. The general condition of patients may have influenced the results of this study.

Conclusions

The present findings provide preliminary insights into the safety profile of TAP use in the Japanese population and into the characteristics of patients likely to discontinue this treatment owing to adverse events. Concomitant use of naldemedine may reduce the risk of TAP discontinuation owing to side effects. Prospective controlled trials are required to evaluate the safety of TAP and validate the present findings.