FormalPara Key Summary Points

This study analyzed, for the first time, the patterns of laxative use for opioid-induced constipation (OIC) in Japanese patients with cancer on the basis of opioid type at initiation and timing of laxative medication using a nationwide hospital claims database.

The proportion of patients who receive laxatives early was higher in those initiated with strong opioids than in those with weak opioids.

For all opioid types, osmotic laxatives were the most frequently used first-line agents in those receiving early medication.

Stimulant laxatives were the most frequently used first-line agents, to the same extent or more than osmotic laxatives, in those not receiving early medication.

Peripheral acting μ-opioid receptor antagonists were the second most used first-line agents in those receiving early medication and oral strong opioids.

Introduction

While opioid analgesics are used for moderate-to-severe cancer, patients often experience several adverse effects, particularly bowel dysfunction such as opioid-induced constipation (OIC) [1,2,3,4]. OIC is characterized by difficult-to-pass hard stools, straining at defecation, sensations of incomplete evacuation, and anorectal obstruction after initiating opioid treatment [4, 5]. OIC causes gastrointestinal, physical, and psychological symptoms with the impairments of analgesic effects of opioids and quality of life [6, 7]. In addition, while the other opioid-related adverse events, such as nausea and vomiting, are gradually alleviated by tolerance, OIC is known to persist unabated during long-term opioid use, even with conventional laxatives [8,9,10]. Observational studies reported that OIC was found in 55–65% of patients with cancer treated with opioid analgesics in Japan [11, 12]. Alternatively, the cumulative incidence of OIC was lower in patients who received prophylactic laxative medication than in those who did not [11, 12].

Osmotic laxatives (i.e., magnesium oxide), stimulant laxatives (i.e., sennoside), and peripherally acting μ-opioid receptor antagonists (PAMORAs) (i.e., naldemedine) are commonly used as pharmacological treatments for OIC in patients with cancer in Japan [13]. The Clinical Guidelines for Cancer Pain Management by the Japanese Society for Palliative Medicine (JSPM) recommends the regular administration of osmotic or stimulant laxatives for OIC simultaneously with or after initiating opioid analgesic therapy, and administration of PAMORA is conditionally recommended when constipation is not improved by other laxatives [14, 15]. Other guidelines on the management of OIC by the American Gastroenterological Association (AGA) and the European Society for Medical Oncology (ESMO) also recommend PAMORAs if the OIC is not relieved by other laxatives [16, 17]. On the contrary, the Multinational Association for Supportive Care in Cancer (MASCC) recommends using PAMORAs with a high priority compared with JSPM, AGA, and ESMO. It recommends that PAMORAs should always be considered in patients with OIC and be routinely coprescribed with opioid analgesics [18].

To date, there is no large-scale survey of the actual use of laxatives for OIC in patients with cancer in Japan. This study aimed to investigate the real-world patterns of laxative use for OIC using a nationwide hospital claims database in Japan to understand the gap between the actual patterns of laxative use and the recommendations of the guidelines for OIC, as well as to clarify the issues to be verified for the proper use of laxatives for OIC.

Methods

Study Design and Data Source

This is an observational descriptive study using a commercially available hospital claims database provided by Medical Data Vision Co., Ltd. (MDV) [19]. The database contains over 39 million patient demographics (including age and sex), ICD-10 coded diagnoses, medical practices, hospitalizations, and prescribed medications from over 460 hospitals, which covers 26% of Japanese hospitals that use an acute inpatient care system called the Diagnostic Procedure Combination [19]. MDV collects the administrative data that are anonymized at the hospitals, receives the consent of the hospital, and processes them into the database.

Ethical approval and consent were not required according to Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare, Japan, because the data had been anonymized.

Patients Selection

From the MDV database, eligible patients were identified on the basis of the following criteria: (i) diagnosis of cancer (ICD-10 codes C00-D09), (ii) initiation of opioid analgesic therapy after the cancer diagnosis, and (iii) long-term opioid prescription (continuous prescriptions for 30 days or more of any of the following opioids: morphine, hydromorphone, oxycodone, fentanyl, tapentadol, methadone, codeine, tramadol, pentazocine, and/or buprenorphine). The continuous prescriptions were defined if the blank periods of opioid prescription were less than 2 days. Opioids designed for rescue therapy and buprenorphine transdermal patch, which is not indicated for cancer pain in Japan, were not included in the initiation of opioid analgesic therapy.

Patients who received laxatives within 3 months or opioids within 7 days before initiating opioid analgesic therapy were excluded. The data period was the initiation of opioid analgesic therapy and was between January 2018 and December 2019. It examined the use of naldemedine, a PAMORA that was launched in Japan in 2017, and avoided the effects of the COVID-19 lockdown, which began in April 2020 in Japan. Each patient was followed for 3 months after initiating opioid analgesic therapy.

Measurements

Baseline Variables

All data were retrospectively obtained from the database. Age, sex, cancer type, outpatient or inpatient status, and opioids at initiation were collected. Codeine, tramadol, and pentazocine were defined as weak opioids, and other opioids were defined as strong opioids (Table S1 in the Supplementary Material) on the basis of the Clinical Guidelines for Cancer Pain Management [14]. The doses of opioids were not considered.

Treatment Patterns

Treatment patterns of laxatives for OIC were investigated in both groups: the early medication initiation group, which received laxatives within 3 days, including the same day after initiating opioid analgesic therapy, and the non-early medication group (Fig. 1). Laxatives were classified into four categories: osmotic laxatives, stimulant laxatives, PAMORAs, and others. The categories of individual laxatives are provided in Table S2 in the Supplementary Material. The first-line laxatives for each opioid type were examined on the basis of the class and route of administration (oral weak opioids, oral strong opioids, and transdermal strong opioids). The proportion of laxatives was calculated as the percentage of the total number of patients who started each opioid type.

Fig. 1
figure 1

A scheme of study design. Patients with cancer who initiated continuous opioid analgesic therapy (≥ 30 days) were included. Early and non-early laxative medication was defined when laxative prescription was initiated within 3 days or not after initiating opioid analgesic therapy, respectively

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In addition, the following were evaluated for each first-line laxative: number of days of first-line laxative medications, duration from the initiation of opioid analgesic therapy to the start of first-line laxative prescription, change or addition of new laxatives, dose increase, number of laxatives used, lost to follow-up, and second-line laxatives. All data aggregations were carried out with SAS v.9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Analysis of the Population

A flowchart of patient selection is shown in Fig. 2. In the database, 1,395,872 patients were recorded. Among 107,825 patients with cancer with long-term opioid prescriptions (≥ 30 days), 26,939 were eligible for the study. At the initiation of opioid analgesic therapy, 13,278 (49.3%) patients used weak opioids and 13,661 (50.7%) patients used strong opioids (Table 1).

Fig. 2
figure 2

Flowchart of patient selection

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Table 1 Baseline characteristics of patients initiating opioid analgesic therapy in early and non-early medication groups
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Assessment of Laxative Prescriptions

Table 1 presents the characteristics of the study patients with early and non-early laxative medication initiation by opioid class. The number of patients with early medication was 11,147 (41.4%) overall. The most common cancer type was lung cancer (13.0%), followed by colon cancer (5.9%) and stomach cancer (4.2%). The proportion of patients who received early medication was relatively high in the strong opioid group (57.3%) compared with the weak opioid group (25.0%). In patients on strong opioids, the proportion of outpatients to inpatients was similar in both the early and non-early medication groups. Early medication tended to not be provided for outpatients on weak opioids (72.1%).

Table 2 presents the proportion of patients with early medication by opioid class. The proportion of patients who received early medication was < 40% in those on weak opioids (23.6% for tramadol, 25.8% for codeine, and 36.5% for pentazocine, respectively). In those on strong opioids, the proportion of patients who received early medication was higher for oral morphine (66.9%), oral oxycodone (64.2%), and oral hydromorphone (60.9%) compared with transdermal fentanyl (37.9%) and injectable opioids (33.0–42.6%).

Table 2 Proportion of patients who received early medication in individual opioids
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Patterns of First-Line Laxatives

Figure 3 shows the first-line laxatives used in patients initiating oral weak opioids, oral strong opioids, and transdermal strong opioids. The proportion of patients who used laxatives during the follow-up period (3 months) was highest for oral strong opioids (88.5%), followed by transdermal strong opioids (75.3%) and oral weak opioids (63.3%). Osmotic laxatives were the most frequently used as first-line early medication therapy for patients on all opioid types (12.3% for those on oral weak opioids; 29.4% for oral strong opioids; 12.8% for transdermal strong opioids). PAMORA was the second most used as monotherapy for patients on oral strong opioids (9.4%) in the early medication group, but not for those on oral weak opioids and transdermal strong opioids. Combinations of laxatives were frequently used for oral and transdermal strong opioids (15.2% and 12.1%, respectively) in the early medication group. In the non-early medication group, stimulant laxatives were frequently used as first-line therapy (13.7% for patients on oral weak opioids, 7.7% for those on oral strong opioids, 15.1% for transdermal strong opioids), to the same extent or more compared with osmotic laxatives.

Fig. 3
figure 3

First-line laxatives. Proportion of patients who received laxatives for the first time after initiating opioid analgesics were shown. Proportions were expressed as the percentage of total patients who started each opioid type. The number of total patients and the proportion of patients who used laxatives were shown in parentheses: a oral weak opioids, b oral strong opioids c transdermal strong opioids. Osmotic osmotic laxatives, Stimulant stimulant laxatives, Others other laxatives, Combination combination therapy with more than two laxatives, PAMORAs peripherally acting μ-opioid receptor antagonists

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Treatment Patterns after Selecting First-Line Laxatives

Next, this study examined the treatment patterns of laxatives after selecting osmotic and stimulant laxatives and PAMORAs as first-line therapy in those starting strong opioids, because weak opioids would be switched to strong opioids for analgesia. Basic characteristics of patients receiving each laxative as first-line for strong opioids are presented in Table S3 in the Supplementary Material. The mean number of prescription days during the 3-month follow-up period for stimulant laxatives was relatively low compared with the other two laxatives in both the early (31.0 days for stimulant; 57.6 days for osmotic; 63.2 days for PAMORA) and non-early (13.9 days for stimulant; 40.6 days for osmotic; 44.8 days for PAMORA) medication groups (Table S4, Table S5 in the Supplementary Material). The proportion of patients lost to follow-up increased from 1 month and reached 40–50% at 3 months for all first-line therapy in both early and non-early medication groups (Table S6, Table S7 in the Supplementary Material).

Patterns of Second-Line Laxatives

In the early medication group, almost half of the patients changed or added other laxatives in the first month in any first-line therapy (45.0% for osmotic; 54.7% for stimulant; 54.8% for PAMORA) (Table S4 in the Supplementary Material). The proportion of patients not receiving second-line laxatives was 36.3% for osmotic laxatives, 26.3% for stimulant laxatives, and 27.0% for PAMORAs (Table S6 in the Supplementary Material). Osmotic and stimulant laxatives were the most frequently used as second-line laxatives for each other (Fig. 4, Table S6 in the Supplementary Material). PAMORAs were not the most frequently used second-line laxatives following osmotic or stimulant laxatives. In the non-early medication group, the treatment patterns of second-line laxatives were similar to those in the early medication group (Fig. 4, Table S7 in the Supplementary Material).

Fig. 4
figure 4

Second-line laxatives. Proportion of patients who received laxatives as second-line therapy were shown. Proportions were expressed as the percentage of patients who use each laxative as first-line therapy. a Early medication group patients who did not receive second-line laxatives were 36.3% (osmotic), 26.3% (stimulant), and 27.0% (PAMORA). b Non-early medication group patients who did not receive second-line laxatives were 49.0% (osmotic), 32.9% (stimulant), and 38.1% (PAMORA). Second-line osmotic or stimulant laxatives are different from first-line laxatives. Osmotic osmotic laxatives, Stimulant stimulant laxatives, Others other laxatives, PAMORAs peripherally acting μ-opioid receptor antagonists

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Discussion

To the best of our knowledge, this is the first study to investigate the real-world patterns of laxative use for OIC in Japanese patients with cancer using a nationwide hospital claims database. This study showed that a total of 41.4% of patients received early laxative medication, and the proportion of patients receiving early medication was substantially higher in those who started strong opioids compared with weak opioids, and in those who started oral opioids compared with transdermal and injection opioids among the strong opioids. A previous retrospective multi-institutional study in Japan showed that 73.7% of patients with cancer received prophylactic laxatives [11]. This difference may be because the previous study included oral strong opioid users and those who were prescribed regular laxatives before starting opioids.

In addition, twice as many patients starting strong opioids as those starting weak opioids received early laxative medication (57.3% versus 25.0%). The difference in the proportion of those receiving early medication between opioid classes may be due to the physicians’ assessment of the risk of OIC for each opioid. Tramadol was reported to cause less constipation in patients with cancer pain [20], and physicians might refrain from early laxative prescription for patients on weak opioids. However, constipation has been reported even in patients using weak opioids [21]. Few guidelines have recommended the management of OIC by opioid class, and further studies are needed to examine the effect of early laxative use in patients on weak opioids.

The proportion of patients receiving laxatives early was lower in those initiating transdermal fentanyl compared with oral strong opioids (Table 2). The patients who started transdermal fentanyl might be unable to take laxatives orally, or physicians might think that fentanyl would be less likely to cause OIC, as per previous reports [22]. However, our study results showed that the difference in the proportion of laxative use during the 3-month follow-up period was limited between oral strong opioids (88.5%) and transdermal strong opioids (75.3%, Fig. 3), suggesting that the proper use of laxatives for OIC is required not only for patients on oral opioids but also for those on transdermal fentanyl.

This study showed that osmotic laxatives were most frequently used as first-line therapy in the early medication group, and both osmotic and stimulant laxatives were used as first-line therapy in the non-early medication group with equal frequency. Osmotic and stimulant laxatives were also frequently used as second-line laxatives for each other. In contrast, PAMORAs were the second most used in patients starting oral strong opioids as first-line monotherapy in the early medication group, but not in other conditions such as for oral weak opioids and transdermal strong opioids in the early medication group, and for all opioid types in the non-early medication group. Moreover, PAMORAs were not most frequently used as second-line therapy for other laxatives. These results may indicate that the actual patterns of laxative use are in line with the Japanese guidelines [14].

Currently, many types of laxatives are available in Japan; however, there is limited evidence directly comparing the efficacy and safety of different laxatives [23]. Therefore, the suitability of laxatives as first-line and second-line agents and for early medication is unclear. Further studies are required to develop the algorithm for OIC management and appropriately update its guidelines.

This study used a large-scale hospital-based administrative claims database; however, the database had limitations. First, the database covered data only from hospitals that had introduced an acute inpatient care system, so small hospitals and clinics were not included and medication from other hospitals and over-the-counter drugs were not tracked. In addition, cancers diagnosed in the past could not be differentiated from cancers currently being treated, which increased the proportion of multiple cancers. Second, 40–50% of patients were lost to follow-up within 3 months after initiating opioid analgesic therapy, which would be mainly due to death. The treatment patterns of laxatives in the later follow-up period may not be accurate and could not be compared directly. Third, as the data were based on payment-related information, it is unclear whether the patient had actually taken the laxatives or not, and whether they had taken second laxatives as add-on or switch treatment. Finally, clinical symptoms, severity of constipation, and general condition of patients, which might affect the selection of laxatives, were not accounted for.

Conclusion

This is the first study to demonstrate the real-world patterns of laxative use for OIC in Japanese patients with cancer using a nationwide hospital claims database. This study showed that the real-world patterns of laxative use for OIC were nearly consistent with the recommendations of the current Japanese guidelines. However, the timing of laxative initiation depends on opioid class and route of administration, and the frequency of individual laxative use was different based on the timing of laxative initiation and opioid type. These results clarified the issues to be verified for the proper use of laxatives to manage OIC. Further studies will be needed to determine the optimal timing of laxative initiation and the selection of laxatives for OIC management.