Impact of Interventions by Certified Pharmacists for Outpatients with Cancer Pain on Hospital Admission after the Introduction of Opioid Analgesics

Abstract

The treatment of patients with cancer in an outpatient setting is important for maintaining patients’ QOL and reducing the social burden of therapy, thus requiring extensive intervention by pharmacists in the outpatient setting. Japan has a system to certify pharmacists with specialized knowledge and skills in palliative care. However, few studies have investigated the impact of certified pharmacists’ activities and of pharmacists’ interventions on hospitalization and outpatient visits. Therefore, in this study, we retrospectively investigated the effects of interventions by certified pharmacists during the period from the introduction of opioid analgesics to hospitalization for pain management and the duration of outpatient visits at a single acute care hospital. Analysis using the Cox proportional hazards model showed that interventions by certified pharmacists significantly reduced hospitalizations for pain management (p = 0.014). Further, the results of the log-rank test showed that interventions by certified pharmacists significantly prolonged the period from the introduction of opioid analgesics to hospitalization compared with the absence of such interventions (p = 0.013). Additionally, interventions by certified pharmacists significantly increased the duration of outpatient visits compared with the absence of such interventions (p < 0.001). These results suggest that active and careful interventions by pharmacists, including certified pharmacists, contribute to the maintenance of the patients’ QOL and healthcare economics by extending the period from the introduction of opioid analgesics to hospitalization for pain management and the duration of outpatient visits.

INTRODUCTION

Cancer is projected to become a leading cause of morbidity and mortality worldwide in the coming decades.¹⁾ Many patients experience pain during cancer development. Pain prevalence rates have been reported to be 39.3% after curative treatment; 55.0% during anticancer treatment; and 66.4% in patients with advanced, metastatic, or terminal disease.^2,3) Up to 70–80% of patients with progressive cancer experience moderate to severe pain.⁴⁾

Inadequate pain control remains a widespread problem despite the availability of effective treatments and guidelines for cancer pain management.^5–7) Untreated or undertreated pain significantly diminished health-related QOL in patients with cancer.^8,9) In end-of-life care for cancer, early palliative care results in marked improvements in QOL and mood in patients with metastatic non-small cell lung cancer. Compared to the standard care group, the early palliative care group received less active treatment at the end of life but survived longer.¹⁰⁾ This indicates that it is important that patients receive the same palliative care in the outpatient as well as the inpatient setting.

In recent years, a multidisciplinary team (MDT) approach has become an increasingly important pain management strategy in the outpatient setting.¹¹⁾ Pharmaceutical care activities as part of palliative care provided by pharmacists in MDTs may include assessing patients’ pain control, optimizing drug therapy, monitoring adverse drug reactions, evaluating and improving patients’ medication adherence.¹²⁾ These pharmaceutical care activities have led to positive outcomes.^13–16) However, the reports published thus far are of evaluations of the usefulness of the process. Few studies have evaluated outcomes such as the duration of hospital stay or outpatient visits.

In Japan, the Japanese Society of Pharmaceutical Palliative Care and Science launched the Board Certified Pharmacist in Palliative Pharmacy (BCPPP) program in 2010 to foster pharmacists’ understanding of the spirit of palliative medicine, acquire knowledge of palliative pharmacotherapy, and contribute to patient care. However, there are no reports on the effect of BCPPP activity on patients with cancer pain. Hence, this study was aimed at investigating the effect of pharmacist interventions by BCPPPs for the period from the introduction of opioid analgesics for outpatients with cancer pain at a single acute care hospital to hospitalization for pain management and the duration of outpatient visits.

PATIENTS AND METHODS

Patients

Patients who were first prescribed opioid analgesics at our outpatient clinic between April 2013 and August 2023 were included. The exclusion criteria were as follows: (1) patients for whom opioid analgesics had been introduced for the management of chronic pain, (2) patients whose last confirmed date of survival was the date of the introduction of opioid analgesics owing to a change in doctor or introduction of doctors who visited patients' homes to provide medical care, and (3) patients under observation for less than 7 d after the induction of opioid analgesics. The pharmacist intervention group included patients who received the intervention directly or under the supervision of the BCPPP at the request of a physician who decided to introduce opioid analgesics. The no-pharmacist intervention group comprised patients for whom no such request was received from a physician.

Intervention

The interventions were initiated at the patient’s first visit for opioid introduction and via a telephone call from the doctor who decided to introduce opioid analgesics. Pharmacists performed pain assessments and educated patients when delivering opioid analgesics to them. After the introduction of opioid analgesics, telephone interviews and counseling were conducted for the patients at their homes between 3 and 7 d after the first visit. Pharmacists taught the following items to the patients: how to assess pain intensity and pain response to analgesics, treat breakthrough pain using rescue doses, and prevent or treat side effects caused by analgesics. The interventions were performed before physician consultations on visiting days and were repeated at every visit until the patients were hospitalized or no longer visited the hospital. The pharmacist interviews comprised questions related to pain patterns and intensities, use and efficacy of rescue doses, types and severity of side effects. The pharmacists made an assessment based on the results of the patient interview and suggested prescriptions to the physician.

Data Collection

All data were collected retrospectively from the electronic medical records of the hospital. The following background factors were recorded: sex, age, cancer type, types of opioid analgesics prescribed for cancer pain treatment, and presence of pharmacist interventions. The primary outcome was hospitalization for pain management within the first year after the introduction of opioid analgesics. The secondary outcome was length of outpatient visits to the hospital during the first year after the induction of opioid analgesics or until the date of the last known survival. The date of the last confirmation of survival was the date of the last hospital visit or last discharge from the hospital as recorded in the medical records.

Statistical Analysis

The Kaplan–Meier method was used to estimate the time-dependent probability of hospitalization for pain management within 1 year after the introduction of opioid analgesics in the pharmacist intervention and no-intervention groups. The two groups were compared using a log-rank test. The Cox proportional hazards regression model was used to calculate 95% confidence intervals (CI) and hazard ratios (HRs) to analyze the factors affecting outcomes.

The secondary endpoint, the duration of outpatient visits after opioid analgesic induction, was compared using the Mann–Whitney U test. Collinearity was examined using the variance inflation factor (VIF). Multivariate analysis was performed for all possible factors influencing hospitalization: sex, age, cancer type, opioid analgesics and Pharmacist intervention. The variable used for multivariate analysis was VIF <5. Statistical significance was set at a p-value of <0.05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan),¹⁷⁾ which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria, version 4.3.1).

Ethical Approval and Informed Consent

This study was performed in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects and was approved by the Ethics Committee of Saiseikai Noe Hospital (Approved on April 10, 2024). Informed consent was obtained in the form of an opt-out option at the hospital.

RESULTS

Table 1 shows patient background characteristics. Overall, opioid analgesics were introduced during outpatient care for 428 patients with cancer. The age (mean ± standard deviation (S.D.)) of the participants was 70.0 ± 10.9 years. Lung cancer was the most common type of cancer; however, digestive cancers accounted for a higher proportion overall. Three certified pharmacists were involved in the intervention. The three pharmacists had at least three years of experience in palliative pharmacotherapy at beginning of the intervention. The only certification related to cancer and palliative medicine was BCPPP. Pharmacist intervention by BCPPPs was provided to 311 (72.7%) patients; however, 117 (27.3%) were unable to receive it. Throughout the attendance period, 148 (34.6%) patients experienced one or more hospital admissions for pain management. Of these 148, 78 (52.7%) had been admitted to the hospital for pain management within 50 d after the introduction of opioid analgesics. Most patients had outpatient hospital days of ≤50 d. The Kaplan–Meier curve in Fig. 1 compares the probability of hospitalization for pain management within 1 year of the introduction of opioid analgesics in the two groups. The pharmacist intervention group had a lower probability of hospitalization for pain management after opioid administration (p = 0.013).

Table 1. Patient Characteristics

	n
Sex (male/female, total)	253/175 (428)
Age (years) *	70.0 ± 10.9
Cancer types
Lung	114 (26.6%)
Colorectal	90 (21.0%)
Pancreatic	41 (9.6%)
Gastric	40 (9.3%)
Breast	37 (8.6%)
Others	106 (24.8%)
Opioid analgesics
Oxycodone	356 (83.2%)
Morphine	41 (9.6%)
Fentanyl	11 (2.6%)
Others	20 (4.7%)
Pharmacist intervention
Yes	311 (72.7%)
No	117 (27.3%)
Hospital admissions for pain management after the induction of opioid analgesics
Yes	148 (34.6%)
No	280 (65.4%)
Time to hospital admission for pain management after the induction of opioid analgesics within 1 year **
≤50 d	78 (52.7%)
51–100 d	30 (20.3%)
101–200 d	23 (15.5%)
>200 d	17 (11.5%)
Total outpatient days after introduction of opioid analgesics within 1 year
≤50 d	181 (42.2%)
51–100 d	76 (17.8%)
101–200 d	60 (14.0%)
>200 d	111 (25.9%)

* Mean ± S.D. ** Indicates percentage of 148 patients who have experienced hospitalization.

Fig. 1. Kaplan–Meier Curves Showing the Probability of Hospital Admission for Pain Control

The data were statistically analyzed by log-lank test. Log-lank: p = 0.013

Table 2 shows the hazard ratios for the time-dependent probability of hospitalization for pain management after the introduction of opioid analgesics, calculated using a Cox proportional hazards model. Age was categorized as above or below the median value. In a multivariate analysis that included factors considered to be associated with hospitalization for pain management, pharmacist intervention significantly reduced the probability of hospitalization for pain management (HR, 0.550; 95% CI, 0.378–0.800; p = 0.002). The total number of outpatient days in the year following the introduction of opioid analgesics in the pharmacist and no-pharmacist intervention groups was compared using the Mann–Whitney U test. (Fig. 2) The median (interquartile range) for the pharmacist and no-pharmacist intervention groups was 76 (29–258.5) and 49 (17–109) days, respectively. Pharmacist interventions significantly increased the duration of outpatient visits (p < 0.001).

Table 2. Cox Proportional Hazards Model for Time to Hospital Admission for Pain Management after the Induction of Opioid Analgesics

Factors that attenuate the effect	Univariate analysis		Multivariate analysis
	HR (95% CI)	p-Value	HR (95% CI)	p-Value
Sex (male)	0.820 (0.592–1.134)	0.230	0.779 (0.545–1.114)	0.172
Age of ≥70 years	1.020 (0.738–1.408)	0.906	0.972 (0.697–1.356)	0.866
Cancer type
Lung	0.707 (0.478–1.046)	0.083	0.902 (0.546–1.492)	0.689
Colorectal	1.408 (0.979–2.025)	0.065	1.573 (0.964–2.566)	0.070
Pancreatic	1.295 (0.757–2.213)	0.346	1.320 (0.702–2.480)	0.390
Gastric	1.071 (0.618–1.858)	0.807	1.341 (0.700–2.569)	0.377
Breast	0.977 (0.580–1.645)	0.930	1.025 (0.493–2.132)	0.948
Opioid analgesics
Oxycodone	1.198 (0.767–1.869)	0.427	0.988 (0.408–2.390)	0.977
Morphine	0.877 (0.505–1.521)	0.639	0.794 (0.276–2.283)	0.668
Fentanyl	0.603 (0.149–2.435)	0.477	0.406 (0.075–2.185)	0.294
Pharmacist intervention (yes)	0.648 (0.458–0.916)	0.014*	0.550 (0.378–0.800)	0.002**

* p < 0.05 ** p < 0.01

Fig. 2. Box Plot Showing Comparisons between the Pharmacist and No-Pharmacist Intervention Groups on the Duration of Outpatient Visits within 1 Year after the Introduction of Opioid Analgesics

DISCUSSION

In this study, we investigated the factors influencing the period from the introduction of opioid analgesics in outpatients with cancer pain to admission for pain management, particularly pharmacist interventions by BCPPPs. The results suggest that pharmacist interventions through BCPPPs for outpatients with cancer pain contribute to the incidence of hospitalization for pain management and extend the time patients can spend at home.

Pharmacist interventions for outpatients with cancer pain have been actively developed not only in Japan but also in other countries.¹⁸⁾ Pharmacist interventions improve patient QOL by contributing to pain and side-effect management.¹¹⁾ Furthermore, pharmacist interventions have been reported to significantly reduce hospital return visits, emergency department visits, and hospital readmissions related to adverse drug events in areas other than cancer pain.¹⁹⁾ However, the impact of pharmacist interventions on the event of “hospitalization,” which is also related to healthcare economics, has not been reported in palliative care. Therefore, in this study, we focused on interventions by BCPPPs and investigated the factors that influence the time from the introduction of opioid analgesics to hospitalization for pain management.

A BCPPP is a pharmacist with the knowledge, skills, and attitude required to contribute to palliative pharmacotherapy. We have reported that pharmacist interventions for outpatients with cancer pain provide good pain and side-effect management for opioid analgesics¹⁶⁾; however, we did not examine the impact on hospitalization. This study revealed that pharmacist interventions by BCPPPs extended the period from the introduction of opioid analgesics to hospitalization for pain management.

There have been no reports of outpatient visits and hospitalizations as indicators of pharmacists’ contributions. A comparison of the number of outpatient hospital days between the two groups, with and without pharmacist intervention, which was a significant factor in the Cox proportional hazards model analysis, showed that the total number of outpatient hospital days was significantly longer in the pharmacist intervention group. The results suggest that pharmacist interventions by a BCPPP contribute to shorter hospital stays due to longer outpatient visits.

Advanced cancer therapeutics have improved patient survival but have also led to an increase in the number of patients who require long-term outpatient chemotherapy.^20,21) The treatment of patients with cancer in an outpatient setting is important for reducing the social burden of therapy and maintaining the QOL of these patients, because it allows them to integrate treatment into daily life.^22,23) If the introduction of opioid analgesics for cancer pain is performed safely and securely, outpatient treatment is chosen, as is anticancer therapy. The average length of admission and medical costs are positively correlated.²⁴⁾ We believe that pharmacist interventions by BCPPPs for outpatients with cancer pain enable outpatient visits and contribute to maintaining patients’ QOL and health care economics.

One limitation of this study is that it did not consider the social background of the patients. Although social background, such as the presence or absence of family members who support the patient and interventions of other professions are also factors that influence hospitalization, we were unable to investigate these factors. Additionally, medication adjustments for pain management may be performed simultaneously during hospitalization rather than during pain management; however, this was not evaluated. Furthermore, the presence or absence of a pharmacist intervention depends on the physician's request. The expectations of pharmacist interventions by physicians may influence the outcomes. A more detailed multicenter prospective study is required in the future.

Despite these research limitations, this study is very significant in two respects: it allowed us to examine the effects of pharmacist intervention on hospitalization, which affects health care economics and QOL, and the professional role of the BCPPP.

In conclusion, the findings of the present study revealed that active and careful interventions by pharmacists, including BCPPP, for outpatients with cancer pain prolong the period from the introduction of opioid analgesics to hospitalization for pain management. Accordingly, it is important for outpatients to receive intervention by pharmacists, including BCPPP.

Conflict of Interest

The authors declare no conflict of interests.

Supplementary Materials

This article contains supplementary materials. Details of patient characteristics in the pharmacist and no-pharmacist intervention groups are available in Supplementary Materials.

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