In this retrospective survey of oxycodone treatment for refractory dyspnea as palliative care in real-world heart failure practice, we found the following results. First, oxycodone treatment significantly decreased MBS without affecting respiratory rate, heart rate, or blood pressure. Second, adverse effects due to oxycodone were effectively managed with dosage adjustment and symptomatic treatment without inducing serious adverse effects, such as respiratory depression. This study’s findings indicate that oxycodone may be a new treatment option for patients with end-stage heart failure in real-world practice.

Dose and timing of oxycodone treatment in end-stage heart failure practice

The efficacy of morphine for dyspnea in patients with end-stage heart failure has been reported, with its effect at smaller doses than those for pain control [9, 10, 14]. Although no consensus on the dosage exists for heart failure, symptomatic relief has been reported with morphine tablets 5 mg four times a day (morphine injection equivalent 10 mg/day) [10]. In the field of heart failure, there are numerous reports on the introduction of morphine at 5–10 mg/day or smaller doses by continuous intravenous or subcutaneous infusion, similar to that in the field of oncology. However, caution should be exercised in patients with impaired renal function (creatinine clearance should be less than 30 mL/min), as the accumulation of morphine-3-glucuronide and 6-glucuronide, the active metabolites of morphine, may cause hypersedation, delirium, and respiratory depression [15, 16]. However, oxycodone, similar to morphine, has been reported to be useful for dyspnea in oncology [16, 17]. It can be used relatively safely even in cases of impaired renal function (as a rule of thumb, creatinine clearance of 10 mL/min or more) and can be administered to patients who have difficulty receiving morphine [18]. In heart failure, continuous intravenous or subcutaneous administration of oxycodone 4.8–10 mg/day has been reported to improve dyspnea, and it can be safely administered to patients with severe renal dysfunction [12, 19]. In this study, induction was conducted at 5–10 mg/day, and its efficacy was confirmed. Oxycodone should be carefully considered as an alternative drug in cases where morphine is difficult to use, such as in patients with impaired renal function who develop delirium. The method for initiating opioids for dyspnea is detailed in the “Approaches to Managing Pharmacotherapy in Palliative Care for Heart Failure,” published by the Japan Society of Hospital Pharmacists in April 2021. However, it should be noted that, in Japan, oxycodone is indicated only for cancer pain and is not applicable to patients with heart failure. Introducing opioids in patients with end-stage heart failure experiencing dyspnea even after adequate heart failure treatment should be considered. As demonstrated in this study, there were cases where dyspnea significantly improved and oxycodone was withdrawn; therefore, it is necessary to consider its introduction at an earlier stage in the future. Because of the retrospective study design, we could not determine the optimal dose and timing of oxycodone administration in our survey, and these issues should be further investigated in future studies.

Efficacy of oxycodone for refractory dyspnea in patients with end-stage heart failure

Opioid treatment has been reported to be effective in the treatment of dyspnea due to cancer and/or non-cancer diseases such as chronic obstructive pulmonary disease [20, 21]. Oxycodone has also been reported to be as effective as morphine in the treatment of dyspnea in patients with terminal cancer [16, 17]. Although the mechanism of action of morphine and other opioids in improving dyspnea has not been fully elucidated, decreased perception of the central nervous system and sensitivity of the medullary respiratory center to carbon dioxide have been reported [22]. However, in heart failure, the opioid group showed significantly improved symptoms compared with the placebo group, although symptoms did not disappear. Although the goal of opioid treatment for dyspnea is to alleviate symptoms, the symptoms of dyspnea in patients with heart failure are highly severe, and opioids may be useful in improving their quality of life. MBS, a measure of dyspnea, in hospitalized patients with end-stage heart failure is shown in Fig. 1. The MBS score significantly decreased, suggesting the efficacy of oxycodone in treating refractory dyspnea in patients with end-stage heart failure. However, the study’s sample size was small, and thus it did not adequately demonstrate the efficacy of dyspnea. Further studies, including high-quality, large-scale prospective cohort studies and possibly randomized controlled trials, are required to determine the efficacy of oxycodone treatment compared with morphine for refractory dyspnea in patients with end-stage heart failure.

Safety of oxycodone in patients with end-stage heart failure

Adverse events, including respiratory depression, nausea, vomiting, constipation, and delirium, are often experienced by cancer patients receiving morphine treatment [23]. Although there are concerns that oxycodone may cause adverse effects similar to those of morphine, in this study, the adverse effects caused by oxycodone were adequately managed with dose adjustments and symptomatic treatments. In two patients in this study, midazolam was concomitantly administered after oxycodone initiation; however, no serious adverse effects, such as respiratory depression, were observed. Morphine undergoes glucuronidation in the liver, whereas oxycodone is primarily metabolized by the CYP enzymes 2D6 and 3A4. Because the beta-blockers bisoprolol and carvedilol are metabolized by CYP2D6 and CYP3A4, it was hypothesized that their concomitant use with oxycodone could potentiate the effects of beta-blockers and decrease blood pressure and heart rate. However, in this study, no effects on these parameters were observed because the doses were small. Oxycodone does not inhibit CYP2C9, the major metabolizing enzyme of warfarin; therefore, its effect on warfarin pharmacokinetics and action is expected to be minimal. However, in this study, a prolonged PT-INR was observed in patients treated with the combination of oxycodone and warfarin. In particular, Case 5, involving a patient who was started on oxycodone while receiving warfarin showed a prolonged PT-INR. Although serum albumin level fluctuations are considered to be a potential contributing factor, the serum albumin level in this case remained stable between 2.7 and 3.0 g/dL during the entire treatment period, suggesting that there were no significant fluctuations. Therefore, it was hypothesized that oxycodone may have enhanced the anticoagulant effects of warfarin. This observation aligns with the findings of Hosokawa et al., who reported that the anticoagulant effects of warfarin were significantly enhanced when co-administered with oxycodone in patients with cancer. Specifically, the PT-INR increased significantly, and the Warfarin Sensitivity Index also increased, indicating an enhanced anticoagulant effect despite a reduction in the warfarin dose [24]. Therefore, it is recommended that PT-INR be closely monitored when initiating oxycodone therapy in patients receiving warfarin to prevent potential complications from enhanced anticoagulant effects [25].

Study limitations

This study has several limitations. First, this was a single-center retrospective study with a small sample size; therefore, it was subject to various biases inherent to the data. Second, this study was conducted at a single institution, which limits its generalizability. Third, we could not ascertain whether dyspnea was relieved by treatment with oxycodone alone because of the various simultaneous treatments for heart failure. Fourth, we retrospectively evaluated adverse events based on descriptions in medical records. The frequency of adverse events may have been falsely decreased owing to the failure to record all events in the medical records, even though there were unacceptable symptoms. Fifth, clear inclusion/exclusion criteria and protocols for oxycodone administration were not established in this study. Moreover, the frequency of symptom evaluation and titration of oxycodone administration generally depended on the attending medical staff and varied among patients during the study period.