Abstract
Background
Appropriate prophylactic rescue dosing of opioids is considered effective for cancer pain relief, but no study has reported the safety of such prophylactic rescue. We compared the safety of prophylactic rescue dosing of immediate-release oral opioids with that of regular rescue dosing.
Methods
The study included 103 cancer patients who used either immediate-release morphine syrup or immediate-release oxycodone powder at Shizuoka Cancer Center between January and December 2016. Patients were divided into those who mostly used (prophylactic group) and those who never used (regular group) prophylactic rescue doses of opioids and compared the incidence of adverse events (AEs). We also investigated whether the prophylactic rescue dose negatively interfered with its objective activity, such as meals.
Results
Incidence of each AE in the prophylactic versus regular groups was as follows: somnolence, 20.6% versus 14.3%; nausea, 22.1% versus 17.1%; constipation, 19.1% versus 20.0%; urinary retention, 1.5% versus 2.9%; delirium, 4.4% versus 8.6%; and pruritus, 0% versus 2.9%. No serious AE associated with prophylactic rescue dosing was observed. No significant difference was observed in the incidence of any AE between the two groups (p > 0.05, Fisher’s exact test). No AE interfered with the objective activity of the prophylactic rescue dose.
Conclusion
Incidence of AEs associated with prophylactic rescue dosing is not different from that associated with regular rescue dosing. In addition, the prophylactic rescue dose did not adversely affect its objective activity, suggesting the safety of appropriate prophylactic rescue dosing was similar to that of regular rescue dosing.
Trial registration
The study approval number in the institution; H29-J30–29–1-3. Registered June 5, 2017.
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Background
Appropriate use of immediate-release opioid oral agents is a critical component of cancer pain relief. This is also supported by the principles of analgesics use specified in the WHO cancer pain relief program [1, 2], which state that immediate-release agents should be administered orally at individualized doses with meticulous care.
Until recently, oral opioids were only available in an immediate-release form requiring multiple daily doses. The subsequent development of the extended-release oral formulations of morphine [3], oxycodone [4], and tapentadol [5], and the fentanyl extended-release patch [6] has led to decreased daily regular dosing frequency of opioids. Improvements have also been made to immediate-release agents, such as the development of the buccal tablet [
Tables 4 and 5 show the results of subgroup analysis based on opioid type in the morphine and oxycodone subgroups, respectively. In both subgroups, no significant difference in AE incidence was observed between the prophylactic and regular groups.
Discussion
This study showed no significant difference between the prophylactic and regular rescue dose groups in the incidence of any of the AEs evaluated, including somnolence, nausea, constipation, urinary retention, delirium, and pruritus (Table 3), suggesting that the use of prophylactic rescue dosing and associated increase in total opioid dose do not increase the incidence of AEs. Moreover, with no reported cessation of eating due to nausea, cessation of rehabilitation, intervention or radiation therapy due to somnolence, or refusal of prophylactic rescue dose by patients, it is likely that appropriate prophylactic rescue dosing also improves patients’ QOL. The results of subgroup analysis also suggest the safety of prophylactic rescue dosing regardless of whether morphine syrup or oxycodone powder is used (Tables 4 and 5).
However, comparison of AE incidence between the morphine and oxycodone subgroups showed a lower incidence of constipation in patients using rescue-dose oxycodone, especially in those using prophylactic rescue-dose oxycodone, compared with that in those using rescue-dose morphine. This difference may be explained by the differences in the amount of each rescue single dose and daily total dose between the two subgroups (Table 1). The minimum standard strength of the immediate-release morphine syrup and the immediate-release oxycodone powder in Japan is 5 mg morphine and 2.5 mg oxycodone (3.75 mg morphine equivalence), respectively. The morphine subgroup was associated with a higher frequency of prophylactic rescue doses before meals, with many of these patients having at least 3 doses per day; this might have also contributed to the difference. Another possible explanation is that the patients included in this study were administered relative low doses of extended-release opioids, with a median morphine equivalent dose of 15 mg/day, along with the pharmacological difference that the threshold concentration for causing constipation is lower with morphine than oxycodone [23].
Regarding the purpose of use, patients used prophylactic rescue dosing most commonly before meals in the morphine subgroup and before bedtime in the oxycodone subgroup (Table 2). This may be because many of the patients requiring prophylactic rescue dose before meals experienced pain during swallowing due to underlying disease or prior radiation therapy of the esophagus, and therefore selected the syrup formulation rather than powder, because they are easier to swallow. In contrast, those requiring prophylactic rescue dose before bedtime tended to be concerned about pain during nighttime resting or while falling asleep, and therefore selected oxycodone for the longer-lasting analgesic effect because the half-life is longer than that of morphine [24] (T1/2 = 2.2 h for the immediate-release morphine syrup [12] and 6.0 h for the immediate-release oxycodone powder [13]). The higher frequency of use of prophylactic rescue for respiratory distress in the morphine subgroup was probably because evidence for efficacy in the relief of respiratory distress is widely available for morphine [25].
Future prospective studies using a predetermined rescue dose, a dosing frequency, a purpose, a dosing schedule, and a concomitant extended-release agent are needed to accumulate more detailed evidence. Also, we plan to compare other AEs which were unaddressed in the present study and to investigate the efficacy of prophylactic rescue dosing (e.g., by examining decreases in NRS pain assessment results).
Regarding concomitant extended-release opioids, due to the retrospective nature of the study, the presence of patients who used extended-release opioids containing types of opioids different from the immediate-release opioids and those who used no extended-release opioids, might have served as a confounding factor that affected the incidence of AEs. However, given that no serious AE, such as fall, loss of consciousness, respiratory depression, or drug dependence, was observed in the prophylactic group and that no increase in the incidence of somnolence or other AEs was observed in the analysis of the entire population, it is unlikely that serious problems could occur from using a prophylactic rescue dose of an immediate-release opioid with a concomitant extended-release agent containing a different type of opioid or without any concomitant extended-release agent.
Conclusion
The present results suggest that the incidence of AEs associated with prophylactic rescue dosing is not different from that associated with regular rescue dosing. Moreover, no AE interfered with the objective activity for which the prophylactic rescue dose was used, suggesting the safety of appropriate prophylactic rescue dosing was similar to that of regular rescue dosing.
