Background

For patients with cancer, up to 70% suffered from pain caused by their disease or its treatment [1]. For patients with advanced cancer, pain was described as moderate-severe in approximately 40%-50% and as very severe in 25%-30% [2]. Because pain was an important symptom and occurred frequently in cancer patients, especially for moderate-severe cancer pain, relief of pain should therefore be seen as part of a comprehensive pattern of cancer care.

Since the 1980s, treatment of cancer pain was based on the WHO analgesic ladder. Strong opioids were classified at the highest step of the analgesic ladder. But studies of cancer pain control consistently revealed that up to half of patients received inadequate analgesia and 30% did not receive appropriate drugs for their pain [1]. In China, sustained-release oral morphine and transdermal fentanyl were strong opioids available for the treatment of moderate-severe cancer pain.

Fentanyl is a lipid soluble synthetic opioid, which can be delivered in a transdermal controlled systemic delivery formulation for up to 72 hours. Transdermal fentanyl was accepted to be an effective drug for treating moderate-severe cancer pain. Because it takes 12-24 hours for serum levels to stabilize after starting the patch or changing the dose, it was less flexible and suitable for patients with unstable pain. However, transdermal fentanyl may reduce the rates of some typical opioid-related adverse effects, particularly constipation [3]. In addition, transdermal fentanyl was conveniently administrated, which simplified the procedure of chronic pain treatment and improved the compliance for using the analgesic.

Three systematic reviews of European and American literatures suggested both transdermal fentanyl and sustained-release oral morphine could effectively control moderate-severe cancer pain, but some adverse effects (mainly constipation) seemed to favor transdermal opiates in the preference of patients with moderate-severe cancer pain [4–6]. Our previous meta-analysis of 12 Chinese literatures also found similar result [14, 17, 14, 17, 14, 17, 32–34]. Especially, one of trials supported more patients got better QOL after sustained-release oral morphine transferred to transdermal fentanyl [34].

Cost effectiveness was not an endpoint in the present systematic review, but it was a valuable index to evaluate a drug for clinical use. 2 out of selected trials reported data about cost effectiveness that transdermal fentanyl had higher expenditure to control certain pain than oral morphine [35, 36]. However, we should keep in mind that cost effectiveness was affected by many factors in fact and only 2 out of 32 trials reported data about cost effectiveness when we concluded cost effectiveness was higher in transdermal fentanyl.

Similar with European and American data [4–6], our data also showed that both transdermal fentanyl and sustained-release oral morphine were effective in treating stable moderate-severe cancer pain in Chinese population with less adverse effects for transdermal fentanyl. However, two differences should be pointed out. First, QOL was only analyzed in our study, and data suggested that transdermal fentanyl potentially improved QOL of cancer pain patients and resulted in better compliance compared with oral morphine. Second, more patients were included in the present systematic review and all patients were Chinese.

To explain the results reasonably, several issues should be considered as follow. First, the data source was extracted from abstracted data and not individual patient data (IPD). In general, an IPD-based meta-analysis would give a more robust estimation for the association; therefore, we should interpret the results with care, especially for a positive result. Clearly, further investigations using IPD should be conducted to examine the main end points. Second, all selected trials were cohort studies, which is not most suitable clinical trial to explore the difference of two drugs. Third, heterogeneity existed among the trials when pooled analysis of adverse effects (constipation and nausea/vomiting), fortunately, the data was not materially changed in sensitivity analysis. Fourth, side effects seemed to be lower in our selected trials compared with clinical practice. We thought that these results might be explained in two aspects of small sample in single trial and better tolerance in Chinese population. At last, transdermal fentanyl takes 12-24 hours for serum levels to stabilize after starting the patch and dose increment was trouble in clinic practice, so it is less flexible and needs to be used with caution in patients with unstable pain.

Conclusions

In summary, the present study supported that transdermal fentanyl and sustained-release oral morphine were effective for maintenance therapy of moderate-severe cancer pain in Chinese population, and the former might have less adverse effects. Our results were similar with European and American data, which might suggest that both of opioids have no race choose. In addition, our data suggested transdermal fentanyl might improve QOL more easily. Well-designed randomised control trials should be further conducted in this area.