Transdermal fentanyl for cancer pain Stable (no update expected for reasons given in 'What's new')
Opioid drugs have been used for many years to relieve pain. Transdermal fentanyl offers one option for delivering and maintaining pain relief in patients with moderate or severe cancer pain.
To determine the analgesic efficacy of transdermal fentanyl for relief of cancer pain, and to assess the adverse events associated with the use of transdermal fentanyl for relief of cancer pain.
The following databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 4 of 12); MEDLINE (1966 to May 2013); EMBASE (1974 to May 2013; CANCERLIT (PubMED) (November 2012); and ClinicalTrials.gov (May 2013).
Published randomised controlled trials (RCTs) using placebo or active comparators reporting on the analgesic effect of transdermal fentanyl in adults and children with cancer pain. Studies with fewer than 10 participants were excluded.
Data collection and analysis
Data were extracted independently by two review authors. We extracted any available data on the number or proportion of patients with ‘no worse than mild pain’ or treatment success (very satisfied, or very good or excellent on patient global impression scales), together with information about adverse events and withdrawals.
We identified nine studies meeting the inclusion criteria, including a Turkish study that is awaiting formal translation. There were 1244 participants randomised in classically designed RCTs, of whom 1197 had evaluable data, and 138 patients enrolled in an enriched enrolment, randomised withdrawal (EERW) trial. Overall, 600 participants were treated with transdermal fentanyl patches, 382 with various formulations of morphine, 36 with methadone, and 221 with paracetamol plus codeine. There were major sources of potential bias, including lack of blinding, small size, high levels of attrition, and inconsistent reporting.
We could not compare data in a meaningful analysis regarding adverse events such as nausea, abdominal pain, gastrointestinal bleeding, and confusion. These events may have been attributable to the underlying disease process.
There were insufficient comparable data for meta‐analysis to be undertaken or to produce numbers needed to treat (NNT) for the analgesic effect. In seven studies with 461 participants reporting pain intensity results after about two weeks, the mean or median pain scores were on the borderline of mild and moderate pain. Most participants would have had no worse than mild pain on treatment. Another reported that 77% of participants using transdermal fentanyl had an undefined successful outcome. Fewer participants experienced constipation with transdermal fentanyl (28%) than with oral morphine (46%), giving a risk ratio of 0.61 (95% CI 0.47 to 0.78); the NNT to prevent constipation was 5.5 (95% CI 3.8 to 10).
The randomised trial literature for effectiveness of transdermal fentanyl is limited, but it is an important medicine. Most studies recruited fewer than 100 participants and did not provide data appropriate for meta‐analysis. Only a few reported how many patients had good pain relief but, where data were reported, a majority had no worse than mild pain within a reasonably short time period. The evidence pointed to a useful and significant reduction in complaints about constipation for transdermal fentanyl compared with oral morphine.
Gina Hadley, Sheena Derry, R Andrew Moore, Philip J Wiffen
Plain language summary
Transdermal fentanyl for cancer pain
Fentanyl patches placed on the skin produced good pain relief for most people with moderate or severe cancer pain.
One person in two or three who gets cancer will suffer from pain that becomes moderate or severe in intensity. The pain tends to get worse as the cancer progresses. Morphine taken by mouth has been used since the 1950s for controlling cancer pain. Since that time a number of different drugs with morphine‐like actions have been produced for treating cancer pain, one of which is fentanyl. Fentanyl is particularly useful because it can be absorbed through the skin from patches. The ability of any drug to achieve consistent drug levels in the blood and the brain could, in theory, lead to better control of cancer pain. It also relieves the need to take medicines several times a day, as patches can often last for several days before changing.
We found nine studies involving 1244 patients. The studies were often small, used different study designs, and compared fentanyl with many different drugs. Most patients had pain that went from moderate or severe before transdermal fentanyl to no worse than mild pain when using transdermal fentanyl. Only 3 in 10 patients were constipated using transdermal fentanyl compared with 5 in 10 using oral morphine. We could not analyse the data in a meaningful way regarding harmful (adverse) events such as nausea, abdominal pain, gastrointestinal bleeding, and confusion. These events may have been attributable to the underlying disease processes.
The effect of the patch can continue after it has been taken off due to medicine that has been taken up by the skin. Used patches need to be disposed of carefully.
We could wish for more consistency in study design, and especially in study reporting, which should include the outcome of pain reduced to tolerable levels – no worse than mild pain – so that patients with cancer are not bothered by pain.
Gina Hadley, Sheena Derry, R Andrew Moore, Philip J Wiffen
Implications for practice
Transdermal fentanyl is already widely used in the palliative care setting, but we found few studies of its use in cancer‐related pain. The studies were small, generally of poor quality, and none reported primary outcomes of importance to clinical practice. However, based on the end of treatment scores for people treated with transdermal fentanyl, we were able to make a judgement of the number of participants who achieved a state of 'no worse than mild pain'. We conclude that if patients were able to tolerate the medication and survived to the end of the study, pain appeared to be improved and the majority of patients would have no worse than mild pain.
In terms of side effects, lower rates of constipation have been demonstrated with transdermal fentanyl. These findings are however subject to the methodological weaknesses identified in the primary literature, and the analysis was conducted based on several assumptions. Rash and pruritis, commonly a concern with transdermal preparations, were in fact infrequent and improved with time. This review is unlikely to change current practice, but will hopefully stimulate further research in the area.
Implications for research
Most studies in this review have very low methodological quality. Future studies should improve their design, use clinically important outcome measures, and be explicit in their methods of analysis so more meaningful comparisons can be made. Given the difficulty of conducting randomised controlled trials in the palliative care setting, observational studies that meet criteria for quality, validity and size could make a significant contribution to studies of cancer pain treatment (Hadley 2009). The single most important development would be the use of outcomes that are important to patients and relevant to clinical practice, namely achieving no worse than mild pain by, say, two weeks of treatment. The efficacy of transdermal fentanyl is comparable to morphine and it probably causes less constipation than morphine. However, clinical decision‐making based on this review would also need to take into account other factors, such as the balance of cost, preference, and speed of response needed (that is not for those who need rapid analgesic titration) when considering treatment for cancer pain.