Description of the condition
Cancer is a common disease. There is a greater than 1 in 3 risk of developing cancer over a person’s lifetime. In 2010 (the latest year for which statistics are available), approximately 325,000 people were diagnosed with cancer in the UK, or nearly 900 each day (Cancer Research UK). A recent review of the pharmacologic management of cancer pain reported that 24% to 62% of adult patients have pain at the time of cancer diagnosis, and almost all patients will be in pain in the terminal stages of the disease (Cleary 2007). Pain can be debilitating and have a serious impact on the quality of life of these patients.
Description of the intervention
Fentanyl patches are available as generic formulations and branded names include Fentalis
How the intervention might work
Fentanyl is a synthetic opioid that acts at the mu opioid receptor. It takes 8 to 16 hours before the full effect of transdermal fentanyl is observed, and steady state is not observed until after two to four applications of the '72-hour' patches. This is because initially there is depot accumulation of the drug within skin tissues (Jeal 1997). Levels in the blood fall gradually by approximately 50% within 16 hours of removal (Lehmann 1992). This prolonged elimination can be problematic with side effects such as hypoventilation, for example (Kornick 2003). Fentanyl is ideal for transdermal administration due to its lipophilicity (Cachia 2011). It is also highly potent and has a low molecular weight (Muijsers 2001), and differs from other opioids in penetration characteristics, for example through the dura (Moore 1982). A transdermal route of administration is useful in patients who are unable to swallow or who have gastrointestinal problems (Kornick 2003).
Why it is important to do this review
A previous meta-analysis has compared the efficacy and safety of transdermal fentanyl and sustained release oral morphine (Clark 2004). This Canadian group, however, looked at both cancer and chronic non-cancer pain, at a variety of study designs, including open label, uncontrolled trials, and randomised trials, and reported group mean results. Some of these study designs and methods are known to introduce bias, leading to overestimation of benefits. Another systematic review of transdermal opioids (fentanyl and buprenorphine) looked at evidence to support use of transdermal formulations as front line agents in moderate to severe cancer pain (Tassinari 2011), but did no quantitative analysis, while a systematic review of adverse events found reduced rates for some events for fentanyl and buprenorphine in a combined analysis compared with slow release morphine (Tassinari 2008).
This Cochrane Review is one of a series of reviews concerning individual drug interventions for cancer pain and will ultimately be included in an overview.
- To determine the analgesic efficacy of transdermal fentanyl for relief of cancer pain.
- To assess the adverse events associated with the use of transdermal fentanyl for relief of cancer pain.
Criteria for considering studies for this review
Types of studies
- Randomised (described as ‘randomised’ anywhere in the manuscript)
- Ideally double blind, but open studies will be included as second tier evidence
- Placebo or active controls, or both
- Minimum of 10 participants per treatment arm
- Studies with a minimum duration of 7 days for efficacy (it can take 'several 72-hour patches to reach steady state' (Jeal 1997))
We excluded non-randomised studies, studies of experimental pain, case reports and clinical observations. Studies had to be fully published or available as extended abstracts (for example from clinical trials websites); we did not include short (usually conference) abstracts.
Types of participants
- Inpatients or outpatients with chronic pain of moderate to severe intensity, due to malignant disease (any stage)
- Male or female
- There were no limits on age
Types of interventions
Transdermal fentanyl (fentanyl patches) compared to placebo or active controls, in any dose, frequency, or duration of treatment.
Types of outcome measures
Pain had to be measured using a validated assessment tool. For pain intensity, for example, this could be a 100 mm visual analogue scale (VAS) (no pain to worst pain imaginable) or a four-point categorical scale (none, mild, moderate, severe), and for pain relief a 100 mm VAS (no relief to complete relief), or five-point categorical scale (none, a little, some, a lot, complete or words to that effect). Measures of ≥ 30% (moderate) and ≥ 50% (substantial) reduction of pain over baseline are recommended outcomes for chronic pain studies from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) (Dworkin 2008). When considering Patient Global Impression of Change (PGIC), ≥ 30% reduction of pain over baseline equates to much improved or very much improved, and ≥ 50% to very much improved.
- Number of participants with pain reduction of ≥ 30% from baseline
- Number of participants with pain reduction of ≥ 50% from baseline
- Number of participants with pain no worse than mild
- Number of participants with PGIC of much improved or very much improved (or equivalent wording)
- Quality of life measures
- Use of rescue medication
- Patient satisfaction or preference
- Adverse events: any, serious
- Attrition: withdrawals due to lack of efficacy or adverse events (including death)
Search methods for identification of studies
We searched the following databases:
- the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 4);
- MEDLINE (1950 to 3 May 2013);
- EMBASE (1974 to 3 May 2013);
- CANCERLIT (PubMED) (searched to November 2012).
Searching other resources
- All included studies
- Key textbooks
- Previous systematic reviews
- Personal communication with authors
- Personal communication with pharmaceutical companies
There was no language restriction.
Data collection and analysis
Selection of studies
Two review authors independently read the titles and abstracts of all studies identified by the searches, and excluded those that clearly did not meet the inclusion criteria. For the remaining studies, we read the full manuscript to assess if it should be included. We resolved discrepancies between review authors by discussion; if necessary a third review author would have been consulted. We did not anonymise studies before selection.
Data extraction and management
Two review authors independently extracted data using a standard form and agreed on the data before entry into RevMan (RevMan 2011). Data extracted included information about the number of participants treated and demographic details, type of cancer, drug and dosing regimen, study design (placebo or active control) and methods, study duration and follow-up, analgesic outcome measures and results, withdrawals and adverse events.
Assessment of risk of bias in included studies
We assessed methodological quality using a validated scoring system (Jadad 1996) (Appendix 4). Two authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion. The following were assessed for each study.
- Random sequence generation (checking for possible selection bias). The method used to generate the allocation sequence was assessed as: low risk of bias (any truly random process, e.g. random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). Studies using a non-random process (e.g. odd or even date of birth; hospital or clinic record number) were excluded.
- Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment and whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment, was assessed as: low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). Studies that did not conceal allocation (e.g. open list) were excluded.
- Blinding of outcome assessment (checking for possible detection bias). The methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received were assessed as: low risk of bias (study stated that it was blinded and describes the method used to achieve blinding e.g. identical tablets; matched in appearance and smell); unclear risk of bias (study stated that it was blinded but does not provide an adequate description of how it was achieved); high risk of bias (studies that were not double blind).
- Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). The methods used to deal with incomplete data were assessed as: low risk (< 10% of participants did not complete the study; or used ‘baseline observation carried forward’ analysis); unclear risk of bias (used 'last observation carried forward' analysis); high risk of bias (used 'completer' analysis).
- Size of study (checking for possible biases confounded by small size). Studies were assessed as being at: low risk of bias (≥ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (< 50 participants per treatment arm).
Measures of treatment effect
We used dichotomous data to calculate risk ratios (RR) with 95% confidence intervals (CI), and calculated numbers needed to treat to benefit (NNTs) as the reciprocal of the absolute risk reduction (McQuay 1998). For unwanted effects, the NNT becomes the number needed to treat to harm (NNH), and is calculated in the same manner.
We use the following terms to describe adverse outcomes in terms of harm or prevention of harm.
- When significantly fewer adverse outcomes occur with fentanyl than with control (placebo or active) we use the term number needed to treat to prevent one event (NNTp).
- When significantly more adverse outcomes occur with fentanyl compared with control (placebo or active) we use the term number needed to harm or cause one event (NNH).
We did not plan to use continuous data for the primary outcome because it is inappropriate where there is an underlying skewed distribution, as is usually the case with analgesic response.
Unit of analysis issues
The unit of randomisation was the individual patient.
Dealing with missing data
We planned to use intention-to-treat (ITT) analysis: participants who were randomised, took the study medication and gave a minimum of one post-baseline assessment. Where there were missing participants or information, we assigned them to a zero improvement category where possible. We also looked for information about how data from withdrawals and dropouts were handled. In original studies, patients may have been analysed using ‘last observation carried forward' (that is their level of pain when stopping the medication), or returned to their baseline observation.
Where there were substantial numbers (> 10%) of participants missing from analyses, we comment on this. There were insufficient data for sensitivity analyses.
Assessment of heterogeneity
We planned to assess statistical heterogeneity using L'Abbé plots, a visual method for assessing differences in results of individual studies (L'Abbé 1987), and by use of the I
The aim of this review was to use dichotomous data of known utility (Moore 2010). The review does not depend on what authors of the original studies chose to report or not.
We carried out data synthesis and statistical analysis using the Review Manager software (RevMan 2011). Where appropriate, we pooled data for each dichotomous outcome and calculated RRs with 95% CIs using the fixed-effect model (Morris 1995), together with NNTs with 95% CIs (Cook 1995). We assumed a statistically significant benefit of active treatment over control when the lower limit of the 95% CI of the RR was greater than one, and of control over active treatment when the upper limit of the 95% CI was less than one. RR and NNH were calculated for adverse outcomes in the same way.
We planned to analyse studies carried out under double blind conditions separately from those that were not. We did not carry out pooled analysis where there would be fewer than 200 participants in the comparison (Moore 1998).
We planned to test for statistically significant differences between subgroups using the z test (Tramèr 1997).
Subgroup analysis and investigation of heterogeneity
We planned subgroup analysis for different types of cancer and different areas of the body, but were able only to distinguish differences in overall death rates between participants with primary cancers and those with metastatic disease.
Different doses were not considered as patients are titrated to effective dose.
We planned to carry out sensitivity analyses for duration of study, age of participants (< 18 years versus ≥ 18 years), and setting (inpatient versus outpatient), but there were insufficient data.
Description of studies
All studies were identified using electronic database searches; no additional studies were found through communication with Janssen-Cliag UK.
We identified nine studies meeting the inclusion criteria (Ahmedzai 1997; Kongsgaard 1998; Kress 2008; Mercadante 2008; Mystakidou 2005; Oztürk 2008; Pistevou-Gompaki 2004; van Seventer 2003; Wong 1997).
There were 1244 participants randomised in classically designed randomised controlled trials, of whom 1197 had evaluable data, and 138 patients enrolled in an enriched enrolment, randomised withdrawal (EERW) trial (Kongsgaard 1998). In total, 600 participants were treated with transdermal fentanyl patches, 382 with various formulations of morphine, 36 with methadone, and 221 with paracetamol plus codeine.
Details of individual studies are in the Characteristics of included studies table. The mean age of participants in the included studies was 59 to 65 years (range 18 to 91 years), and 57% were male. There were no studies in children.
Type of cancer
Two studies (Mystakidou 2005; Pistevou-Gompaki 2004) specifically concentrated on the pain of bony metastasis; sites included thoracic spine, lumbar spine, cervical spine, thoracic and lumbar spine, pelvis, limbs, and scapula. The remaining studies enrolled participants with primary cancer; sites included lung, prostate, breast, stomach or gallbladder, kidney, uterus, liver, head and neck, pancreas, multiple myeloma, cervical, and other or unknown.
Life expectancy or performance status criteria
The majority of studies made some estimation of life expectancy or performance status criteria at enrolment.
- Life expectancy > 1 month (Ahmedzai 1997).
The following study designs were used.
- One randomised, double blind, placebo controlled EERW study: double blind period of nine days (Kongsgaard 1998).
- One open label, active controlled, cross-over study: 2 x 15 day treatment periods with no washout (Ahmedzai 1997).
All studies except Pistevou-Gompaki 2004 titrated the dose of medication at the start, and rescue medication was available.
Transdermal fentanyl versus oral morphine
- Transdermal fentanyl patch (TDF) every 72 hours versus sustained release oral morphine (SRM) every 12 hours (Ahmedzai 1997). N = 202 (TDF 122, SRM 122).
- Fentanyl investigational matrix patch (FIT) versus standard opioid treatment (Durogesic patch (TDF) or Oramorph) (Kress 2008). N = 220 (FIT 117, Durogesic 65, Oramorph 38).
- TDF versus SRM or oral methadone (Mercadante 2008). N = 108 (TDF 36, SRM 36, methadone 36).
- TDF versus SRM (Oztürk 2008). N = 50 (TDF 25, SRM 25).
- TDF every 72 hours versus SRM every 12 hours (van Seventer 2003). N = 131 (TDF 67, SRM 64).
- TDF every 72 hours versus SRM every 12 hours (Wong 1997). N = 47 (TDF 20, SRM 20).
Transdermal fentanyl versus paracetamol and codeine
- Radiotherapy plus: TDF every 72 hours or paracetamol plus codeine (P/C) four times daily (Mystakidou 2005). N = 460 (TDF 201, P/C 221).
- Radiotherapy plus: TDF every 72 hours or paracetamol plus codeine (P/C) four times daily (Pistevou-Gompaki 2004). N = 26 (TDF 13, P/C 13).
Transdermal fentanyl versus placebo
- TDF or placebo (Kongsgaard 1998). N = 138 (TDF 47, placebo 48, not randomised 43).
Pain and analgesic measurement tools
Studies used a variety of pain and analgesic measurement tools. Almost half used a visual analogue scale (VAS) (Ahmedzai 1997; Kongsgaard 1998; Mystakidou 2005; Pistevou-Gompaki 2004) and two used the Greek brief pain inventory (G-BPI) 0 to 10 (Mystakidou 2005; Pistevou-Gompaki 2004). A detailed list of tools for each study can be found in the Characteristics of included studies table.
Risk of bias in included studies
We assessed the methodological quality of each study using the Oxford Quality Scale (Jadad 1996), which awards points for adequate reporting of randomisation (2), blinding (2), and study withdrawals (1). Overall, the methodological quality of the included studies was poor, with a median score of two (range one to three); studies scoring three or more give more conservative estimates of effect. The results for each study can be found in the Characteristics of included studies section.
We also assessed each study using the Cochrane risk of bias tool. Overall findings are presented in the 'Risk of bias' graph (Figure 1), which reviews the authors' judgements about each risk of bias item presented as percentages across all included studies, and the 'Risk of bias' summary (Figure 2), which reviews the authors' judgements about each risk of bias item for each included study.
|Figure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
All studies reported that they were randomised, but only one properly described the method used to generate the random sequence (Mercadante 2008), and only one adequately described the method used to conceal the allocation (Kress 2008).
Only one study (Kongsgaard 1998) was double blind, although there was an inadequate description of how sequence generation and allocation were achieved.
Incomplete outcome data
Five studies (Ahmedzai 1997; Mercadante 2008; Mystakidou 2005; Oztürk 2008; Wong 1997) analysed only participants who completed the study, and another (van Seventer 2003) used last observation carried forward imputation; these studies were considered to be at high risk of bias. Kongsgaard 1998 reported an ITT analysis, but in both this and Pistevou-Gompaki 2004, the imputation method was unclear; these studies were considered to be at unknown risk of bias. Kress 2008 was not a true ITT analysis because participants with missing values for any analysis did not contribute to that analysis.
Other potential sources of bias
Treatment group size was an issue. Small studies are thought to be at increased risk of bias, probably because the conduct of small studies is more likely to be less rigorous, allowing critical criteria to be compromised. Only one of the treatment groups in this review was large enough to give a low risk of bias (Mystakidou 2005). Four studies (Ahmedzai 1997; Kress 2008; Oztürk 2008; van Seventer 2003) were judged to have an unclear risk of bias due to size, and four, notably including the only double blind placebo controlled trial (Kongsgaard 1998), were judged to carry a high risk of bias.
Effects of interventions
None of the studies we identified reported any of our pre-specified primary outcomes. We were, however, able to make a judgement as to outcomes equivalent to no worse than mild pain.
No worse than mild pain
We examined reports to ascertain whether an outcome of no worse than mild pain was achieved, based on a VAS pain intensity of 30 mm or less on a 100 mm scale or the equivalent in other pain scales. Seven studies reported an outcome indicating achievement of this level of pain relief, for the most part apparently using data from completers, and all reporting mean outcomes (Kress 2008; Mercadante 2008; Mystakidou 2005; Oztürk 2008; Pistevou-Gompaki 2004; van Seventer 2003; Wong 1997). Summary table A shows that for all 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. The indications were therefore that most participants would have had no worse than mild pain on treatment.
In addition, Ahmedzai 1997 reported that 94/122 participants on transdermal fentanyl had a successful outcome (not clearly defined). Kongsgaard 1998 by contrast reported an outcome of no worse than moderate pain, but it was unclear what that meant.
Results for comparator drugs indicated a similar response with SRM, Durogesic patch, Oramorph, and methadone, and a slightly reduced response with paracetamol plus codeine.
Summary table B below describes patients experiencing any adverse event, but it was not always possible to attribute the adverse event to a specific group.
Specific adverse events
In four studies (Ahmedzai 1997; Oztürk 2008; van Seventer 2003; Wong 1997) it was possible to compare the impact of constipation between TDF and SRM (Figure 3; Analysis 1.1). Fewer participants experienced constipation with TDF (28%) than with oral SRM (46%), giving a risk ratio of 0.61 (95% CI 0.47 to 0.78); the NNTp was 5.5 (3.8 to 10). This analysis was however conducted making assumptions about the primary data it was based upon. The numbers used were not ITT, they were based on completers and those who reported on adverse events. In Ahmedzai 1997 for example, data were taken from the 'bowel function' questionnaire rather than 'adverse events'. Data used from van Seventer 2003 were taken from patients reporting constipation at 28 days in Table 5 of that paper. Wong 1997 reported constipation in completers only.
|Figure 3. Forest plot of comparison: 1 Fentanyl versus sustained release morphine, outcome: 1.1 Constipation.|
Reports of constipation were inconsistent. Constipation rates were much higher when bowel function was specifically asked about, using a questionnaire in Ahmedzai 1997 and direct questioning in van Seventer 2003, which may well skew the data. Using constipation reported as an adverse event in Ahmedzai 1997 and van Seventer 2003 gave a relative risk of 0.50 (0.34 to 0.74) and an NNTp of 8.2 (5.2 to 19).
Rash and pruritis
Rash and pruritis are adverse effects commonly associated with fentanyl patches. In the studies that reported on these the rates were low and symptoms improved with time. In the 161 participants who received skin assessments in the study by Ahmedzai 1997, five (3%) patients had erythema, eight had mild itching, and three (2%) had moderate itching at the patch site after the patches were removed. Over a two-week period in Mystakidou 2005, 3/201 patients in the TDF group and 2/221 patients in the P/C group were noted as having rash or pruritis. In Wong 1997 two patients in the TDF group had itching and a skin rash which improved with time.
Other adverse events included nausea, vomiting, dry mouth, gastritis, abdominal pain, gastrointestinal haemorrhage, and confusion. It is difficult to say how many of these could be attributed to the underlying disease process, and no meaningful analysis was possible.
Serious adverse events
No serious adverse events were judged to be attributable to the study medications.
The participants included in this review had an inherently high risk of mortality. It was impossible to accurately predict life expectancy, but most studies tried to ensure that those that enrolled would survive to the end of the study, based on their clinical condition at entry. Ahmedzai 1997 reported 14 deaths as a reason for study withdrawal (eight in the group fentanyl then morphine and six in the group morphine then fentanyl). Kress 2008 listed death as the reason for four participants withdrawing from the study (including one suicide). In addition, they reported that seven participants (6%) treated with the FIT patch and 12 (12%) treated with standard therapy died. There was one death reported in each of the SRM and TDF groups in Mercadante 2008. Seven of the withdrawals in Mystakidou 2005 were attributable to death; the group to which they belonged was not specified. Pistevou-Gompaki 2004 reported one death due to advanced lung cancer in the fentanyl group, van Seventer 2003 reported seven deaths in the fentanyl group and four in the morphine group, and two patients died in the Wong 1997 study, although they are not attributed to a particular group. There were four deaths during the open label titration phase of Kongsgaard 1998, all attributed to disease progression. Oztürk 2008 did not report any deaths in the 15-day study period. The number of participants who died is given in Summary table C.
Summary table C: deaths in studies where reported
Over the period of all of the studies, almost 5% of the participants died. In studies lasting one month or less (participants with primary cancers) the death rate was 6.8%, and in those lasting two or three months (participants with bony metastases) it was 1.6%.
Withdrawal due to adverse events
Trials conducted in the palliative care setting inherently have a high dropout rate due to the frailty of the patients included. Most studies provided some information on withdrawals (Ahmedzai 1997; Kongsgaard 1998; Kress 2008; Mercadante 2008; Mystakidou 2005; Pistevou-Gompaki 2004; van Seventer 2003). However, withdrawals were not always reported per treatment group and few data were reported according to ITT, as many patients were not accounted for.
Five studies reported withdrawal of participants due to adverse events (Ahmedzai 1997; Kress 2008; Mystakidou 2005; van Seventer 2003; Wong 1997). In three it was not clear whether participants withdrew whilst taking TDF or SRM (Ahmedzai 1997; Mystakidou 2005; Wong 1997). Furthermore, due to the unethical nature of prolonged washout, in the cross-over study (Ahmedzai 1997) it was impossible to say whether adverse effects were due to morphine withdrawal in the TDF phase.
Summary table D lists the adverse event withdrawals described. Since not all studies reported adverse event withdrawals, and of those that did some did not specify in which group they occurred, it was possible to derive only a crude withdrawal rate of 9% from these studies. In only one study (van Seventer 2003) was there a clear difference in adverse event withdrawals between groups (TDF and SRM), but group numbers were too small to draw any conclusions.
Summary table D: adverse event withdrawals
Summary of main results
For studies in cancer pain, it is useful to know what proportion of patients starting treatment are likely to be able to tolerate it, and what proportion of those who tolerate it are likely to obtain adequate pain relief. The studies did not report results in a way that unequivocally answers these questions.
None of our preferred outcomes were reported in any of the studies, but we were able to make a judgement of the number of participants who achieved a low pain state equivalent to 'no worse than mild pain'. It is clear that a majority of participants were able to continue with therapy for at least two to four weeks, and that the majority of those on therapy achieved this low pain state. This result is in general agreement with that for oral morphine (Wiffen 2013).
Overall completeness and applicability of evidence
Given the wide use of transdermal fentanyl in the palliative care setting, the evidence base for its use is limited. Studies enrolled patients who displayed heterogeneity in both the underlying malignancy and resultant pain. Two studies concentrated on painful bony metastasis, but again with heterogeneous primary cancer types. Comparator interventions ranged from a placebo control to paracetamol plus codeine and sustained relief oral morphine.
The only meaningful analysis when it came to adverse events concerned constipation. This analysis made a number of assumptions but seemed to favour transdermal fentanyl over oral morphine for lower rates of this troublesome side effect. Rash or pruritis is often quoted as a problem with transdermal fentanyl, but where reported in these studies it occurred at low rates and seemed to improve over time.
One of the useful outcomes from this systematic review is to highlight the inherent mortality of patients enrolled in these studies. Even though most studies included some measure of prognosis to ensure that life expectancy exceeded that of the proposed study duration, almost 7% of participants being treated for their primary cancer died over a study period of one month.
Quality of the evidence
The quality of evidence in these studies is severely limited. Overall, the methodological quality of the included trials was poor with a median quality score of two (range one to three) on the Oxford Quality Scale. Of the nine studies, only one was double blind and placebo controlled. It scored 3/5 on the Oxford Quality Scale due to failure to report the methods used to generate the random sequence and maintain blinding, and was judged to be at 'high risk of bias' using the risk of bias tool, owing to small sample size.
Potential biases in the review process
We are unaware of any potential biases in the review process.
Agreements and disagreements with other studies or reviews
This is the first systematic review looking at transdermal fentanyl in cancer pain compared to placebo or active controls. In a systematic review of adverse effects, comparing transdermal opiates with slow release morphine in moderate-severe cancer pain, there was no overall difference in the adverse effect profile (Tassinari 2008). There was agreement with our finding that constipation was less of an issue in patients treated with transdermal fentanyl (taking into account the assumptions made concerning the primary literature upon which the analysis was based).
In their review of transdermal opioids in moderate to severe cancer pain, Tassinari 2011 concluded that slow release oral morphine was favoured, with transdermal opioids only recommended for use in selected patients. However, no quantitative analyses were undertaken.
In a recent systematic review of randomised trials evaluating the effectiveness of opioids in cancer pain, ‘fair evidence' was found for the effectiveness of transdermal fentanyl whereas other opioids were evaluated as being 'poorly efficacious' (Koyyalagunta 2012). This review excluded Kress 2008 because the ‘Cochrane score’ assigned to it did not meet the review's inclusion criteria. The included studies were van Seventer 2003, Mystakidou 2005, Mercadante 2008, and Marinangeli 2007. The latter study was a prospective randomised open label study looking at the influence of tramadol on dose adjustment of transdermal fentanyl in advanced cancer pain, and did not meet our inclusion criteria.
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.
This review received infrastructure support from the Oxford Pain Relief Trust. The authors would like to thank Hatun Bulut, a student at Wycliffe Hall, University of Oxford for her translation of Oztürk 2008.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. MEDLINE (via Ovid) search strategy
- exp Fentanyl/
- (fentanyl or phentanyl or fentora or durogesic or duragesic or fentanest or sublimaze or r-4263 or r4263).mp.
- 1 or 2
- exp Neoplasms/
- (neoplasm* or cancer* or carcinoma* or malignan* or tumor* or tumour* or adenocarcinoma* or choriocarcinoma* or leukemia* or leukaemia* or metasta* or sarcoma* or teratoma*).mp.
- 4 or 5
- exp Pain/
- Pain Management/
- Pain Measurement/
- 7 or 8 or 9 or 10
- 3 and 6 and 11
- randomized controlled trial.pt.
- controlled clinical trial.pt.
- drug therapy.fs.
- 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20
- 12 and 21
Appendix 2. EMBASE (via Ovid) search strategy
- exp fentanyl/
- (fentanyl or phentanyl or fentora or durogesic or duragesic or fentanest or sublimaze or r-4263 or r4263).mp.
- 1 or 2
- exp neoplasm/
- (neoplasm* or cancer* or carcinoma* or malignan* or tumor* or tumour* or adenocarcinoma* or choriocarcinoma* or leukemia* or leukaemia* or metasta* or sarcoma* or teratoma*).mp.
- 4 or 5
- exp pain/
- 7 or 8
- randomized controlled trial/
- 10 or 11 or 12 or 13 or 14
Appendix 3. CENTRAL search strategy
- MeSH descriptor: [Fentanyl] explode all trees
- (fentanyl or phentanyl or fentora or durogesic or duragesic or fentanest or sublimaze or r-4263 or r4263):ti,ab,kw
- #1 or #2
- MeSH descriptor: [Neoplasms] explode all trees
- (neoplasm* or cancer* or carcinoma* or malignan* or tumor* or tumour* or adenocarcinoma* or choriocarcinoma* or leukemia* or leukaemia* or metasta* or sarcoma* or teratoma*):ti,ab,kw
- #4 or #5
- MeSH descriptor: [Pain] explode all trees
- pain or painful or analgesi*:ti,ab,kw
- #7 or #8
- #3 and #6 and #9
- Limit #10 to Clinical Trials (CENTRAL)
#19 Search (#18) AND #9
#18 Search (#10 or #11 or #12 or #13 or #14 or #15 or #16 or #17)
#17 Search groups [tiab]
#16 Search trial [tiab]
#15 Search randomly [tiab]
#14 Search drug therapy [sh]
#13 Search placebo [tiab]
#12 Search randomized [tiab]
#11 Search controlled clinical trial [pt]
#10 Search randomized controlled trial [pt]
#9 Search (#8) AND #2 Filters: Cancer
#8 Search (((#7) OR #6) OR #5) OR #4 Filters: Cancer
#7 Search pain*[Title/Abstract] Filters: Cancer
#6 Search Pain Measurement[MeSH Major Topic] Filters: Cancer
#5 Search Pain Management[MeSH Major Topic] Filters: Cancer
#4 Search pain[MeSH Terms] Filters: Cancer
#3 Search (#1) OR #2 Filters: Cancer
#2 Search ((fentanyl or phentanyl or fentora or durogesic or duragesic or fentanest or sublimaze or r-4263 or r4263).[Title/Abstract]) Filters: Cancer
#1 Search Fentanyl[MeSH Terms] Filters: Cancer
Appendix 4. Assessing methodological quality
Validated scoring system (Jadad 1996):
- Was the study described as randomised? (1 point)
- Is the randomisation appropriate? (1 point)
Deduct one point if the method of randomisation is inappropriate
- Was the study described as double blind?
- Is the blinding appropriate?
Deduct one point if the method of blinding is inappropriate
- Was there a description of withdrawals and dropouts?
Appendix 5. Results for individual studies
Contributions of authors
All authors contributed to writing the protocol. GH and SD carried out searches, study selection, data extraction, and analyses. All authors were involved in interpretation and writing the review. RAM and PW acted as arbitrators in the event of disagreement.
Declarations of interest
RAM and SD have received research support from charities, government, and industry sources at various times. RAM has consulted for various pharmaceutical companies, and has received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions. PW and GH have no relevant interests to declare.
Sources of support
- Oxford Pain Relief Trust, UK.General institutional support
- No sources of support supplied
Medical Subject Headings (MeSH)
Administration, Cutaneous; Analgesics, Opioid [*administration & dosage]; Fentanyl [*administration & dosage]; Methadone [administration & dosage]; Morphine [administration & dosage]; Neoplasms [*complications]; Pain [*drug therapy; etiology]; Pain Measurement; Randomized Controlled Trials as Topic
MeSH check words