Buprenorphine for treating cancer pain
Many patients with cancer experience moderate to severe pain that requires treatment with strong analgesics. Buprenorphine, fentanyl and morphine are examples of strong opioids used for the relief of cancer pain. Strong opioids are, however, not effective for pain in all patients nor are they well‐tolerated by all patients. The aim of this Cochrane review is to assess whether buprenorphine is associated with superior, inferior or equal pain relief and tolerability compared to other analgesic options for patients with cancer pain.
To assess the effectiveness and tolerability of buprenorphine for pain in adults and children with cancer.
We searched CENTRAL (the Cochrane Library) issue 12 or 12 2014, MEDLINE (via OVID) 1948 to 20 January 2015, EMBASE (via OVID) 1980 to 20 January 2015, ISI Web of Science (SCI‐EXPANDED & CPCI‐S) to 20 January 2015, ISI BIOSIS 1969 to 20 January 2015. We also searched ClinicalTrials.gov (http://clinicaltrials.gov/; metaRegister of Controlled Trials (mRCT) (http://www.controlled‐trials.com/mrct/), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/) and the Proceedings of the Congress of the European Federation of International Association for the Study of Pain (IASP; via European Journal of Pain Supplements) on 16 February 2015. We checked the bibliographic references of identified studies as well as relevant studies and systematic reviews to find additional trials not identified by the electronic searches. We contacted authors of included studies for other relevant studies.
We included randomised controlled trials, with parallel‐group or crossover design, comparing buprenorphine (any formulation and any route of administration) with placebo or an active drug (including buprenorphine) for cancer background pain in adults and children.
Data collection and analysis
Two review authors independently extracted data pertaining to study design, participant details (including age, cancer characteristics, previous analgesic medication and setting), interventions (including details about titration) and outcomes, and independently assessed the quality of the included studies according to standard Cochrane methodology. As it was not feasible to meta‐analyse the data, we summarised the results narratively. We assessed the overall quality of the evidence for each outcome using the GRADE approach.
In this Cochrane review we identified 19 relevant studies including a total of 1421 patients that examined 16 different intervention comparisons.
Of the studies that compared buprenorphine to another drug, 11 studies performed comparative analyses between the randomised groups, and five studies found that buprenorphine was superior to the comparison treatment. Three studies found no differences between buprenorphine and the comparison drug, while another three studies found treatment with buprenorphine to be inferior to the alternative treatment in terms of the side effects profile or patients preference/acceptability.
Of the studies that compared different doses or formulations/routes of administration of buprenorphine, pain intensity ratings did not differ significantly between intramuscular buprenorphine and buprenorphine suppository. However, the average severity of dizziness, nausea, vomiting and adverse events as a total were all significantly higher in the intramuscular group relatively to the suppository group (one study).
Sublingual buprenorphine was associated with faster onset of pain relief compared to subdermal buprenorphine, with similar duration analgesia and no significant differences in adverse event rates reported between the treatments (one study).
In terms of transdermal buprenorphine, two studies found it superior to placebo, whereas a third study found no difference between placebo and different doses of transdermal buprenorphine.
The studies that examined different doses of transdermal buprenorphine did not report a clear dose‐response relationship.
The quality of this evidence base was limited by under‐reporting of most bias assessment items (e.g., the patient selection items), by small sample sizes in several included studies, by attrition (with data missing from 8.2% of the enrolled/randomised patients for efficacy and from 14.6% for safety) and by limited or no reporting of the expected outcomes in a number of cases. The evidence for all the outcomes was very low quality.
Based on the available evidence, it is difficult to say where buprenorphine fits in the treatment of cancer pain with strong opioids. However, it might be considered to rank as a fourth‐line option compared to the more standard therapies of morphine, oxycodone and fentanyl, and even there it would only be suitable for some patients. However, palliative care patients are often heterogeneous and complex, so having a number of analgesics available that can be given differently increases patient and prescriber choice. In particular, the sublingual and injectable routes seemed to have a more definable analgesic effect, whereas the transdermal route studies left more questions.
Mia Schmidt‐Hansen, Nathan Bromham, Mark Taubert, Stephanie Arnold, Jennifer S Hilgart
Plain language summary
Buprenorphine for treating people with cancer pain
Buprenorphine produced good pain relief for most people with moderate or severe cancer pain, but its role in the treatment of cancer pain is still unclear.
Many patients with cancer experience moderate‐to‐severe pain that requires treatment with strong pain relief medicines. Buprenorphine and morphine are examples of strong pain relief medicines that are used for the relief of cancer pain. However, strong pain relief medicines are not effective for pain in all patients nor are they well‐tolerated by all patients. The aim of this Cochrane review is to assess whether buprenorphine is associated with better, worse or equal pain relief and tolerability compared to other pain relief medicines for patients with cancer pain.
We searched the literature on 20 Janurary 2015 and found 19 relevant studies with a total of 1421 patients that compared different types of buprenorphine to each other or to other strong pain relief medicines or to placebo. The reported average ages of the patients ranged from 49.1 years to 67.16 years, and the duration of the studies ranged from single dose treatment to six months.
Generally, the studies showed that buprenorphine is an effective strong pain relief medicine that in some cases may be slightly better than other strong pain relief medicines. However, the evidence provided by these studies were of very low quality and on the basis of the available evidence, it is still hard to say where buprenorphine fits in in the treatment of cancer pain with strong opioids. All the strong pain relief medicines examined in the studies are also associated with a number of unwanted effects, such as vomiting, constipation and drowsiness.
Mia Schmidt‐Hansen, Nathan Bromham, Mark Taubert, Stephanie Arnold, Jennifer S Hilgart
Implications for practice
In clinical practice, morphine is accepted as the first‐line strong opioid of choice for the relief of cancer pain; other opioid analgesics such as oxycodone and fentanyl are considered as second‐line options (NICE 2012). Side‐effects can mean that one opioid may need to be substituted with another opioid, so having a wider ranging choice is practical. Furthermore, having a choice with regard to route of administration can be of great importance in some patients, who, for example, are unable to swallow. Data on the efficacy of buprenorphine compared to other opioids in this Cochrane review was of varying, mostly low quality. However, the available data demonstrate that it is an effective pain reliever compared to comparison analgesics in the studies that were analysed. It performed less well in terms of side‐effect profile when compared to other analgesics, such as tramadol.
The results provide the treating clinician with limited data on the efficacy of different routes of administration for buprenorphine. Having said that, in those settings where buprenorphine is seen to be an acceptable drug for treating cancer pain, a clinician may decide that the type of pain may suit one delivery mode more than another. For instance, a patient with pain specifically on movement due to bone metastases may find it useful to have access to SL buprenorphine prior to movement. Also, its quicker action would make it a suitable medication to take, compared to having an injection. It would also mean that the patient could use this analgesic strategy at home, whereas the injectable route would be more dependent on being delivered in a healthcare setting such as a hospital ward or hospice.
Two studies found TD buprenorphine to be superior to placebo (placebo versus TD buprenorphine at 35 μg/h, 52.5 μg/h, 70 μg/h; placebo versus 70 μg/h TD buprenorphine). However, a third study found no difference between placebo and different doses of TD buprenorphine (placebo versus TD buprenorphine at 35 μg/h, 52.5 μg/h, 70 μg/h). Studies examining different doses of TD buprenorphine also did not report a clear dose‐response relationship, making recommendations on starting doses very difficult for the TD route. It also makes guidance on the titration of TD buprenorphine difficult, in so far as it would have to be initiated at the lowest dose, very gradually uptitrated and then have varying, unpredictable efficacy, whereas the response from another analgesics may be more easy to predict and control. TD buprenorphine therefore becomes a less attractive choice for a prescriber who wants to resolve cancer pain swiftly and efficiently.
In summary, clinicians who are faced with a choice of analgesics to consider for cancer pain should use morphine as a first‐line on the grounds of price, at least until inferiority of morphine has been established (NICE 2012). This Cochrane review did not find sufficient evidence to make buprenorphine a valid first‐line choice alongside standard therapies like morphine, oxycodone and fentanyl. However it has a place as an analgesic and its different routes of administration may make it a practical option for limited types of cancer pain, for limited numbers of patient in limited types of clinical setting. Where its place is exactly, is still hard to say. It seems reasonable to suggest that it might be considered to rank as a fourth‐line option compared to the more standard therapies like morphine, oxycodone and fentanyl, and even there it would only be suitable for some patients. Having said that, palliative care patients are often heterogeneous and complex, so having a number of analgesics available that can be given differently increases patient and prescriber choice. In particular, the SL and injectable routes seemed to have a more definable analgesic effect, whereas the TD route studies left more questions than they resolved.
Implications for research
Overall, the evidence was of poor quality. In a large number of studies it was unclear whether an appropriate randomisation sequence had been used. Moreover, we could not establish in any of the included studies whether there had definitely been concealed allocation to the treatment groups. Any future research studies should take this into account. Heterogeneity of methods and outcome reporting was a further problem, which makes it very difficult to apply the current body of evidence to clinical and research settings through further meta‐analytic and summative analyses. There is a need to establish efficacy and safety of buprenorphine in its various formulations and routes, and its dose‐response relationship needs to be analysed further and compared to standard first‐line therapies, such as morphine sulphate, in adequately powered, well‐designed studies of sufficient duration in the setting of cancer pain.