Tramadol with or without paracetamol (acetaminophen) for cancer pain Stable (no update expected for reasons given in 'What's new')
Tramadol is an opioid analgesic licensed for use in moderate to severe pain. It is considered as a low risk for abuse, so control regulations are not as stringent as for 'strong' opioids such as morphine. It has a potential role as a step 2 option of the World Health Organization (WHO) analgesic ladder.
To assess the benefits and adverse effects of tramadol with or without paracetamol (acetaminophen) for cancer‐related pain.
We searched the following databases using a wide range of search terms: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched three clinical trials registry databases. The date of the last search was 2 November 2016.
We selected studies that were randomised, with placebo or active controls, or both, and included a minimum of 10 participants per treatment arm. We were interested particularly in blinded studies, but also included open studies.
We excluded non‐randomised studies, studies of experimental pain, case reports, and clinical observations.
Data collection and analysis
Two review authors independently extracted data using a standard form and checked for agreement before entry into Review Manager 5. We 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. We collated multiple reports of the same study, so that each study, rather than each report, was the unit of interest in the review. We assessed the evidence using GRADE and created a 'Summary of findings' table.
The main outcomes of interest for benefit were pain reduction of 30% or greater and 50% or greater from baseline, participants with pain no worse than mild, and participants feeling much improved or very much improved.
We included 10 studies (12 reports) with 958 adult participants. All the studies enrolled participants with chronic malignant tumour‐related pain who were experiencing pain intensities described as moderate to severe, with most experiencing at least 4/10 with current treatment. The mean ages were 59 to 70 years, with participants aged between 24 and 87 years. Study length ranged from one day to six months. Five studies used a cross‐over design. Tramadol doses ranged from 50 mg as single dose to 600 mg per day; doses of 300 mg per day to 400 mg per day were most common.
Nine studies were at high risk of bias for one to four criteria (only one high risk of bias for size). We judged all the results to be very low quality evidence because of widespread lack of blinding of outcome assessment, inadequately described sequence generation, allocation concealment, and small numbers of participants and events. Important outcomes were poorly reported. There were eight different active comparators and one comparison with placebo. There was little information available for any comparison and no firm conclusions could be drawn for any outcome.
Single comparisons of oral tramadol with codeine plus paracetamol, of dihydrocodeine, and of rectal versus oral tramadol provided no data for key outcomes. One study used tramadol combined with paracetamol; four participants received this intervention. One study compared tramadol with flupirtine ‐ a drug that is no longer available. One study compared tramadol with placebo and a combination of cobrotoxin, tramadol, and ibuprofen, but the dosing schedule poorly explained.
Two studies (191 participants) compared tramadol with buprenorphine. One study (131 participants) reported a similar proportion of no or mild pain at 14 days.
Three studies (300 participants) compared tramadol with morphine. Only one study, combining tramadol, tramadol plus paracetamol, and paracetamol plus codeine as a single weak‐opioid group reported results. Weak opioid produced reduction in pain of at least 30% from baseline in 55/117 (47%) participants, compared with 91/110 (82%) participants with morphine. Weak opioid produced reduction in pain of at least 50% in 49/117 (42%) participants, compared with 83/110 (75%) participants with morphine.
There was no useful information for any other outcome of benefit or harm.
There is limited, very low quality, evidence from randomised controlled trials that tramadol produced pain relief in some adults with pain due to cancer and no evidence at all for children. There is very low quality evidence that it is not as effective as morphine. This review does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high. The place of tramadol in managing cancer pain and its role as step 2 of the WHO analgesic ladder is unclear.
Philip J Wiffen, Sheena Derry, R Andrew Moore
Plain language summary
Tramadol with or without paracetamol (acetaminophen) for cancer pain
No firm conclusions could be drawn about the effectiveness or harms of tramadol, alone or with paracetamol, in 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.
Tramadol hydrochloride is an opioid analgesic available since 1977. In 2016, tramadol, alone or in combination with paracetamol, was available in products for oral use and by injection from almost 90 companies. Oral formulations include those designed for immediate release, and for modified release over a longer time. Preparations for rectal administration are also available.
In this review, we set out to estimate how well tramadol worked, how many people had side effects, and how severe those side effects were ‐ for example, whether they were so severe that participants stopped taking their tramadol.
In November 2016, we found 10 studies with 958 adult participants and no studies in children. The studies were often small and compared different tramadol preparations with different comparator drugs, and did not report important outcomes well. This made it difficult to work out whether tramadol was as good or better or worse than any other drug for cancer pain.
No firm conclusions could be drawn for any outcome in any comparison. Tramadol may not be as good as morphine.
Quality of evidence
We judged all the evidence available to be of very low quality. This means that the research does not provide a reliable indication of the likely effect.
Philip J Wiffen, Sheena Derry, R Andrew Moore
Implications for practice
For people with cancer pain
There is limited very low quality evidence from randomised controlled trials that tramadol produces pain relief in some adults with pain due to cancer. The place of tramadol in managing cancer pain is unclear.
For clinicians managing cancer pain
There are few options to treat mild to moderate cancer pain before moving to strong opioids such as morphine. There is no clear evidence to support the use of tramadol in mild to moderate pain, or severe pain.
For policy makers
Tramadol may have a role if other opioids are not tolerated, providing the issues of dose titration and possible severe adverse effects are considered. There is no information for the use of tramadol in paediatrics.
For organisations or bodies making decisions about funding treatment options
Tramadol may have a place on formularies but its role as an analgesic for cancer pain is unclear.
Implications for research
Research in this patient population is challenging, and a large trial of high quality that minimises bias has not been conducted. Furthermore, there are few options for step 2 on the WHO analgesic ladder.
Implications for study design
Key issues for study design are now well understood, yet we continue to see published studies that do not adequately describe randomisation and allocation concealment. Blinding of studies is still not routinely undertaken, and numbers of participants remain low (Bandieri 2016). These issues should be of concern to research ethics committees.
Implications for measurement and outcomes
As the distribution of response to analgesics is often bimodal, we strongly recommend the collection of dichotomous data in preference to mean pain scores. Data should be available to allow the estimation of the proportion of participants who achieve no worse than mild pain, defined as below 30 mm on a 100‐mm visual analogue scale (VAS) pain intensity scale. Adverse events should always be reported but we advocate specific reporting of events affecting appetite, thirst, consciousness, and somnolence ‐ issues that seriously affect people's lives in the last stages of illness.
Other considerations for future study design include:
- use of standard and comparable pain intensity scores, which would allow closer comparison between different studies and potentially facilitate meta‐analysis;
- inclusion of only participant‐reported pain and other data;
- larger numbers of participants in studies where differentiation by condition has been attempted, to answer the question as to whether tramadol is particularly valuable in cancer‐related bone or neuropathic pain;
- participant satisfaction and quality of life appraisal.
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