Single fixed‐dose oral dexketoprofen plus tramadol for acute postoperative pain in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the analgesic efficacy and adverse effects of a single fixed‐dose of oral dexketoprofen plus tramadol for moderate to severe postoperative pain in adults, using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes.
Background
This protocol is partly based on suggested wording from the Pain, Palliative and Supportive Care Cochrane Review Group (PaPaS CRG) that has been used in other reviews from this series.
Description of the condition
Acute pain occurs as a result of tissue damage either accidentally due to an injury or as a result of surgery. Acute postoperative pain is a manifestation of inflammation due to tissue injury or nerve injury, or both. The management of postoperative pain and inflammation is a critical component of patient care.
This is one of a series of reviews whose aim is to increase awareness of the range of analgesics that are potentially available, and present evidence for relative analgesic efficacy through indirect comparisons with placebo, in very similar trials performed in a standard manner, with very similar outcomes, and over the same duration. Such relative analgesic efficacy does not in itself determine choice of drug for any situation or person, but guides policy‐making at the local level. The series covers all analgesics licensed for acute postoperative pain in the UK, and dipyrone, which is commonly used in Spain, Portugal, and Latin‐American countries. The results have been examined in overviews of efficacy and harm (Moore 2015a; Moore 2015b), and related individual reviews include ibuprofen (Derry 2009); paracetamol (acetaminophen) (Toms 2008); ketoprofen and dexketoprofen (Barden 2009); codeine (Derry 2010); and combinations such as ibuprofen plus paracetamol (Derry 2013a), ibuprofen plus codeine (Derry 2013b), and paracetamol plus codeine (Toms 2009). Single dose tramadol was the subject of a review of otherwise unpublished clinical trial data (Moore 1997a).
Description of the intervention
Acute pain trials
Single dose trials in acute pain are commonly short in duration, rarely lasting longer than 12 hours. The numbers of participants are small, allowing no reliable conclusions to be drawn about safety. To show that the analgesic is working, it is necessary to use placebo (McQuay 2005). There are clear ethical considerations in doing this. These ethical considerations are answered by using acute pain situations where the pain is expected to go away, and by providing additional analgesia, commonly called rescue analgesia, if the pain has not diminished after about one hour. This is reasonable, because not all participants given an analgesic will have significant pain relief. Approximately 18% of participants given placebo will have significant pain relief (Moore 2006), and up to 50% may have inadequate analgesia with active medicines. Hence, the use of additional or rescue analgesia is important for all participants in the trials.
Clinical trials measuring the efficacy of analgesics in acute pain have been standardised over many years (McQuay 2012). Trials have to be randomised and double‐blind. Typically, in the first few hours or days after an operation, patients develop pain that is moderate to severe in intensity, and will then be given the test analgesic or placebo. Pain is measured using standard pain intensity scales immediately before the intervention, and then using pain intensity and pain relief scales over the following four to six hours for shorter‐acting drugs, and up to 12 or 24 hours for longer‐acting drugs. Pain relief of half the maximum possible pain relief or better (at least 50% pain relief) is typically regarded as a clinically useful outcome (Moore 2011). For patients given rescue medication, it is usual for no additional pain measurements to be made, and for all subsequent measures to be recorded as initial pain intensity or baseline (zero) pain relief (baseline observation carried forward). This process ensures that analgesia from the rescue medication is not wrongly ascribed to the test intervention. In some trials, the last observation is carried forward, which gives an inflated response for the test intervention compared to placebo, but the effect has been shown to be negligible over four to six hours (Moore 2005). Patients usually remain in the hospital or clinic for at least the first six hours following the intervention, with measurements supervised, although they may then be allowed home to make their own measurements in trials of longer duration.
Knowing the relative efficacy of different analgesic drugs at various doses can be helpful (Moore 2015a).
Dexketoprofen
Dexketoprofen is the optically pure S(+)‐enantiomer of ketoprofen, (RS)2‐(3‐benzoylphenyl)‐propionic acid. It is one of the propionic acid class of nonsteroidal anti‐inflammatory drugs (NSAIDs) and has analgesic and antipyretic effects (Moore 2008a). The trometamol salt of dexketoprofen is thought to be particularly rapidly absorbed from the gastrointestinal tract, giving a rapid onset of effects. The duration of effect is only about four to five hours (Barden 2009).
Dexketoprofen is available as 12.5 mg and 25 mg tablets for oral administration, and injectable and topical forms are also available. It is normally used for the treatment of mild to moderate pain over short periods of time. In postoperative pain, its license typically limits its use to about one week, but licensed indications vary between countries. In some countries, it is available without prescription.
Tramadol
Tramadol is a synthetic analogue of codeine. Immediate‐release formulations are usually as 50 mg tablets or capsules, and oral drops (100 mg/mL) and injectable forms are also available. The analgesic effect of tramadol begins after about one hour, and is lasts for about six hours with the immediate‐release formulation (Grond 2004). Sustained‐release formulations (12‐hour and 24‐hour) are available as tablets with doses ranging from 50 mg to 400 mg. It is normally used for treatment of moderate to severe pain.
The fixed‐dose combination is currently at the pre‐registration phase and not yet available, but marketing approval is likely to be sought in the near future (Menarini 2016).
How the intervention might work
NSAIDs are the most commonly prescribed analgesic medications worldwide, and their efficacy for treating acute pain has been well demonstrated (Moore 2003). They reversibly inhibit cyclooxygenase (prostaglandin endoperoxide synthase), the enzyme mediating production of prostaglandins and thromboxane A2 (FitzGerald 2001). Prostaglandins mediate a variety of physiological functions, such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in inflammatory and nociceptive processes. Dexketoprofen, like most NSAIDs, causes reversible inhibition of the cyclooxygenases, which interferes with thromboxane and prostaglandin synthesis, and increases production of anti‐inflammatory lipoxins.
Dexketoprofen is the S(+)‐enantiomer of ketoprofen. This S(+)‐enantiomer is responsible for the analgesic effect seen with racemic ketoprofen, while the R(‐)‐enantiomer is devoid of analgesic activity (Barbanoj 2001). Ketoprofen is one of the most potent in vitro inhibitors of prostaglandin synthesis, but is also implicated as having an association with higher risk of serious gastrointestinal bleeding events than other NSAIDs (Hernández‐Díaz 2000; Laporte 2004). Because the R(‐)‐enantiomer does appear to have ulcerogenic activity, at least in rats (Barbanoj 2001; Herrero 2003), the implication is that use of dexketoprofen alone should produce the same analgesic effect as ketoprofen, but at half the dose, potentially lowering the risk of harm.
Tramadol is a centrally acting analgesic. It has dual action, binding to µ‐opioid receptors and also inhibiting serotonin and noradrenaline (norepinephrine) re‐uptake, with effects on spinal pain transmission. The (+)‐enantiomer of tramadol and its metabolite (+)‐O‐desmethyl‐tramadol are agonists of the µ‐opioid receptor, and (+)‐tramadol is also an inhibitor of serotonin re‐uptake while (‐)‐tramadol is an inhibitor of noradrenaline re‐uptake (Grond 2004). The actions of tramadol are affected by genetic factors, with the principal focus on CYP2D6 polymorphisms, which may be influenced by ethnicity (Lassen 2015).
Combination analgesics
We now have convincing evidence that combining two analgesics can provide additional levels of analgesia in acute pain and headache (Moore 2012; Moore 2015a), and that the drug‐specific effects are essentially additive. Results confirm that the assumption that the efficacy of combination analgesics is the sum of the efficacies of the individual analgesic components is broadly true across a range of different drug combinations, in postoperative pain and migraine headache, and when tested in the same and different trials (Moore 2012). There is no convincing evidence for combination analgesics in chronic pain, however (Chaparro 2012).
Why it is important to do this review
No single analgesic provides good levels of pain relief in everyone, and increasing the dose of an analgesic is likely to increase the problems of adverse events. One approach is to combine two analgesics with different modes of action, with the aim of delivering better analgesia using lower doses of each drug, and therefore potentially reducing adverse events. In similar reviews in acute pain, combination analgesics have provided some of the best results (Moore 2015a).
Menarini have developed a fixed combination of oral dexketoprofen trometamol and tramadol hydrochloride to treat acute pain of moderate to severe intensity. Their rationale was based on the two drugs having different mechanisms of action (peripheral and central) and different pharmacokinetic profiles (rapid onset and long duration). This combination has been tested in clinical trials, is currently at a pre‐registration phase, and marketing approval is likely to be sought in the near future (Menarini 2016).
Objectives
To assess the analgesic efficacy and adverse effects of a single fixed‐dose of oral dexketoprofen plus tramadol for moderate to severe postoperative pain in adults, using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs), with at least 10 participants randomly allocated to each treatment group, and double‐blind assessment of participant outcomes. We will include multiple dose studies if appropriate data from the first dose are available, and cross‐over studies provided that data from the first arm are presented separately or can be obtained.
We will exclude:
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review articles, case reports, and clinical observations;
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studies of experimental pain;
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studies of less than four hours' duration or studies that do not present data over four to six hours post dose.
For postpartum pain, we will include studies if the pain investigated is due to episiotomy or Caesarean section irrespective of the presence of uterine cramps; we will exclude studies investigating pain due to uterine cramps alone.
We will require full journal publication, with the exception of online clinical trial results, summaries of otherwise unpublished clinical trials, and abstracts with sufficient data for analysis.
Types of participants
We will include studies of adults (aged over 15 years) with established postoperative pain of moderate to severe intensity following day surgery or inpatient surgery. For studies using a visual analogue scale (VAS) (see Glossary: Appendix 1), we will consider that pain intensity of greater than 30 mm equates to pain of at least moderate intensity (Collins 1997).
Types of interventions
Dexketoprofen plus tramadol, administered as a single oral dose, for the relief of acute postoperative pain, and compared to placebo.
Types of outcome measures
Primary outcomes
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Participants achieving at least 50% pain relief over a four to six hour period.
Secondary outcomes
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Median (or mean) time to use of rescue medication.
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Number of participants using rescue medication over a four to six hour period.
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Number of participants with: any adverse event; any serious adverse event (as reported in the study); withdrawal due to an adverse event, at the end of the (single dose) study period.
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Other withdrawals: withdrawals for reasons other than lack of efficacy (participants using rescue medication) at the end of the (single dose) study period.
Quality of the evidence
Two review authors (TC, SD) will independently rate the quality of each outcome. We will use the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system to rank the quality of the evidence using the GRADEprofiler Guideline Development Tool software (GRADEpro GDT 2015), and the guidelines provided in Chapter 12.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (Appendix 2).
'Summary of findings' table
We will include a 'Summary of findings' table as set out in the PaPaS author guide (PaPaS 2012) and recommended in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 4.6.6 (Higgins 2011), to present the main findings in a transparent and simple tabular format. In particular, we will include key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes of at least 50% of maximum pain relief over four to six hours, participants using rescue medication within four to six hours, participants with at least one adverse event, and participants with a serious adverse event.
Search methods for identification of studies
Electronic searches
We will search the following databases without language restrictions.
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The Cochrane Central Register of Controlled Trials (CENTRAL) (via CRSO).
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MEDLINE (via Ovid) from 1946 to present.
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EMBASE (via Ovid) from 1974 to present.
We will use controlled vocabulary appropriate for each search platform and text word terms. There will be no language restrictions. We will tailor searches to individual databases. The search strategy for MEDLINE is in Appendix 3.
Searching other resources
We will search clinicaltrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) for ongoing trials. In addition, we will check reference lists of reviews and retrieved articles for additional studies and perform citation searches on key articles. We will contact experts in the field for unpublished and ongoing trials. We will contact study authors where necessary for additional information.
Data collection and analysis
Selection of studies
Two review authors (TC, SD) will independently determine eligibility by reading the abstract of each study identified by the search. Review authors will independently eliminate studies that clearly do not satisfy inclusion criteria, and obtain full copies of the remaining studies. They will read these studies independently to select relevant studies, and in the event of disagreement, a third review author will adjudicate (TP). We will not anonymise the studies before assessment. We will include a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow chart in the full review, which will show the status of identified studies (Moher 2009), as recommended in Part 2, Section 11.2.1 of the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). We will include studies in the review irrespective of whether measured outcome data are reported in a 'usable' way.
Data extraction and management
Two review authors (TC, TP) will independently extract data using a standard form and check for agreement before entry into Review Manager 5 (RevMan 2014). We will collate multiple reports of the same study, so that each study, rather than each report, is the unit of interest in the review. We will collect information about the included studies (eg study methods, study population, baseline pain intensity) in sufficient detail to complete a table of 'Characteristics of included studies' in the full review.
Assessment of risk of bias in included studies
Two review authors (TC, SD) will independently assess risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8, Higgins 2011), and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion. We will complete a 'Risk of bias' table for each included study using the 'Risk of bias' tool in Review Manager 5 (RevMan 2014).
We will assess the following for each study.
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Random sequence generation (checking for possible selection bias). We will assess the method used to generate the allocation sequence as: low risk of bias (any truly random process, eg random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). We will exclude studies using a non‐random process (eg odd or even date of birth; hospital or clinic record number).
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Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We will assess the methods as: low risk of bias (eg telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). We will exclude studies that do not conceal allocation (eg open list).
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Blinding of participants and personnel (checking for possible performance bias). We will assess the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We will assess methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, such as identical tablets matched in appearance or smell, or a double‐dummy technique); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). We will exclude studies that were not double‐blind.
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Blinding of outcome assessment (checking for possible detection bias). In this review, outcomes will be self assessed, so that the same considerations apply to detection bias as performance bias.
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Size of study (checking for possible biases confounded by small size). We will assess studies as being at low risk of bias (200 participants or more per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (fewer than 50 participants per treatment arm).
Measures of treatment effect
We will use risk ratio (RR) to establish statistical difference, and number needed to treat for an additional beneficial outcome (NNT) and pooled percentages as absolute measures of effect.
We will use the following terms to describe adverse outcomes in terms of harm or prevention of harm.
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When significantly fewer adverse outcomes occur with treatment than with control (placebo or active) we will use the term the number needed to treat to prevent one additional harmful event (NNTp).
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When significantly more adverse outcomes occur with treatment compared with control (placebo or active) we will use the term the number needed for one additional harmful event (NNH).
Unit of analysis issues
We will accept only randomisation of the individual participant. If we identify multiple dose studies, we will use data for the first dose only, and for cross‐over studies, we will use data from the first treatment arm.
Dealing with missing data
The only likely issue with missing data in these studies will be from imputation using last observation carried forward when a participant requests rescue medication. We have previously shown that this does not affect results for up to six hours after taking study medication (Moore 2005).
Assessment of heterogeneity
We will examine heterogeneity using L'Abbé plots (L'Abbé 1987), a visual method for assessing differences in results of individual studies, and using the I2 statistic.
Assessment of reporting biases
We will assess publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean an NNT of 10 or higher; Moore 2008b).
Data synthesis
For efficacy analyses, we will use the number of participants in each treatment group who were randomised, received medication, and provided at least one post‐baseline assessment. For safety analyses, we will use the number of participants randomised to each treatment group who took the study medication.
For each study, we will convert the mean total pain relief (TOTPAR), or summed pain intensity difference (SPID), VAS TOTPAR, or VAS SPID (see Glossary: Appendix 1) values for the active and placebo groups to %maxTOTPAR or %maxSPID by division into the calculated maximum value (Cooper 1991). We will then calculate the proportion of participants in each treatment group who achieved at least 50%maxTOTPAR using verified equations (Moore 1996; Moore 1997a; Moore 1997b), and convert these proportions into the number of participants achieving at least 50%maxTOTPAR by multiplying by the total number of participants in the treatment group. We will use this information on the number of participants with at least 50%maxTOTPAR for active and placebo groups to calculate RR and NNT.
We will accept the following pain measures for the calculation of TOTPAR or SPID (in order of priority: see Appendix 1).
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5‐point categorical pain relief (PR) scales with comparable wording to 'none', 'slight', 'moderate', 'good', and 'complete'.
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4‐point categorical pain intensity (PI) scales with comparable wording to 'none', 'mild', 'moderate', and 'severe'.
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VAS for pain relief.
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VAS for pain intensity.
If none of these measures is available, we plan to use the number of participants reporting 'very good or excellent' on a 5‐point categorical global scale with the wording 'poor', 'fair', 'good', 'very good', and 'excellent' for the number of participants achieving at least 50% pain relief (Collins 2001).
For each treatment group, we will extract the number of participants using rescue medication and the number reporting treatment‐emergent adverse events.
If there are sufficient data, we will calculate RR estimates with 95% confidence intervals (CIs) using the Mantel‐Haenszel method and a fixed‐effect model in Review Manager 5 (RevMan 2014). We will calculate NNT and NNH with 95% CIs using the pooled number of events and the method of Cook and Sackett (Cook 1995). We will assume a statistically significant difference from control when the 95% CI of the RR does not include the number one.
We do not plan to pool data from individual studies for time to use of rescue medication.
Subgroup analysis and investigation of heterogeneity
We plan to analyse different doses separately, if there are sufficient data. We will determine significant differences between different doses using the z test (Tramèr 1997), if appropriate.
Sensitivity analysis
We do not plan to carry out any sensitivity analyses.
