Single dose oral diflunisal for acute postoperative pain in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and adverse effects of single dose oral diflunisal for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes.
Background
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. The management of postoperative pain and inflammation is a critical component of patient care.
The aim of this series of reviews is to 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 patient, but guides policy‐making at the local level.
Recent reviews include lumiracoxib (Roy 2007) and celecoxib (Derry 2008), and will include updates of existing reviews such as ibuprofen (Collins 1999) and aspirin (Edwards 2000).
Acute pain trials
Single dose trials in acute pain are commonly short in duration, rarely lasting longer than 12 hours. The numbers of participants is 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 an 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. The use of additional or rescue analgesia is hence important for all participants in the trials.
Clinical trials measuring the efficacy of analgesics in acute pain have been standardised over many years. 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. 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. An example is the relative efficacy in the third molar extraction pain model (Barden 2004).
Clinicians prescribe non‐steroidal anti‐inflammatory drugs (NSAIDs) on a routine basis for a range of mild‐to‐moderate pain. 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 (PGs) and thromboxane A2 (Fitzgerald 2001). PGs 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. However, relatively little is known about the mechanism of action of this class of compounds aside from their ability to inhibit cyclooxygenase‐dependent prostanoid formation (Hawkey 1999).
Diflusinal
This review looks at Diflunisal. Diflunisal, 5‐(2,4‐difluorophenyl)‐2‐hydroxy‐benzoic acid, is an NSAID derived from aspirin. It is rarely prescribed in the UK, with only 1460 prescriptions recorded in England in 2007 (PCA 2007). This is about 0.01% of the total NSAID prescriptions in the same period. Diflunisal is available in 250 mg and 500 mg tablets as Dobloid in the UK. In the USA the generic drug is also available. It is indicated for mild to moderate pain. In the UK, this explicitly includes osteoarthritis, rheumatoid arthritis, dysmenorrhea, and dental pain (BNF 53). In the USA, the drug is indicated for mild to moderate pain, primarily for osteoarthritis and rheumatoid arthritis.
The half‐life (eight to twelve hours) is four times that of aspirin, allowing twice daily administration, but with slower onset of analgesia, and the necessity of a loading dose if it is to be continued. It is absorbed rapidly and completely in the GI tract. In contrast to aspirin, diflunisal shows a much greater plasma:CSF ratio than aspirin. Diflunisal provides a small but clinically unhelpful antipyretic effect, and a mild uricosuria. Platelet function and bleeding time were not changed in some patients on a 250 mg BD regime of diflunisal, and only slight changes were noted with a 500 g BD regime. Unlike the effect of aspirin on platelets, that of diflunisal is reversible.
Objectives
To assess the efficacy and adverse effects of single dose oral diflunisal for acute postoperative pain 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
Studies will be included if they are double blind trials of single dose oral diflunisal compared with placebo for the treatment of moderate to severe postoperative pain in adults with at least ten participants randomly allocated to each treatment group. Multiple dose studies will be included if appropriate data from the first dose are available. Cross‐over studies will be included provided that data from the first arm are presented separately. No language restriction will be applied to the search for studies.
The following will be excluded:
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review articles, case reports, and clinical observations;
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studies of experimental pain;
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studies where pain relief is assessed only by clinicians, nurses or carers (i.e., not patient‐reported);
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studies of less than four hours duration or studies that fail to present data over four to six hours post‐dose.
For postpartum pain, studies will be included if the pain investigated is due to episiotomy or Caesarean section irrespective of the presence of uterine cramps; studies investigating pain due to uterine cramps alone will be excluded.
Types of participants
Studies of adult participants (>15 yrs) with established postoperative pain of moderate to severe intensity following day surgery or in‐patient surgery will be included. For studies using a visual analogue scale (VAS), pain of at least moderate intensity will be equated to greater than 30 mm (Collins 1997).
Types of interventions
Diflunisal or matched placebo administered as a single oral dose for postoperative pain.
Types of outcome measures
Data collected will include the following outcomes if available:
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Participant characteristics;
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Patient reported pain at baseline (physician, nurse or carer reported pain will not be included in the analysis);
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Patient reported pain relief expressed at least hourly over four to six hours using validated pain scales (pain intensity and pain relief in the form of VAS or categorical scales, or both);
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Patient global assessment of efficacy (PGE), using a standard categorical scale;
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Time to use of rescue medication;
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Number of participants using rescue medication;
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Number of participants with one or more adverse events;
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Number of participants with serious adverse events;
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Number of withdrawals (all cause, adverse events).
Search methods for identification of studies
To identify studies for inclusion in this review, the following electronic databases will be searched:
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Cochrane CENTRAL
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MEDLINE via Ovid
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EMBASE via Ovid
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Oxford Pain Relief Database (Jadad 1996a)
Please see Appendix 1 for the MEDLINE search strategy, all other database search strategies will be adapted from this search.
Additional studies will be sought from the reference lists of retrieved articles and reviews.
Language
No language restriction will be applied.
Unpublished studies
The manufacturing pharmaceutical company will be not be contacted for unpublished trial data because clinical trial reports of any unpublished trials have been made available.
Data collection and analysis
Selection of studies
Two review authors will independently assess and agree the search results for studies that might be included in the review.
Quality assessment
Two review authors will independently assess the included studies for quality using a five‐point scale (Jadad 1996b) that considers randomisation, blinding, and study withdrawals and dropouts.
Data management
Data will be extracted by two review authors and recorded on a standard data extraction form. Data suitable for pooling will be entered into RevMan 5.
Data analysis
For each study, the mean TOTPAR, SPID, VAS TOTPAR or VAS SPID (Appendix 2) values for active and placebo will be converted to %maxTOTPAR or %maxSPID by division into the calculated maximum value (Cooper 1991). The proportion of participants in each treatment group who achieved at least 50%maxTOTPAR will be calculated using verified equations (Moore 1996; Moore 1997a; Moore 1997b). These proportions will then be converted into the number of participants achieving at least 50%maxTOTPAR by multiplying by the total number of participants in the treatment group. Information on the number of participants with at least 50%maxTOTPAR for active and placebo will then be used to calculate relative benefit/relative risk, and number‐needed‐to‐treat‐to‐benefit (NNT).
Pain measures accepted for the calculation of TOTPAR or SPID will be:
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five‐point categorical pain relief (PR) scales with comparable wording to "none, slight, moderate, good or complete";
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four‐point categorical pain intensity (PI) scales with comparable wording to "none, mild, moderate, severe";
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VAS for pain relief;
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VAS for pain intensity.
If none of these measures are available, the number of participants reporting "very good or excellent" on a five‐point categorical global scale with the wording "poor, fair, good, very good, excellent" will be used for the number of participants achieving at least 50% pain relief (Collins 2001).
The number of participants reporting treatment‐emergent adverse effects will be extracted for each treatment group. Relative benefit/risk estimates will be calculated with 95% confidence intervals (CI) using a fixed‐effect model (Morris 1995). NNT/Number‐needed‐to‐treat‐to‐harm (NNH) and 95% CI will be calculated using the pooled number of events using the method devised by Cook and Sackett (Cook 1995). A statistically significant difference from control will be assumed when the 95% CI of the relative risk/relative benefit does not include one. Homogeneity will be examined visually using L'Abbe plots (L'Abbe 1987).
Sub‐group analyses are planned to determine the effect of dose, presenting condition (pain model), and high versus low (two or fewer versus three or more) quality trials. A minimum of two trials and 200 participants must be available in any sensitivity analysis (Moore 1998).
