Single dose oral gabapentin 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 gabapentin 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.
Recently published reviews include well established analgesics such as paracetamol (Toms 2008), naproxen (Derry C 2009a), diclofenac (Derry P 2009), and ibuprofen (Derry C 2009b), and newer cyclo‐oxygenase‐2 selective analgesics, such as celecoxib (Derry 2008), etoricoxib (Clarke 2009), and parecoxib (Lloyd 2009).
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 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 4 to 6 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 4 to 6 hours (Moore 2005). Patients usually remain in the hospital or clinic for at least the first 6 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).
Non‐steroidal anti‐inflammatory drugs (NSAIDs) are prescribed on a routine basis for a range of mild to moderate pain and are the most commonly prescribed analgesic medications worldwide. Their efficacy for treating acute pain has been well demonstrated (Moore 2003). Antiepileptic drugs (also known as anticonvulsants) have been used in pain management since the 1960s, very soon after they were first used for their original indication in medicine. They have most often been used in chronic pain conditions, particularly neuropathic pain (like painful diabetic neuropathy). Their efficacy in acute nociceptive pain is not established.
Gabapentin
This review looks at gabapentin. Gabapentin (original trade name Neurontin, but also now available as generic products in some parts of the world) is an antiepileptic drug licensed for the treatment of peripheral and central neuropathic pain in adults in the UK, and has marketing approval in the US for postherpetic neuralgia, other painful neuropathies, and nerve related pain. The efficacy of gabapentin in chronic neuropathic pain will be evaluated in a separate review (Wiffen 2009).
Gabapentin is thought to act by binding to calcium channels and modulating calcium influx. This mode of action confers antiepileptic, analgesic and anxiolytic effects, and may provide useful analgesia in acute postoperative pain. In chronic neuropathic pain the maximum recommended (approved) dose is 3600 mg/day. Some patients are started or treated at doses as low as 100 mg/day, often with titration from lower to higher doses over days, or possibly weeks.
The use of gabapentin in acute pain is uncommon, and its efficacy unproven. There are two unanswered questions. The first, and simplest, is whether gabapentin has analgesic efficacy in standard tests in participants with established pain of moderate or severe intensity. This is an established, classical, method of detecting analgesic activity in acute pain, different from neuropathic pain efficacy. The second question is whether use of gabapentin before or immediately after surgery (perioperatively) reduces the requirement for analgesia in the postoperative period. This is much more difficult, and the methods used to establish any effects, have never been validated, and have been heavily criticised (Kissin 2009; McQuay 2008). In addition, several research papers on this topic are likely to have used fabricated data (Shafer 2009). More recently, gabapentin has been used in an attempt to prevent development of chronic neuropathic pain, but the amount of evidence so far is small and efficacy is unproven (Dworkin 2009; Fassoulaki 2005; Osipova 2005; Pogatzki‐Zahn 2006; Sen 2009).
This review concentrates on whether gabapentin has analgesic activity in established postoperative pain, where there are no methodological problems. The use of gabapentin perioperatively cannot be determined in the present state of knowledge; it requires new, validated, methods.
Objectives
To assess the efficacy and adverse effects of single dose oral gabapentin 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 gabapentin compared with placebo for the treatment of moderate to severe postoperative pain in adults with at least 10 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 4 hours duration or studies that fail to present data over 4 to 6 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 on a 100 mm scale (Collins 1997).
Types of interventions
Gabapentin or matched placebo administered as a single oral dose for postoperative pain.
Types of outcome measures
Data collected will include the following:
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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 4 to 6 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).
A search strategy will be developed for use in MEDLINE, and revised appropriately for other databases, in co‐operation with the Cochrane Pain, Palliative Care and Supportive Care Cochrane Review Group. For the MEDLINE search, the strategy will combine the subject search with The Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomized trials in MEDLINE: sensitivity maximizing version as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of The Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (Higgins 2008). A similar study design filter will be used for other databases, as appropriate.
The subject search will use a combination of controlled vocabulary and free text terms based on the search strategy for MEDLINE via OVID (see Appendix 1)
Additional studies will be sought from the reference lists of retrieved articles and reviews.
Language
No language restriction will be applied.
Unpublished studies
Clinical trials databases will be searched for unpublished studies. Clinical trial reports of a number of unpublished studies have already been made public following litigation in the US.
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 (RB)/relative risk (RR), 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. RB/RR estimates will be calculated with 95% confidence intervals (CI) using a fixed‐effect model (Morris 1995). NNT and 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 RR or RB does not include the number one. Homogeneity will be examined visually using L'Abbé plots (L'Abbe 1987).
Sub‐group analyses are planned to determine the effect of dose, presenting condition (pain model), and high versus low (two versus three or more) quality trials. A minimum of two studies and 200 participants must be available in any sensitivity analysis (Moore 1998).
Further details of the scales and derived outcomes are in the glossary (Appendix 2).
