Liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effect of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain in patients aged 18 years and older undergoing elective surgery compared with other types of analgesia delivered systemically, via local infiltration or epidural or spinal routes.
Background
Description of the condition
The treatment of acute postoperative pain remains an unmet health need. Despite the development of guidelines to assist clinicians and allied health professionals to recognise and treat the so‐called ‘fifth vital sign’, it has been reported that up to three quarters of surgical patients receive inadequate pain relief (Apfelbaum 2003; Gan 2014; Lorentzen 2012; Nimmaanrat 2007). Optimising postoperative pain management, and reducing the requirement for systemic analgesia, in particular opiates, through the use of multi‐modal analgesia has many benefits. These include patient benefits such as reduced morbidity and mortality as well as benefits to the healthcare system through enhanced patient satisfaction and reduced healthcare‐associated costs including a reduced postoperative length of stay. Furthermore, there is increasing evidence that optimising perioperative and postoperative analgesia reduces the incidence of chronic post‐surgical pain as well as enhances long term patient reported functional outcomes (Kehlet 2006).
Description of the intervention
The concept of multi‐modal analgesia was introduced over 20 years ago and its use has expanded to many surgical specialties (Kehlet 1993). Multi‐modal analgesia employs a range of techniques all aiming to inhibit the multiple pathways of nociceptive stimuli along their path, from the site of surgical injury, passing through the peripheral nervous system to the central nervous system. Using paracetamol, non‐steroidal anti‐inflammatory drugs (NSAIDs), gabapentanoids as well as local and regional anaesthetic techniques the need for oral or parenteral opioids in the postoperative period, and as a consequence their side effects, is reduced. Local anaesthetic incisional infiltration, where local anaesthetic is infiltrated at the site of the surgical incision at the time of surgery, and local anaesthetic peripheral nerve blocks are commonly used as part of a multi‐modal regime with the view that modification of pain stimuli at their origin will reduce the transmission of nociceptive stimuli, thereby reducing downstream organ dysfunction and pain and stress responses, including centrally mediated changes in the spinal cord or cerebral cortex (Kehlet 2006). The use of liposomal bupivacaine for peripheral nerve blockade will be the subject of a separate review (Hamilton, in press).
Local anaesthetic incisional infiltration is used in a wide range of operations. The local anaesthetic can be administered prior to wound incision as pre‐emptive analgesia, during surgery, or immediately following wound closure. Bupivacaine hydrochloride is the most commonly used local anaesthetic for local infiltration, however its duration of action is a major limiting factor. Despite the addition of drugs such as epinephrine and clonidine to enhance the duration of action many patients report significant rebound pain when the effect of the local anaesthetic wears off (Apfelbaum 2003). As such, there has been a great deal of interest in sustained release local anaesthetics such as liposomal bupivacaine, which are administered in the same manner but have been reported to have an effect that lasts significantly longer than currently used drugs (Grant 2004).
The adverse effects of bupivacaine and liposomal bupivacaine administered at the surgical site are typical of those associated with other amide‐type local anaesthetics. A major cause of adverse reactions to these drugs is high plasma levels, which may be due to overdosage, rapid absorption from the injection site, diminished tolerance, accidental intravascular injection or slow metabolic degradation. The most common side effects that require immediate countermeasures are related to the central nervous system and cardiovascular toxicity. These reactions are generally dose related and due to excessive plasma levels. Other side effects include gastrointestinal problems (nausea, vomiting, constipation), nervous system side effects (dizziness, headache, syncope, somnolence), skin side effects (pruritus), fungal infections and pyrexia. In addition, for liposomal bupivacaine the potential exists for local adverse effects due to the liposomal component, which is known to undergo slow lipid degradation and clearance at the injection site.
How the intervention might work
Liposomal bupivacaine consists of bupivacaine hydrochloride encapsulated within multiple, non‐concentric lipid bi‐layers. This encapsulation technique produces vesicles of a diameter of 10 to 20 micrometres that contain the active drug, which offers a novel method of sustained release (Spector 1996). Release of the active drug from these multi‐vesicular liposomes is via three mechanisms, membrane breakdown, membrane reorganisation and diffusion (Mantripragada 2002). The relative importance of each mechanism is not known.
Following its release from the liposome vesicles, the active component bupivacaine hydrochloride, an amide local anaesthetic, binds to the intracellular portion of voltage‐gated sodium channels thereby preventing depolarisation of the nerve cell and thus conduction of nociceptive stimuli. Bupivacaine hydrochloride is subsequently metabolised, primarily in the liver via a microsomal cytochrome P450 3A4 mediated pathway to pipcolyloxylidine, with 5% undergoing renal excretion and around 15% being excreted unchanged (Gantenbein 2000). The multi‐vesicular liposome component of liposome bupivacaine undergoes a slow process of lipid degradation and clearance; studies have demonstrated that a significant proportion of the liposome component is detectable at the injection site at periods exceeding 21 days following administration (Mantripragada 2002).
Why it is important to do this review
Regional anaesthetic techniques using local anaesthetics have an established role as part of a multi‐modal technique across a wide range of surgical specialties. Currently their duration of action is a major limiting factor with patients reporting rebound pain. Liposomal bupivacaine is a new therapy utilising a novel mechanism to provide sustained release of local anaesthetic at the origin of pain, which has the potential to address this limitation. At present there are a limited number of trials evaluating liposomal bupivacaine for the management of postoperative pain. This independent review has been designed to critically appraise the current literature on liposomal bupivacaine administered at the surgical site in patients aged 18 years and over undergoing elective surgery to evaluate its clinical and cost effectiveness in managing postoperative pain.
Objectives
To assess the effect of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain in patients aged 18 years and older undergoing elective surgery compared with other types of analgesia delivered systemically, via local infiltration or epidural or spinal routes.
Methods
Criteria for considering studies for this review
Types of studies
We will include prospective randomised and quasi‐randomised controlled trials (including cluster randomised trials) if they have at least two comparisons groups for liposomal bupivacaine infiltration compared against placebo or other types of analgesia. Data from clinical trials registries and clinical trials records, if available, will be eligible for inclusion in the review. Studies will be included irrespective of publication status and language.
Types of participants
We will include all trials with participants aged 18 years and older undergoing elective surgery at any surgical site, without restriction on any co‐morbidities.
Types of interventions
We will include all double blind randomised controlled trials (RCTs) that compare the effects of a single dose of liposomal bupivacaine infiltrated at the surgical site against placebo or other types of analgesia delivered systemically, via local infiltration, perineural injection, or epidural or subarachnoid (spinal) routes. Studies reporting on pre‐emptive, intraoperative and postoperative wound infiltration will be included provided the drug is administered not earlier than 30 minutes prior to the procedure or no later than 30 minutes after wound closure.
Types of outcome measures
We will include patient reported outcome measures of pain, use of supplementary opiate analgesia (incidence of supplementary analgesia, time to supplementary analgesia, mean and total opiate consumption, opiate or other analgesia related adverse events) and measures of cost effectiveness. We will also include withdrawals from the trials and adverse events.
Primary outcomes
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Cumulative pain intensity assessed on a 100 mm visual analogue scale (VAS) over the initial 72 hours following surgery, at rest or with activity. We will standardise pain intensity data described by other means than a 100 mm VAS to such a scale, where possible. However, all types of pain scales will be considered
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Adverse event outcome, specifically incidence of cardiac events and incidence of wound complications within 30 days of surgery
Secondary outcomes
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Mean pain score, at rest or with activity, assessed on a 100 mm VAS at 12, 24, 48, 72 and 96 hours following surgery. All pain scores will be considered and we will standardise pain intensity data described by other means
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Time to first postoperative opioid dose over initial 72 hours
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Total postoperative opioid consumption over first 72 hours
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Percentage of patients not requiring postoperative opioids over initial 72 hours
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Health economics assessed using a recognised health economic technique
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Incidence of adverse events within 30 days of surgery
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Patient reported outcomes, using a validated outcome scores, at any timepoint following surgery
Search methods for identification of studies
Electronic searches
The following electronic databases will be searched:
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CENTRAL (in The Cochrane Library),
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MEDLINE (Ovid),
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EMBASE (Ovid)
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Web of Science (ISI Web of Knowledge).
Medical subject headings (MeSH) or equivalent and text word terms will be used. There will be no language restrictions. Searches will be tailored to individual databases. The search strategy for MEDLINE is shown in Appendix 1.
Searching other resources
We will search the metaRegister of controlled trials (mRCT) (www.controlled‐trials.com/mrct), clinicaltrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/) for ongoing trials. In addition, reference lists of reviews and retrieved articles will be checked for additional studies and citation searches will be performed on key articles. Experts in the field will be contacted for unpublished and ongoing trials. Authors will be contacted where necessary for additional information.
Data collection and analysis
Selection of studies
Studies will be assessed independently and in duplicate for eligibility (TWH, VA). In the first instance, studies will be selected from the title and abstract. For those deemed relevant, the full text will be obtained. Different pairs of authors (TWH, VA, DM) will assess the full text according to the eligibility criteria. Disagreement will be resolved by consensus or, if necessary, by a third review author (SM, MT); if needs be, the opinion of the senior author (HP) will be specifically sought. A summary of the search strategy yield and study selection will be presented as a PRISMA flowchart (Liberati 2009). The full texts of eligible studies will be retrieved with collating of data from multiple publications of the individual studies and removal of duplicate data.
Data extraction and management
Data will be extracted independently and in duplicate by two authors (TWH, VA) and recorded onto a pre‐tested, standardised, electronic data collection pro forma. Inconsistency in data collection will be resolved by discussion with the input of a third review author (SM, MT) as required. If additional information is required the study authors and study sponsors will be contacted.
Assessment of risk of bias in included studies
We will use the Oxford Quality Score (Jadad 1996) as the basis for inclusion, limiting inclusion to studies that are randomised and double blind as a minimum.
Two authors (TWH, VA) will independently assess risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion. 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, e.g. random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). Studies using a non‐random process (e.g. odd or even date of birth; hospital or clinic record number) will be excluded.
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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 (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). Studies that do not conceal allocation (e.g. open list) will be excluded.
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Blinding of outcome assessment (checking for possible detection bias). We will assess the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We will assess the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, e.g. identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). Studies that were not double blind will be excluded.
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Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). We will assess the methods used to deal with incomplete data as: low risk (< 10% of participants did not complete the study or used ‘baseline observation carried forward’ analysis, or both); unclear risk of bias (used 'last observation carried forward' analysis); high risk of bias (used 'completer' analysis).
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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 per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (< 50 participants per treatment arm).
Measures of treatment effect
For dichotomous data we will consider the risk ratio (RR) and for continuous data the standardised mean difference (SMD), along with 95% confidence intervals (95% CI). We will obtain the incidence rates of opioid related adverse effects. Where possible, for efficacy outcomes we will calculate numbers needed to treat (NNT) to benefit and NNT to harm for adverse events.
Unit of analysis issues
Outcomes will be assessed at the patient level. Studies involving multiple treatment arms will be analysed by dividing the sample size of the control group into the appropriate number of groups depending on the number of arms of the trial. If there are eligible cluster randomised trials in this review, the intraclass correlation coefficients will be employed prior to meta‐analysis.
Dealing with missing data
Study authors and sponsors will be contacted to request further information in the event of missing data.
Care will be taken to explore the reasons for missing data, especially if the percentage of missing data is more than 20%, in which case any pooled result will be assessed though a sensitivity analysis to explore the effects of the missing data on the overall pooled result.
We will not attempt data imputation because of the controversies associated with imputing data from multiple scoring schemes, especially due to possible small sample sizes per scoring scale.
Assessment of heterogeneity
We will examine the heterogeneity of included studies using the I2 statistic as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)
If there is substantial heterogeneity (that is I2 > 85%) we will not attempt pooled analysis. We are expecting a degree of variability among the eligible studies, in terms of the measurement scale used and the subjectivity of the outcome, and hence we will be using the random‐effects model in all meta‐analyses in this review.
Assessment of reporting biases
To assess for publication bias due to non‐reporting of negative studies, the principal investigators of unpublished relevant trials registered as completed on trial registries will be contacted to determine the study outcome. If there are more than 10 studies included in a meta‐analysis we will explore publication bias by means of a funnel plot.
Data synthesis
Where outcome data are of sufficient quality and participants, interventions, comparisons and outcomes are judged to be sufficiently similar to ensure an answer that is clinically meaningful, a meta‐analysis will be performed.
Analysis will be performed using standard statistical techniques as described in the Cochrane Handbook for Systematic Reviews of Interventions, using Review Manager 5.3 (RevMan 2014). For continuous data we will calculate the pooled SMD using the inverse variance method for meta‐analysis, and the 95% CI.
Standardised results will be reversed to the original scale format in order to relate to the pooled result. For dichotomous outcomes the pooled RR and 95% CI will be estimated using the Mantel‐Haenzsel method. Depending on data availability, we will report the pooled incidence ratio of opioid related adverse effects using the generic inverse variance method.
Subgroup analysis and investigation of heterogeneity
Subject to data availability, subgroup analysis will be carried out for different doses (based on the licensed recommendations for dosage) of liposomal bupivacaine administered and different surgical sites. The indications for these subgroup analyses are that in basic science studies it has been demonstrated that a dose response curve is seen and, as such, the dose of liposomal bupivacaine may have an effect on outcome. Furthermore, different surgeries will have different pain profiles and, in addition, the release pattern of bupivacaine hydrochloride from liposomal bupivacaine may be altered by the local environment and therefore different efficacies may be observed at different surgical sites.
Sensitivity analysis
We will perform sensitivity analysis based on the following domains from the risk of bias tool: blinding of outcome assessment and incomplete outcome data.
