Topical glyceryl trinitrate for lateral elbow pain
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objectives of this systematic review are to assess the effectiveness and safety of topical glyceryl trinitrate in treating lateral elbow pain.
Background
Lateral elbow pain (or tennis elbow or lateral epicondylitis) is common; the prevalence in the population is 1‐3%, with a peak incidence at 40‐50 years of age (Allander 1974) and causes considerable morbidity and financial cost. Although lateral elbow pain is generally self limiting, in a minority of people symptoms persist for 18 months to two years and in some cases for much longer (Hudak 1996). A small proportion eventually undergo surgery, although reliable data on surgical rates in unselected patients are lacking. The cost is therefore high, both in terms of lost productivity and healthcare use. In a general practice trial of an expectant waiting policy, 83% of people were improved or recovered at one year (Smidt 2002a).
It is believed that the majority of cases of lateral elbow pain are due to a musculotendinous lesion of the common extension origin at the attachment to the lateral epicondyle (Chard 1989). Pain is usually due to degeneration at the site of attachment of the tendon and bone; focal changes such as focal hypoechoic areas of degeneration, discrete cleavage tears (both partial and complete) and involvement of the lateral collateral ligament can be identified on sonographic examination of the common extensor origin in participants with lateral elbow pain (Connell 2001).
Many treatments are used to treat lateral elbow pain including corticosteroid injections (Smidt 2002b), analgesics and non‐steroidal anti‐inflammatories (NSAIDS) (Paoloni 2005a), acupuncture (Green 2002), shock wave therapy (Buchbinder 2005), physiotherapy (Smidt 2003) and surgery (Buchbinder 2002), but in most instances it is not clear whether the result would have been the same by simply waiting for the pain to go away by itself.
Topical glyceryl trinitrate has been proposed as a promising new treatment for soft tissue injuries, including musculotendinous injuries (Paoloni 2005a). Its exact mechanism of action in healing tendon or other soft tissue injuries is unknown. Glyceryl trinitrate is a nitric oxide donor and there is evidence that nitric oxide is needed for soft tissue repair. Animal studies show that inhibition of endogenous nitric oxide production decreases the rate of healing of experimentally‐induced injured tendons (Murrell 1997). Soft tissue needs collagen produced by fibroblastic cells for repair, thus the mechanism of action may be that nitric oxide stimulates collagen synthesis by fibroblasts needed for tendon repair (Murrell 1997; Paoloni 2005a).
Randomised controlled trials have assessed the efficacy of topical glyceryl trinitrate in reducing shoulder pain due to supraspinatus tendonitis (Berrazueta 1996; Paoloni 2005b), and relieving symptoms of chronic tendon conditions including Achilles tendinopathy (Paoloni 2004) and lateral elbow pain (Paoloni 2003). Common side effects of treatment with glyceryl trinitrate include rash and headache, which are reversible once treatment is discontinued (Paoloni 2005a). We aim to systematically review the literature of the effectiveness and safety of topical glyceryl trinitrate in treating lateral elbow pain.
Objectives
The objectives of this systematic review are to assess the effectiveness and safety of topical glyceryl trinitrate in treating lateral elbow pain.
Methods
Criteria for considering studies for this review
Types of studies
Randomised or quasi‐randomised (methods of allocating participants to a treatment which are not strictly random, e.g., date of birth, hospital record number or alternation) clinical trials (RCTs) will be considered for inclusion in this review. Studies which reviewed a previously studied cohort, or a subset of the original cohort, for a second time with a longer follow‐up duration will be excluded from the data analysis. Studies reported in abstracts without data will be included in the 'studies awaiting assessment' category and authors will be contacted for further detailed data. There is no restriction on length of follow up. There are no language restrictions on included studies and non‐English articles will be translated.
Types of participants
We will include studies of participants of all ages with lateral elbow pain. Lateral elbow pain is defined as elbow pain which is maximal over the lateral epicondyle, and increased by pressure on the lateral epicondyle and resisted dorsiflexion of the wrist and/or middle finger. Studies of various soft tissue diseases and pain due to tendinopathy at all sites will be included provided that the lateral elbow pain results were presented separately, or > 90% of participants in the study had lateral elbow pain. RCTs that include participants with a history of significant trauma or systemic inflammatory conditions such as rheumatoid arthritis will be excluded.
Types of interventions
We will include studies comparing topical glyceryl trinitrate (also known as nitroglyceride patch, topical nitric oxide, transdermal glycerin) administered at any dose or regimen, alone or combined with another treatment, to placebo or another active therapy. Control interventions may include all types of conservative treatments e.g. bandaging or strapping, expectant waiting, ultrasound, laser, massage, electrotherapy, acupuncture, other topical treatments, physiotherapy, oral steroids or corticosteroid injections, analgesics and NSAIDS; and surgery
Types of outcome measures
We will report all outcomes measured in the included trials, and at all time points reported in the trials.
Primary outcomes may include pain (e.g. overall pain, pain at rest or with activities and pain with resisted movements; function (e.g.. Disabilities of the Arm, Shoulder and Hand [DASH], Upper Extremity Function Scale [UEFS]); and adverse events.
Secondary outcomes may include quality of life, grip strength, satisfaction with abilities to perform full activities and sport, composite endpoints of 'success' of treatment as defined in the various trials.
Search methods for identification of studies
We will search the following electronic databases and sources to identify studies.
1. MEDLINE (OVID);
2. EMBASE (OVID);
3. CINAHL (OVID);
4. SPORTDiscus (OVID);
5. CENTRAL Cochrane Central Register of Controlled Trials;
6. PEDro;
7. Australian Clinical Trials Registry;
8. Current Controlled Trials;
9. The Cochrane Musculoskeletal Review Group Registry;
10. Reference lists in review articles and trials retrieved;
11. Personal communication with experts in the field.
We will combine search terms describing rotator cuff disease and terms describing topical glyceryl trinitrate for all databases and we will also add an RCT filter for the MEDLINE, EMBASE, CINAHL and SPORTDiscus databases. The following search strategy applies to the MEDLINE database. We will adapt this strategy to apply to the other databases. The MEDLINE search strategy combines medical subject headings and text terms describing lateral elbow pain with terms describing topical glyceryl trinitrate, and with the optimally sensitive search strategy, phases 1 and 2, to identify reports of RCTs in MEDLINE, as recommended by the Cochrane Collaboration (Higgins 2005).
1 exp Tennis Elbow/
2 exp Tendinopathy/
3 exp Tendons/
4 exp Tendon Injuries/
5 tendon$.mp
6 (tennis elbow or elbow pain or epicondylitis or tendonitis or tendinitis or tendinosis or common extensor origin).mp.
7 exp Nitroglycerin/
8 nitroglycer$.mp.
9 exp Vasodilator Agents/
10 topical glycer$.mp.
11 transdermal glycer$.mp.
12 topical nitric oxide.mp.
13 nitro‐dur.mp.
14 nitroplast.mp.
15 or/1‐6
16 or/7‐14
17 15 and 16
Data collection and analysis
STUDY SELECTION
Two review authors will assess the titles and available abstracts of all studies identified by the initial search and exclude any clearly irrelevant studies. Two authors will independently assess full paper copies of reports of potentially eligible studies using the inclusion criteria. The review authors will resolve disagreements on inclusion by consensus and if this fails, by arbitration with a third reviewer.
METHODOLOGICAL QUALITY ASSESSMENT
Two review authors will independently assess the methodological quality of each included trial. Reviewers will resolve disagreements by consensus, and consult a third review author to resolve disagreements if necessary.
We will assess the methodological quality of included trials against key methodological criteria (appropriate randomisation, allocation concealment, blinding, number lost to follow up and intention to treat analysis). Failure to fulfill these criteria will be considered to have potentially biased the overall outcome of the trial. Two review authors will assess whether each quality assessment item is met, unmet, or unclear, and derive an overall assessment of the validity of the results of individual trials by assigning one of three categories‐ low, moderate, and high risk of bias‐ corresponding to all criteria met, one or more criteria partially met, and one or more criteria not met. Allocation concealment will also be ranked as: A: adequate; B: unclear; C: inadequate; or D: not used. We will assess the methodological quality along with any other information about the trials on a pre‐piloted data extraction sheet , and transpose the information into the Table of Characteristics of Included Studies.
Methodological quality of trials will be assessed in this qualitative way as opposed to using a numerical or summary scale due to concerns regarding the validity of such scales and lack of information about whether all the criteria included in such scales impact on the overall outcome of the trial.
DATA EXTRACTION
Two reviewers will independently extract data from the included trials including source of funding, study population, intervention, analyses and outcomes using standardised data extraction forms. The authors of recent original studies will contacted to obtain more information as needed.
In order to assess efficacy, we will extract raw data for outcomes of interest (means and standard deviations for continuous outcomes and number of events for binary outcomes) where available in the published reports. Wherever reported data is converted or imputed, we will record this in the notes section of the Table of Characteristics of Included Studies.
ANALYSIS
We will plot the results of each RCT as point estimates, i.e., relative risks with corresponding 95% confidence interval for dichotomous outcomes and mean difference and 95% confidence intervals for continuous outcomes. When the results cannot be shown in this way, we will describe them in the table of included studies. For continuous measures, we will calculate weighted mean differences if possible as these results are easier for readers to interpret. If individual outcome measures vary but the construct being measured is the same (i.e. use of different scales across trials and/or inability to convert data into the same scale), then we will use standardized mean differences.
Prior to meta‐analysis, we will assess studies for clinical homogeneity with respect to study population (chronic versus acute complaints), type of therapy, control group and the outcome measures. We will not combine clinically heterogeneous studies in the analysis, but describe them separately. For studies judged as clinically homogeneous, we will test statistical heterogeneity by Q test (chi‐square) and I2. We will pool clinically and statistically homogeneous studies using the fixed effects model. We will pool clinically homogeneous and statistically heterogeneous studies using the random effects model. We will construct funnel plots if at least 10 studies are available for the meta analysis.
If the data are appropriate for meta‐analysis and there is available data, subgroup analysis will be conducted to determine if outcomes differ between those with acute and chronic symptoms.
If there are sufficient data, a sensitivity analysis will be conducted to assess for any bias attributed to allocation concealment.
GRADING THE STRENGTH OF THE EVIDENCE
A common system for grading the strength of scientific evidence for a therapeutic agent has been described in the CMSG module scope and in the Evidence‐based Rheumatology BMJ book (Tugwell 2004) and will be used to rank the evidence included in this systematic review. Four categories are used to rank the evidence from research studies from highest to lowest quality:
Platinum Level Evidence: A published systematic review that has at least two individual controlled trials each satisfying the following:
1.Sample sizes of at least 50 per group. If they do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome. 2.Blinding of patients and assessors for outcomes.
3.Handling of withdrawals> 80% follow up (imputations based on methods such as Last Observation Carried Forward (LOCF) acceptable.)
4. Concealment of allocation.
Gold Level Evidence: The gold ranking is given to evidence if at least one randomised clinical trial meets all the following criteria for the major outcome as reported:
1. Sample sizes of at least 50 per group. If they do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome. 2.Blinding of patients and assessors for outcomes.
3.Handling of withdrawals> 80% follow up (imputations based on methods such as Last Observation Carried Forward (LOCF) acceptable.)
4. Concealment of allocation.
Silver Level Evidence: The silver ranking is given if a systematic review or randomised trial does not meet the above criteria. Silver ranking would also include evidence from at least one study of non‐randomised cohorts who did or did not receive therapy or evidence from at least one high quality case‐control study. A randomised trial with a 'head to head' comparison of agents is considered silver ranking unless a reference is provided to a comparison of one of the agents to placebo showing at least a 20% relative difference.
Bronze: The bronze ranking is given to evidence if at least one high quality case series without controls (including simple before/after studies in which patients act as their own control) or if the conclusion is derived from expert opinion based on clinical experience without reference to any of the foregoing (for example, argument from physiology, bench research or first principles).
In this review, as only RCTs will be included, the bronze ranking of evidence will not apply. The ranking will be included in the synopsis, abstract and clinical relevance tables of the review.
CLINICAL RELEVANCE TABLES
Clinical relevance tables will be compiled under additional tables to improve the readability of the review. For dichotomous outcomes, the number needed to treat will be calculated from the control group event rate and the relative risk (or odds ratio for beneficial events) using the Visual Rx NNT calculator (Cates 2003). Continuous outcome tables will also be presented under additional tables. Absolute benefit will be calculated as the improvement in the intervention group minus the improvement in the control group, in the original units. Relative difference in the change from baseline will be calculated as the absolute benefit divided by the baseline mean of the control group.
