Abstract
There has been considerable controversy about the use of Botulinum toxin (Botox) in cranial neuralgias including trigeminal neuralgia. A recent systematic review concluded that there was no high-quality evidence to support the use of Botox (1). They showed that the results were very disparate and used different methodologies and outcomes. Wu et al. is the first report of a randomized controlled trial (RCT) of Botox in trigeminal neuralgia (2). The CONSORT statement and extensions have now been extensively published, and a recent review of the quality of published RCTs indexed in PubMed over a single month showed that reporting is still of insufficient quality to ensure that readers can be confident that the results are valid (3). Using the criteria Hopewell et al. (3) used and in light of Schriger and Altman’s editorial (4) that stated there is a lack of post-publication review, I would like to review Wu et al.’s paper (2) as currently reported in the hope that it will stimulate some responses.
It is not clear which is the primary outcome as it is stated that they were both pain severity and pain frequency. These are two very different outcomes that need to be separated, as patients will point out that a single attack of high intensity interferes less with activities of daily living than 20 attacks of lower intensity. As is generally accepted, any therapy that results in a 50% pain intensity reduction from baseline can be considered to be an effective therapy. It is not clear in this study, however, how this mean score was obtained, from a single last visit or daily diaries? The second outcome measure was “patient global impression of change” but it is not clear at which time point it was taken. The International Association for the Study of Pain has suggested that more measures are needed in order to capture all aspects of the pain experience (5) and that the two used in this study may not be sufficient. Given the potential success of the treatment, was no attempt made to look at reduction of medication as an outcome measure, especially as the drugs used all cause significant side effects? It is of interest to note that three patients were on opioids and 16 on gabapentin, not generally recommended therapies.
Sample size calculation has not been provided, and it is unclear how the number enrolled was determined and why 25 patients were not randomised. The method of randomisation is not stated nor how allocation concealment achieved. It is stated that the study was double blind, but only the patients were asked about their estimate of allocation. Who else was blinded? Were the investigators who injected the Botox the same as the assessors and were they both blinded? Who checked the syringes for content? It is stated that 1.5 mL were injected yet the syringes were of 1 mL size, so they would have needed to be refilled or two would need to be used. The figure and text show 15 points that were injected, which would cover only the maxillary and mandibular divisions of the trigeminal nerve; it is also stated that some injections were intraoral. No details are provided of the location of trigger areas and numbers injected on each patient; presumably those who had triggers in only one division had fewer injections. How was it determined that all the trigger points were injected? Could trigger points be identified in all patients given that clinical experience shows that not all patients have clearly identifiable trigger points? How were the assessments carried out and did all patients attend all the follow-up appointments? We are provided with details of attrition, which was very low and an intention to treat analysis was done as suggested by CONSORT.
Trigeminal neuralgia is a long-term condition and 12 weeks of pain relief is very short. Other studies have suggested that repeat injections are needed, so how many can be given before the treatment is abandoned? Although high-quality evidence for outcomes after surgical procedures is lacking, there is no doubt that microvascular decompression provides the longest period of complete pain relief and means that patients can stop taking medications that cause significant side effects (6). Thus, I would suggest that Linde et al.’s conclusion (1) remains: There is no high-quality evidence to suggest that Botulinum toxin is an effective treatment for trigeminal neuralgia.