Treating painful envenoming: Searching the bath water of cloudy evidence for the baby

The treatment of envenoming syndromes continues to be fraught with recommendations and guidelines being based on low-level evidence, often anecdotes and case reports. Irukandji syndrome has certainly not been exempt, with magnesium being recommended based on a single case report.1 This is more problematic when the treatment is for pain which is a subjective experience and a difficult outcome to measure. Simply the intervention of a doctor, whether administering a novel medicine or antidote, a placebo, or even the mere ‘laying on of hands’, may suffice to treat pain. This effect is clearly seen in a post-hoc comparison of the RAVE-I and RAVE-II studies, both investigating antivenom for the pain of red-back envenoming. The knowledge of receiving antivenom was almost two times as likely to produce a clinical improvement in pain, compared to analgesia alone.2 So how do we interpret this retrospective study of the use of clonidine for severe pain in Irukandji syndrome?3 First, we must review the use of magnesium for Irukandji syndrome, in which there have been case reports,1 case series, a randomised controlled trial (RCT)4 and a systematic review of the evidence.5 Its initial avid use and recommendations as standard of care in some regions were based on a single case.1 This was followed by case series demonstrating adverse effects and ultimately an RCT demonstrating no benefit of magnesium for the syndrome.4 Despite this, magnesium is still recommended by the Queensland Ambulance Service and more than half of the patients in the present study received magnesium, despite recruitment after the publication of the RCT, demonstrating clinicians' difficulty in abandoning any treatment, even if ineffective.6 Similar to the experience with magnesium, clonidine is reported to cause complete resolution of extreme pain in a single patient with Irukandji syndrome.7 Clonidine is now routinely used by the local toxicology service for refractory cases – in fact, half of the cases between 2016 and 2020 received clonidine.3 In this issue, we read a retrospective review of this clonidine use in Irukandji syndrome.3 The challenge for the reader and for clinicians treating this syndrome is how to interpret this early and low-level evidence, when we want to give patients the best current treatment, but not expose them to unsafe, untested or exciting novel therapies with little evidence of efficacy. The results are difficult to interpret as there is no primary outcome. Instead, there are some rather complicated statistical analyses that provide some evidence that patients receiving a dose(s) of clonidine required less opioid medication following a variable dose of clonidine. There is only one adverse event, possibly related to clonidine administration. Therefore, based on this evidence we can now re-purpose clonidine for use in Irukandji syndrome. Or can we? This is a small retrospective study with a bias towards severe pain in the treatment group, and no pre-defined outcome. The authors correctly acknowledge these limitations and state that this is a hypothesis-generating study. However, they then conclude by recommending clonidine and providing a dosing regimen based on their clinical experience. Before we accept this message, we should perhaps take the opportunity this offers for further research. A better interpretation of the present study is that clonidine appears to be safe in Irukandji syndrome, consistent with decades of its use for other conditions. More importantly, the study by Isman et al.3 provides sufficient evidence to undertake a well-designed placebo-controlled clinical trial of clonidine for pain in Irukandji syndrome. It will be great to see the investigators undertake such a study (in a hospital that manages large and sufficient numbers of cases of Irukandji syndrome), before clonidine is routinely recommended for treating the syndrome. Otherwise, clinicians will struggle to ever recruit patients to a clinical trial investigating the effectiveness of clonidine if it has already been adopted as standard of care based on low-level evidence. We must demonstrate that the benefit of clonidine is not simply because of the clinician's, and therefore the patient's, belief that they are receiving the new improved treatment for Irukandji syndrome – a toxicologist's laying on of hands. KZI is a section editor for Emergency Medicine Australasia.