Bolton M, Hodkinson A, Boda S, et al. Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis. BMC Med. 2019;17(1):10. Published 2019 Jan 15. doi:10.1186/s12916-018-1242-0
We studied serious adverse events – these are defined as any event in a clinical trial which results in death or permanent disability, is life-threatening, or requires hospitalization. There needs to be no assumption that the drug caused the event. We carried out a systematic review and meta-analysis. This is a research method of combining data from a lot of clinical trials to get one overall statistical result. We showed that the rate of serious adverse events was similar in the naltrexone and the placebo sides of the trials. Placebos are “dummy” tablets which look and taste the same as naltrexone. In placebo-controlled clinical trials, about half of all participants are given the placebo. As people expect to get side-effects, or improve on medication, it is quite usual to get a “placebo response” – either deterioration or improvement in symptoms, in those taking the placebo. So the result of a placebo-controlled clinical trial is the difference in symptoms or response (in our case, the difference in rates of serious adverse events) between those on naltrexone and those on placebo. We studied people taking naltrexone for a wide variety of conditions, though a lot of the clinical trials were in people with alcohol problems. Because of this, there were a lot of serious adverse events - as people can die or be hospitalized due to alcoholism. We also studied naltrexone at any dose – from 3 mg to 250 mg. Surprisingly, there was no difference in serious adverse events between naltrexone and placebo at any dose - which really does confirm its safety. Sadly though, as there were very few clinical trials of LDN, we couldn’t give a statistical result for LDN alone.
Do our results matter? After all, we were only studying extreme events. The answer is that it matters a lot. It’s really good news for prescribers, as they are now able to say there is good evidence that naltrexone is safe – and that protects them because naltrexone is unlicensed in low dose for any disease or illness. So, if you take LDN, it’s worth telling your prescriber about this research. It is also good news for any researcher wanting to study LDN in clinical trials – as they would need to know it was safe when applying for funding for a clinical trial.
Our research didn’t tell us about the long term safety of LDN, as the longest clinical trials included in our research were a year long, and most were much shorter. Longer term safety data usually comes from national databases of prescriptions. For LDN, the best data for long term safety will probably come from the Norwegian Prescription Database. About 0.3% of the Norwegian population has tried LDN, following a TV documentary in 2013, and as Norway has a National Health Service, all prescriptions are monitored centrally. So far, Norwegian researchers have shown that for people with Crohn’s disease, prescriptions for more conventional treatments have reduced in people taking LDN. That suggests LDN is effective over longer periods of time. I hope that the Norwegian researchers will eventually look at safety data for LDN as well.
We are still hoping to set up a clinical trial of LDN in people with ME/CFS in the UK. It’s very difficult, as the regulations are so strict, and that means it costs a lot of money to run any trial. The regulations are in place for really good reasons - to protect participants in clinical trials and to ensure the data can’t be meddled with by drug companies or researchers. Sadly though, this means navigating the systems is slow and complex. So please be patient - but we’ll keep trying, hopefully until we succeed!
By Monica Bolton