Phytalgic: goldfish or flash in the pan? response to editorial Nicholas Moore, University of Bordeaux 16 February 2010 I fully agree with all of this editorial's comments, and would like to answer what I may: - The registration with clinicaltrials.gov was indeed done after the end of the study, because of a confusion between the study sponsor, Phythea, and our department, each thinking the other had done it. When discussing at the end of the study, I asked the sponsor, which is a small non-pharma company, whether they had registered with clintrials as I had asked them to before the study. I realized they had not. This was its first randomized double-blind trial, and they were somewhat at a loss on a number of these things. We had taken care of ethics and regulatory stuff, but forgot about clintrials. I therefore registered the study at that time, and just put in the numbers as they were, including dates. In the same way, when I wrote that the secondary evaluation criterion was the WOMAC functional score, it was not to the function subset of the WOMAC score I was alluding, but to the whole score and all three subsets. I had not thought the data in the clinicatrials.gov database would be subject to such semantic scrutiny or interpretation. The protocol (in french) clearly specified WOMAC, which for me is a functional score, in that it has no Xray or physical measure, or biology. Maybe some translation issues here for which I apologize. In any event the WOMAC was only a secondary item: the main item was the use of analgesia and NSAIDs, as a relatively solid measure of OA activity and impact: this was also because initially the company came to us saying: "we have patient testimonies stating they could stop their NSAIDs after a few months of treatment. How can we verify this?" We just wanted to test this, and make sure that any decrease in analgesic use was not at the expense of pain or function. We also wanted to stay as close as possible to the real-life circumstances, and decided not to change the patients' usual care, which was reasonably effective, but to study phytalgic as an add-on therapy, which is how it would normally be used. The study happened exactly as described in the publication. There were no other excluded patients. We had aimed for 80 patients, and stopped the preinclusion and patient selection process when the number was reached, with a little overshoot (81 in fact by the time we got there). Patient attrition during the study, as reported was related to adverse events (1 per group), pregnancy (1 with placebo) and lack of efficacy (2 with placebo). Lack of effect being more common with placebo could be bias, or placebo-resistance; pregnancy seems to be a coincidence (or an effect of placebo on compliance?): all women were on contraceptives and this one accidentally forgot to take it. We did not consider terminating the pregnancy... All happened very early in the study. We had initially excluded them from the analyses since we had no data beyond inclusion, then reinstated them at the request of the referees (quite rightly) using inclusion data carried forward. Whether these are included in the study or not did not change the overall results. No other patient was lost to follow-up or to attrition. Since the effect was much greater than expected, sample size was not really relevant. In fact, since we had no idea of what the effect might be, we chose 30% difference in use of analgesics as something that would be clinically relevant, which gave a sample size around 30 patients per group, then factored in a 25% dropout rate to come up with the number of 40 per group. We had computed for a 30% decrease in the use of analgesia and NSAIDs, and no change in WOMAC. The results surprised us as much as it did the editorialists, and we consider them with as much circumspection, for exactly the same reasons. There may have been an identification by all patients in the treated group of the fish oil (but only a few complained of fish-smelling burping), but even so, and even if we were comparing in effect two placebos, one with a much stronger effect provided by fishoil smell, this would give a very large placebo effect. Even this may be possible, and maybe we should add some fish scent to a double-placebo study (the same vegetable oil in both capsules, but one with just some fishoil for the smell) to see the effect of the fishoil smelling placebo. I believe there have been tests of cod-liver oil, which does stink if I remeber my youth, and that it was not really effective. Because of the risk of patients and investigator discovering the treatment allocation through the fishoil burps, we minimize the importance of the WOMAC, which might be more sensitive to bias. Our main objective was the use of analgesia and NSAIDs, which was reported on a diary, filled daily by the patients. Would patients have omitted the noting of drugs because they were on active treatment? Over three months, it takes a lot of perseverance. In any event, I believe one should not really consider the magnitude of the effect, but only its existence: in a small single centre study (pilot?) that was done as best we could, we found that the regular use of Phytalgic was associated with a clear reduction in the use (need?) of analgesia and NSAIDs, the latter being quite desirable for someone as involved as I am in drug safety issues, and this reduction was not accompanied by a worsening of symptoms, but in fact may have been the consequence of an improvement in the symptoms. It might be due to the effect of the product on OA, it might be an interaction with the pharmacokinetics or dynamics of the NSAIDs or analgesics (so that the same NSAIDs might be more effective longer) or to an analgesic effect of the product per se (are there natural opiates in fishoil or nettles?) or any other number of reasons. But as the editorialists state, certainly this effect, whatever its magnitude, needs further exporation: - other clinical trials, larger and multicentre - and maybe more fundamental studies to understand this effect if confirmed. In conclusion we in no way wish to affirm that Phytalgic is the new panacea for OA, just that maybe there is something that should be further explored here, maybe a hope for the painful. Like many others it will probably be dashed, but then who knows? Just decreasing the need for and use for NSAIDs is enough for me, and that too warrants further testing of this compound. Competing interests Having designed the study and written the paper, of course I am prejudiced in its favour. I have not received a penny from the sponsor in this case, though the main investigator, Dr Jacquet, who practises research privately within my department (a complicated story), and one of our research assistants were indemnified for the time spent. Neither Dr Girodet nor Dr Pariente received any funding. I have low-grade OA that is beginning to hurt from time to time when the weather changes, but do not use enough analgesia (2 tablet ibuprofen 200 mg about once a week or month) to justify the daily use of Phytalgic, though I have recommended it to my mother who also has OA. Have to ask if it worked, but I'm not sure she actually took it, since it's not reimbursed by healthcare insurance. I've been working on NSAIDs and NSAIDs-related risks for years, so any product that might decrease their use would be great, which is why this study was so inexpensive (the sponsor is not big pharma - yet). On the other hand, apart from providing the treatments and paying the investigator, the sponsor did not have much say on the study design, implementation, analysis or interpretation.