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LDN for Rheumatoid Arthritis

Dr. Guttorm Raknes
April 15, 2019
Interview with Dr. Guttorm Rakness of the University Hospital of North Norway and Raknes Research

Dr. Guttorm Raknes has both a medical degree and a PhD in health services research. He works as a general practitioner, an independent consultant at Raknes Research and a researcher at the Regional Medicines Information and Pharmacovigilance Centre (RELIS) at the University Hospital of North Norway, Tromsø, Norway. In RELIS, he and his colleagues act as advisors for health professionals in drug-related issues, and are responsible for the processing of adverse event reports in the Norwegian health care system.

Dr. Raknes, congratulations on yet another fascinating study- this time on the use of LDN in rheumatoid arthritis and ankylosing spondylitis in over 360 Norwegian patients.

As pointed out in your study, the real world data of large numbers of LDN users presents a unique vantage point which is naturally less biased than clinical studies. In diseases that have not yet benefited from formal clinical trials, your study fills an important void in information. We have several questions that we believe will enable our LDN prescriber and user community to benefit from the important findings you have shared.

Could you please share with us details of how LDN came to be so widely prescribed in Norway?

I think the LDN story in Norway is quite a fascinating one because it demonstrates the impact of mass media on health care.

Up until 2013, there were very few LDN users in Norway. According to the Norwegian prescription database (NorPD), the number of low dose naltrexone users was less than 20 individuals in the preceding years.

But in February 2013, the biggest commercial broadcaster in Norway, TV2, aired a 20 minute documentary on LDN. The background for the show was that a TV2 journalist had personal experience with LDN, and he persuaded the television channel to make the episode. Among other things, the show presented MS patients sharing that the use of LDN had led to almost complete recovery from multiple sclerosis.

The documentary got quite a bit of attention, and LDN became breaking news in the regular news broadcasts over the following couple of days, with titles such as “Unknown medicine LDN gives hope to thousands of patients». But there were also neurologists publicly discouraging the use of LDN due to limited evidence.

Both medical specialists and general practitioners, most of whom had no prior knowledge of LDN, were overwhelmed by patients that wanted a prescription for LDN to treat all kinds of ailments.

Both medical specialists and general practitioners, most of whom had no prior knowledge of LDN, were overwhelmed by patients that wanted a prescription for LDN to treat all kinds of ailments.

It also came as a surprise to pharmacies, which ran out of naltrexone in just a few days. There was only one compounding pharmacy (Kragerø Tablettproduksjon) that provided 3 mg naltrexone to the very few existing LDN users, and it ran out of raw materials within days. For several weeks it was almost impossible to get a hold of LDN.

This sudden rise in LDN prescribing was a fantastic opportunity to perform pharmacoepidemiological studies. I contacted my boss, Trude Giverhaug and Lars Småbrekke at the University of Tromsø, and after submitting the necessary applications, we got a data file from the Norwegian prescription database (NorPD) containing information from all Norwegians that had collected at least one LDN prescription over the past several years.

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If the same proportion of the population suddenly would start using LDN in the USA, it would be equivalent to almost a million individuals.

By using the prescription database, we have found that more than 15,000 Norwegians received (collected) at least one prescription for LDN in 2013 or 2014. If the same proportion of the population suddenly would start using LDN in the USA, it would be equivalent to almost a million individuals. As you can see from this slide, the increase in LDN prescribing was enormous. The figure also shows that a large proportion (40%) only collected LDN once. These one-time collectors are important to our research, as we considered them controls. It is likely that they used LDN only for a very limited time or not at all. The data file enabled us to answer all kinds of research questions.

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For example, as presented in this slide: patients that collected LDN four times or more (persistent users) had a dramatic fall in opioid consumption (by almost half) one year after starting LDN compared with one year before. This reduction was not compensated for by an increase in other kinds of pain medication.

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In our study of multiple sclerosis (MS), there were no differences between the persistent LDN users and the one-time collectors. There were significant differences in the prescribing of different MS drugs, but the change was identical to trends in the total MS population. So, if LDN has any effect in MS, it did not translate into reduction in medication in our findings.

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the number of users of intestinal corticosteroids, a standard treatment for IBD worsening (flares), was reduced by 17% in persistent LDN users.

In a study of inflammatory bowel disease (IBD, Crohn’s disease and ulcerative colitis), we observed some very interesting reductions in the prescribing of several drugs. Here, for example, we see that the number of users of intestinal corticosteroids, a standard treatment for IBD worsening (flares), was reduced by 17% in persistent LDN users. This is a significantly larger reduction than among the one-time LDN prescription collectors.

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Here we see that there were quite large reductions in the average cumulative dose of the corticosteroids after starting LDN in both Crohn’s and ulcerative colitis patients.

Is the cost of LDN wholly or partially reimbursed by governmental health insurance?

No. It is not reimbursed. All patients have to pay for LDN out-of-pocket. The main reason is that it is not yet an established therapy, and it has to be prescribed off-label. It is not very expensive compared to other disease-related expenses, so to most patients the cost of LDN is not a particularly large burden.

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We find that patients seeking LDN from their physicians do so usually due to unsatisfactory disease control on current medications, or because they wish to reduce current medication use. Do you think that Norwegian patients’ reasons for seeking LDN therapy are similar?

Our research cannot answer to this question, but it sounds reasonable that patients want to test alternative therapies if they experience insufficient improvements or struggle with negative side effects.

Remember: these conditions are most often life-long disabling diseases. Even though the current regimen may be of great help, it is understandable that patients are eager to try new and promising treatment alternatives.

The desire to try LDN is probably triggered by the same mechanisms that make patients willing to uncritically try all kinds of therapy, pseudoscientific or not, like herbal medicine, spiritual healing, homeopathy and other alternative medicine.

But I also think LDN appeals to more skeptical patients that comb the internet looking for potential therapies that have some scientific credibility. Plausible mechanisms of action for LDN have been suggested, and increasing clinical evidence seems to confirm some efficacy.

I think most patients would be thrilled to be able to replace immunosuppressants with LDN.

I think most patients would be thrilled to be able to replace immunosuppressants with LDN. I also think the government would be happy if LDN could be used instead of the often extremely expensive biologic immunomodulators.

People are often refused LDN prescriptions by their physicians out of fear of inefficacy when combined with immunosuppressants, or fear of neutralizing the beneficial effect of immunosuppressants. A recent survey we carried out in patients taking both LDN and immunosuppressants showed that very few experienced deterioration from the combination. In fact, a large majority reported benefiting from the combination, and some were even able to reduce the dose of immune suppressants while on LDN. Your findings in persistent LDN users (i.e. 4+ prescriptions) seem to support the findings from our surveyed patients. Would you agree?

I am happy to see that your survey findings are in line with our results. Surveys like the one LDNscience did are a valuable complement to research as hypothesis generators. They are fairly easy and cheap to perform, and it is possible to recruit large numbers of participants. Sometimes you can get answers to questions that more rigid research designs are unable to address. However, there are very important limitations to the scientific value of self-report surveys.

Surveys like the one LDNscience did are a valuable complement to research as hypothesis generators.

First, there is the recruitment bias. There is a risk that people that have experienced positive (or negative) effects are more prone to participating in such surveys, and the answers may not be representative of the average LDN user. There is also no control group. In self-reporting, so-called recall bias is a problem, people tend to exaggerate effects or forget how and when they actually complied with the treatment.

In our prescription register studies we do not have this kind of bias. We included all LDN-using patients in the entire Norwegian population, and thus no inclusion bias. We also use an objective measure: all dispensed of prescriptions, so there is no recall bias either. We cannot be 100% sure that the included patients actually were taking the LDN, but even in randomized trials this may be a limitation.

We even had two kinds of control groups: The patients acted as their own controls. Drug use before starting LDN was compared with drug use after starting LDN. Ideally, we should have had a control group of RA patients that did not use LDN, but we were not allowed to include such patients. But the patients that only collected LDN once can be considered a relevant control group, since a majority of them used LDN for a very limited time or not at all.

The gold standard is, of course, randomized, blinded clinical trials. The individuals volunteering in clinical studies may not be representative, but this is partly overcome by the randomization process.

Our study participants were actual patients that chose to use LDN by themselves, not because they were part of a clinical study.

Our registry based studies have some advantages even over randomized trials: They were quite easy to perform, and did not cost much. We were able to include large number of patients. Most importantly: Our results are real world data. Our study participants were actual patients that chose to use LDN by themselves, not because they were part of a clinical study. In randomized trials, there may be strict inclusion and exclusion criteria (like age, sex, stage of disease, comorbidity, pregnancy, etc.). In clinical studies, the participants are most often followed up very closely, and to an extent that may not be realistic or representative of real world conditions.

Your study seemed to show significant numbers of patients continuing to take LDN (i.e. 4+ prescriptions) regardless of achieving a reduction in immune suppressants or pain medications, correct? Considering that the cost of LDN is not covered by governmental health insurance, do you think the patients’ continued use of LDN therapy reflects that patients feel that combination therapy with LDN is beneficial?

Well, it was actually the other way around. This is an important point: We did not examine whether the included patients continued on LDN; we investigated whether starting continuous use of LDN was followed by changes in the use of painkillers and immunosuppressants.

And that was exactly what we found: Patients with rheumatoid and seropositive arthritis that were persistent users of LDN reduced their average yearly non-steroid anti-inflammatory (NSAID) dose by 15%, whereas among the one-time LDN prescription collectors there was no change.

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Among persistent LDN users, the average opioid consumption was reduced by 47%, and the number of people using opioids decreased by 26%

Even though we observed significant reductions in the number of several disease modifying drugs, there was a convincing reduction in opioid use. Among persistent LDN users, the average opioid consumption was reduced by 47%, and the number of people using opioids decreased by 26%, compared to a small non-significant increase in opioid use among one-time LDN prescription collectors.

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Disease modifying anti-rheumatic drugs (so-called DMARDs) make up a diverse group containing, for example: methotrexate, anti-malarials, and biological immunomodulating drugs like TNF-alpha antagonists. We found a significant 13% reduction in the number of DMARD users among persistent LDN users, but among one-time LDN prescription collectors there was no difference.

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To sum up: Patients with rheumatoid and seropositive arthritis that started continuous use of LDN reduced the use of disease modifying drugs and at the same time reduced their use of painkillers.

To sum up: Patients with rheumatoid and seropositive arthritis that started continuous use of LDN reduced the use of disease modifying drugs and at the same time reduced their use of painkillers. Although the evidence is not as strong as in randomized trials, the efficacy of LDN in rheumatoid arthritis is a probable explanation of our findings.

Your detailed analysis sheds light on the subsets of patients most likely to benefit from LDN therapy. This information can prove invaluable for correctly designing a clinical trial capable of confirming these benefits. Can you please elaborate on which subsets of patients you expect to benefit most from a rigorous clinical trial?

From our three most recent LDN studies, I believe the case for LDN is strongest for inflammatory bowel disease and rheumatoid arthritis, and not so much for multiple sclerosis. There have already been some quite ok, but small, randomized trials in Crohn’s disease, so that would be my choice for a big clinical study. For smaller studies, I would prefer rheumatoid arthritis or ulcerative colitis, since, so far, there are no clinical studies related to them.

Your study goes a long way to encourage formal clinical trials for these challenging rheumatic diseases. You suggest that those who pay for health services would be most motivated to undertake such studies. Can you please expand on the incentive for them to fund such clinical trials?

The most important point is that Big Pharma has an incentive NOT to study LDN. It could displace other profitable medicine.

On the other hand, governments and insurers that pay for these expensive drugs could save billions of dollars even if only a small subset of patients could use LDN instead of biologicals, for example. Only in the US, there are approximately 3 million people with RA or IBD.

The savings would pay for the LDN trials many, many, times over, if efficacy is confirmed.

The challenge is: Who should step forward and do such a study? I think an international government sponsored strategy would be best. This is only achievable with increased awareness of LDN among decision makers.

As you point out in the conclusion of your study, LDN has an excellent safety profile. Considering this, and in the current absence of clinical trial data, do you foresee growing physician practice to prescribe LDN to patients who have either failed standard therapies, or derive incomplete benefit from their current treatments?

Although doctors risk little by prescribing LDN, I can understand the skepticism. LDN is largely unknown, and it is not marketed at all by industry or by colleagues. Pressure from patients to prescribe may often be counterproductive.

I hope that our findings will encourage physicians, both GPs and specialists, to learn more and open up about LDN.

I hope that our findings will encourage physicians, both GPs and specialists, to learn more and open up about LDN. But, realistically, I believe other measures are needed to boost the prescribing. Informing physicians that LDN most often is harmless is one aspect.

Finally, the story of LDN is unique in that most of the new uses and research has been driven by patient proactivity with no pharmaceutical company support or marketing. Do you see areas where patient-driven data collection such as surveys could be designed to complement the findings in your studies?

I absolutely believe that patients and organizations like LDNscience have a crucial role in spreading the word about LDN. Lobbying towards politicians, media and the general population is important, and I think surveys can be an important part of this work. Patients’ success stories about LDN are important because they may appeal to journalists and the general public. If patient-driven work could lead to new documentaries such as the Norwegian one in other countries, the impact could be tremendous.

I absolutely believe that patients and organizations like LDNscience have a crucial role in spreading the word about LDN.

But it is important to realize that surveys and patient stories have very limited scientific value. When reaching out to doctors and the scientific community, I believe the most important thing is to promote high quality laboratory, clinical and epidemiological LDN research.


We at LDNscience thank you very much, Dr. Raknes, for your contribution of time and effort to increase understanding about low dose naltrexone.