Do we need Real World Evidence cluster headache studies?
These are my own personal views as a cluster headache sufferer and nothing else. I’m not a medical professional, or a researcher and this is not medical advice.
If you suffer from cluster headaches you already know there is no other pain that comes close, but you also know the disease is complex in how quickly you can get attacks out of nowhere, cycles come on based on the time of year even without triggers, triggers are individualistic. Medications don’t work the same on everyone.
Attacks can be triggered by certain weather conditions, substances, and activities. More importantly, a bout can be set off purely by the time of the year. If you are chronic, you have no break from them. You kinda have a sense of your good and bad times, when you are likely to get them. But they don’t always follow the pattern. If you are episodic, you likely know when to expect the next cluster cycle, but they too can change sometimes. I was predominantly right sided with at least 1 nighttime attack for 6 years with cycles around April that would go into remission by June. Then in April 2023 I started getting daily attacks, went up to 6 day by December 2023 and after a lot of trial and error went into remission around April 2024. In my last cycle in Dec ‘24/Jan ‘25 however, my attacks were 100% on the left and only 13% were nighttime attacks. We know from research that cluster headaches have temporal patterns and follow circadian and seasonal rhythms [1}. But also, as this paper points out we need more studies to understand the individual contributions of known factors affecting cluster headaches.
And then there are the medications—more than a dozen options between preventives, abortives, and transition treatment. Most of them off-label, and available to you IF it is approved where you live, IF you have a doctor that knows about them (knows about cluster headaches in the first place), and IF they don’t try to limit the amount of medication you need. Yes, we need that many triptans. So when you have a doctor that’s willing to prescribe you those medications, game on to find the right recipe for the mix of cocktails. It took me about 9 years to figure out a recipe of Verapamil, Oxygen, Sumatriptan, and GON blocks to get my cycles under control. What does under control look like? 22 attacks in a month, mostly late afternoons. I feel a lot of us took the scenic route to get there, and a lot more are still en route.
This is not a rant about my woes. I made my peace with cluster headaches last year, sometime. Took me a while after years of denial and being angry and guilty for getting them. In fact, I feel lucky to be in the Netherlands where I’ve been taken seriously and can discuss options with my doctors. I am lucky I get my Oxygen covered by insurance, which can be a downright nightmare for most. What I want to talk about is how the complexity of cluster headaches throws up unique challenges in research.
Studying Ccuster headaches gets tricky [2]. It is not a common occurrence, most of us are episodic, with sporadic attack frequency and variation, spontaneous remission that cannot specifically be attributed to medication. Clinical and Academic research in cluster headaches commonly face challenges in patient recruitment, retention, and protocol deviation. According to the same paper[2], a lack of Randomised Controlled Trials (RCTs) has resulted in a limited selection of medications approved for CH prevention, which has led to off‐label prescription of agents with limited efficacy evidence.
When I was in my worst bout (and thought I was chronic after a bout of 10 months) I took solace in reading medical papers. It helped me understand my disease better. It helped to know that questions we have as patients are also questions researchers are trying to solve. When you read enough papers, you quickly realise how vital research is. We as patients want better understanding of our disease, better treatments, faster diagnosis, better awareness for GPs, better deals with insurance companies, better psychological help, better support from our disability systems. Research is what I believe gets us there.
Randomised Controlled Trials (RCTs) are the gold standard in clinical trials. In setting up an RCT, there are many factors that need to be controlled, placebo/nocebo effects factored in, a balanced inclusion criteria that fits the intended purpose but also not too restrictive in making the study size too small. Imagine doing that in a rare condition like cluster headaches, where a majority of us are episodic, bouts spontaneously go into remission, and it’s painful to put someone in a placebo group. It’s understandable that study participants want to drop out if when the pain gets unbearable. I was a participant in an RCT for 10 months last year. Again, luckily I started getting better. But if I hadn’t, I would’ve dropped out or deviated from the study protocol to try other treatments to feel better. When my attacks switched sides, I did eventually drop out.
As predictable as CH can be for us as patients, it’s unpredictable when it comes to trial design. This is a hard job. I believe we can make it slightly easier by having Real World Evidence(RWE) based studies as an additional tool for researchers.
To name a few, Real World Evidence in CH can help with
Broader patient representation - a bigger scale, diverse sample
Longitudinal studies - observations over longer durations
Comparative analysis with other academic research
Identify gaps in understanding of treatment
Observe circadian and circannual pattern effects in different locations
Explore new areas of investigation based on what we are experiencing
RCT still scores the goal, RWE passes the ball. I genuinely believe this, this is the sword I will fall on. But I am not blind in my belief and know RWE (in its current form) has real limitations. Please read this article on the Pros and Cons of real-word evidence in headache medicine: A debate.
Let’s capture the essence of this debate.
The pros argue (among other things) that RWEs can complement evidence from RCTs, RWEs generally have more of a heterogeneous population. RCTs backed by evidence from other types of data can be stronger, and point to the example of a drug which is approved by the FDA but not by the EMA. I don’t have an opinion if it should be approved. While RCTs have strict exclusion criteria, RWE can be more inclusive and confounding factors can be explained. And if I understood this correctly, strict inclusion criteria standards can be applied to RWE data, which can make it more viable.
The cons argue (among other things) that RWE is unstructured, have non-standard outcome measures, lack of a control group, lack of quality control on recording outcomes, systematic collection of adverse events, misclassification and limited measures to assess treatment. With the biggest gripe being about missing data or non-standard outcome measures and timing. Placebo/Nocebo responses are not measured in RWE. There are some drawbacks to RWE data in that it is not originally intended for research, medication orders, hospital records for example.
Conclusion from the debate chair: ““I hope that we will be able to work as a society to be better at collecting RWE.”
My personal opinion. RWE studies pose more challenges when it comes to drug related studies. cluster headaches still pose a lot of questions with diagnostic delays, pathogenesis, pathophysiology, physical burden, economic burden, psychological burden. We as patients want more research, researchers want to do more research. If we can address the limitations of RWE, we can potentially make a step in the right direction. And perhaps we can agree on one standard way to describe our diseases and symptoms, when we can’t get the right diagnosis we can use the right terms to spread awareness on medically accepted terms.
My take on it: I have cluster headaches, a form of Trigeminal Autonomous Cephalagia, I have very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180 minutes. During an ipsilateral attack I have the following symptoms: Conjunctival injection, lacrimation, rhinorrhea, and miosis, feel restless and agitated.
I’ll conclude by saying again that there are my musings. I am not taking any particular side, the world is too complex for a binary point of view. And I will end with referencing this paper summarising recent advances and future research directions[3]. Do read it
Below is their panel on the research questions
I’ve highlighted some key questions that I think RWE can help answer, and believe that the limitations and cons mentioned above are not impossible to solve. It’s a problem worth solving. I think I’ll try doing my part in solving it.
References
[1] The biological clock in cluster headache: A review and hypothesis
Willemijn C Naber 1, Rolf Fronczek 1, Joost Haan 1 2, Patty Doesborg 1, Christopher S Colwell 3, Michel D Ferrari 1, Johanna H Meijer 4
[2] Challenges and complexities in designing cluster headache prevention clinical trials: A narrative review David W Dodick 1, Peter J Goadsby 2,3, Messoud Ashina 4, Cristina Tassorelli 5,6, Hans‐Peter Hundemer 7, Jennifer N Bardos 7, Richard Wenzel MD 7, Phebe Kemmer 7, Robert Conley 7,8, James M Martinez 7, Tina Oakes 7,✉
[3] Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache Anja S Petersen 1, Nunu Lund 1, Peter J Goadsby 2, Andrea C Belin 3, Shuu-Jiun Wang 4, Rolf Fronczek 5, Mark Burish 6, Soo-Jin Cho 7, Mario F P Peres 8, Rigmor H Jensen 9
