Placebos Are Getting Stronger

Corona and Lyme

Yo the brain is wild lol. When it turns against us it’s horrifying and can make you feel extremely helpless.

Since COVID began I have experienced 2 separate (potentially) psychosomatic issues. The first was feeling like there was a pill stuck in my throat. I wrote the long version here - but in essence I got scoped by an ENT, discovered there was nothing there, and it was most likely stress-induced reflux or something called globus pharyngeus.

The second was after some mysterious joint swelling ended up being Lyme disease. After going through a full course of antibiotics, I still had some residual swelling and pain. That caused me to start reading more on long Lyme because every person I told said “oh Justin Bieber had that and it f***ed him up”. Unfortunately reading more about long Lyme seemed to manifest symptoms I was reading, especially the brain fog and panic attacks. My brain is probably the only thing I have going for me, so not being able to think clearly was a pretty huge impediment. I was no longer a “thinkboi”, simply “boi”.

‍

Eventually my leg was almost completely back to normal, but my head wasn’t. I started reading a lot of things online about how the extended use of strong antibiotics could be the reason for these head symptoms. My doctor said it was possible, but that it was likely not related to Lyme disease itself (actually almost every doctor I mentioned this to was relatively dismissive that long Lyme was even a thing). Once I stopped taking the antibiotics, my head issues seemed to clear away in a couple of days. Was it all in my head the whole time and I convinced myself the antibiotics were the cause? Were they actually the cause? Honestly it didn’t matter because I was better, but it was a scary episode.

A few takeaways from both episodes:

• I’ve generally thought of myself as pretty good at managing stress, but it’s clear that enough prolonged stress will manifest in some detrimental way. Do not ignore this! There are good and bad kinds of stress, and what I realized is that I get a lot of the bad stress when I feel out of control or helpless in a situation. The throat thing was largely caused by me trying to handle a lot of business things I’m not good at (accounting, taxes, Webflow, etc.) and was solved by outsourcing them. The Lyme side effects were caused by feeling not in control of my own healing process and not understanding what was happening to me.
• Information online is a double-edged sword. In the case of my throat issue, the online patient communities helped me identify that it was something stress-related and armed me with the right knowledge when I talked to my doctor. In the case of Lyme it actually made things worse to hear about so many different patients that were still dealing with symptoms for so many years. At a larger scale, social media channels like Tik Tok where patients describe their symptoms/living with a disease is potentially creating a strange secondary effect where viewers manifest those symptoms (this article about teen girls developing tics after watching Tourette syndrome Tik Tok videos is one example). But simultaneously people are also realizing they’ve actually had undiagnosed diseases or get useful lifestyle tips from other patients on Tik Tok too.
  

• Issues with your head are really hard to describe to your doctor. The best way I can describe how I was feeling post Lyme was when you’re really sleep deprived and nothing quite feels like it’s clicking or memories aren’t being formulated. But…does everyone experience that the same way as me? Is that how other patients describe this feeling?

Understanding how powerful the brain is at generating a physiological response, it made me wonder whether we could use this superpower to our own benefit.

The power of the placebo effect

When you first start learning about scientific experiments, you get introduced to the term placebo. It’s supposed to be something “fake” that you compare to the experimental thing you’re testing. In fact, Wikipedia says:

“A placebo (/pləˈsiːboʊ/ plə-SEE-boh) is a sham substance or treatment which is designed to have no therapeutic value.[1] Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery,[2] and other procedures.[3]”

But despite having no therapeutic value, a lot of times the placebo still causes a therapeutic effect because we believe it’s supposed to. We literally will that shit into existence. 

A corollary to this is also the “nocebo effect”, which is when you start imagining negative effects if you believe the intervention will cause harm. This makes explaining side effects tricky - you’re saying a list of bad things that could potentially happen but it’s hard to get patients to internalize the probabilities of occurrence. This can cause patients to feel those side effects even if they didn’t happen. Here’s an interesting paper where patients who originally discontinued statins because of side effects ended up feeling the same side effects taking a statin OR a placebo. Today, you can read about side effects and patient stories all over the internet for any given drug or disease. This is probably what happened to me when I went down the long Lyme rabbithole.

Placebo effects can be so strong that studies and clinical trials can struggle to demonstrate that their intervention has a noticeable efficacy above the placebo arm. Experiments have to do all kinds of funny things to create placebo arms that can keep a patient blinded but unaware - fake solutions that look the exact same as the experimental therapy down to the packaging and viscosity, fake video games for digital therapeutic trials, and my favorite, sham surgeries:

“In the sham surgery group, study participants undergo an imitation of the surgical process going through everything that the actual surgery group does, from fasting to undergoing anesthesia to receiving surgical incisions—but they do not receive the procedure itself. For procedures during which the patient is awake, physicians will imitate the sounds and sensations of the procedure or show patients a video of the procedure that was actually conducted on someone else.”

Like I just read this and imagine a surgeon making the sounds of a surgical drill and can’t stop laughing. VRMMMMMMM- VRMM- VRMMM while the other staff watch horrifyingly.

We’ve known about the placebo effect for 100+ years now, but there are some developments that seem to be happening recently that have piqued my interest:

• The placebo effect appears to be getting stronger, at least in conditions that tend to have more subjective/patient-reported measures (e.g. pain, mental/behavioral health, GI issues, etc.). In a lot of these areas it’s extremely difficult to get a drug approved because the placebo effect is so high. I’ve read lots of theories about why it’s getting stronger. Since this seems to mostly be happening in the US, it might be because we advertise more heavily how well drugs work. Other theories are around clinical trial design itself - trials are longer and more “hands-on” today so the extra monitoring/care means people taking the placebo will improve.

• There are now studies where clinicians use open-label placebos - aka. they actually tell the patients that what they’re giving them is a sugar pill and tell them that it does work. In meta-analyses of studies that use open-label placebos, there’s a medium size effect. Maybe people who choose to enroll in trials where they know they’re getting the placebo are just more hopeful it’ll work, but that itself is important to know!
• Companies are now pushing the boundaries to see if they can actually commercialize the placebo effect. I have a strong suspicion that many digital therapeutics companies are doing this but if it works, it works. IMO we shouldn’t be charging inactive ingredients as if we’re charging active ones. Here’s an example about a company that tested a nitroglycerin gel to address erectile dysfunction (ED), saw that it basically performed as well as the placebo gel they made which actually worked well at addressing ED, and now is…commercializing the placebo! I’ve played too much Crash Bandicoot to believe that nitroglycerin has any other use but blowing stuff up…which I guess is also technically what’s happening here.
• We seem to have some inkling on what causes the placebo effect and potentially who’s susceptible to it. There’s been lots of research looking at the correlation of certain genes like COMT and placebo response (turns out pharma would LOVE to exclude these patients from trials if they can identify them!). Meta-analyses of fMRIs of brains where the placebo effect resulted in pain relief show several regions lighting up in different patients.

{{sub-form}}

Should placebos be a part of clinical practice?

Which brings me to the crux of what I’ve been thinking about - should we be incorporating the placebo effect more frequently into clinical practice? And if we do, how should the placebo be presented?

Let’s start with the main reasons we probably shouldn’t do it. For one, patients already get frustrated when physicians think something is “all in their head” or don’t want to give them pills. Nocebos are even trickier - how can you possibly stop a patient from manifesting the side effect of a drug? At a time where the physician-patient trust seems to be fraying already, should we be introducing something like placebos which already have a bit of mistrust/deceit baked into it? 

But at the same time, I think there’s a reasonable argument for introducing more placebos, even if it’s open-label placebos or placebo-y things like vitamins/supplements:

• The prevalence of diseases where placebos are particularly impactful (e.g. pain, IBS, anxiety, etc.) seem to be increasing. On top of that, anecdotally, these seem to be the areas where patients are most frequently dismissed by the existing medical institutions and causes deeper distrust, because it feels like the doctor doesn’t care. This is when people start going to functional and integrative medicine physicians (which I’m in support of) or less legitimate sources of care. Using placebos, especially for patients that might be particularly susceptible to them, might actually be effective care for this group that otherwise feels neglected.
• Placebos are cheap! If they have a therapeutic effect and no side effect profile, then that seems like one of the most cost-effective solutions we have. Sham surgeries seem to actually be surprisingly effective, and might be able to help us reduce the number of unnecessary surgeries, especially because surgery has very real risks! The negative here is that payers potentially introduce placebos as another hurdle patients have to jump through in step therapy (try a placebo first before trying the real drug).

• This could potentially relieve some of the burden from physicians who get constantly pressured from patients demanding meds for issues that will likely resolve themselves with time and rest (but patients who hate getting that advice). The uncomfortable reality is that physicians who are hard-pressed for time and burnt out will probably acquiesce in writing a prescription for a pushy patient if it’s low-risk, even if there’s long-term negative externalities (e.g. giving antibiotics regularly). I honestly don’t know how I feel about the idea of giving pushy patients placebos, but it’s a possible benefit.

I think for my case, I wish my doc had said that my head issues were a result of the long-term antibiotic course and then basically said that like, turmeric or something would counteract it (all haldi everything). If it turned out to not be true and afterwards they explained why they decided to try that first, I’d feel okay about it. But that’s just me! The problem is that not everyone will be like that.

There seems to be some schisms even within the medical community about how to think about using placebos. The AMA suggests you can use a placebo if the patient is cool with it and not because it makes the doctor’s life easier aka. the exact opposite of what I suggested lol. There are areas where the benefit is clear. For example, birth control packs will include several sugar pills at the end of a course to maintain the once a day behavior and improve adherence, which patients are aware of (sometimes those pills have other active ingredients like iron or folic acid as well). Doctors seem to already be using placebos, though the definition of a “placebo” seems to be debated.

“The Oct. 23, 2008 BMJ study found that, of 679 general internists and rheumatologists surveyed, about half reported using placebo treatments regularly, with 62% saying it was ethically permissible to do so. Over-the-counter analgesics and vitamins were the most commonly used placebos, though 13% of doctors reported using sedatives and antibiotics as placebos. Only 2%-3% said they used sugar pills or saline.”

​​So what do you think, should we incorporate placebos as a part of regular clinical practice? Or are they inherently a trust breaking tool that will negatively impact the physician- patient interaction as a whole?

Thinkboi out,

Nikhil

Twitter: @nikillinit

IG: @outofpockethealth

Other posts: outofpocket.health/posts

P.S. Here are a few random fun placebo studies/facts I came across:

• Choosing your placebo matters quite a bit - apparently olive oil was used as a placebo for cholesterol lowering drugs before they realized olive oil itself has cholesterol lowering properties. The color of the pill itself can have effects (e.g. blue pills make many people sleepy, but give Italian men insomnia? Theoretically because it’s associated with their soccer team and gives them adrenaline lol idk). Pick wisely!
• Patient communities are obsessed with trying to figure out if they’re on the placebo arm of a trial and will ask other members of a community to help them figure it out. They’ll try to compare small details that happened during the visit, or the bottle, etc. This means that developing a placebo that looks and feels exactly like the therapy is super important - everything from the viscosity of the drug to the taste to the amount of time it takes to prepare needs to be identical (but also not use ingredients that might have their own therapeutic effect).

• Here’s a funny, small study from 2008 where people were given a “pain relief pill” (a sugar pill), and one group was told it was $2.50 while the other were given the same pill but told it was originally $2.50 and discounted to $0.10 (with no explanation why). They then were given light electrical shocks, and the group with the more “expensive” pill felt more of a pain reduction than the discount pill. People think more expensive things are better! Which could potentially explain why some people think their generic drugs don’t feel like they’re working? 

Thanks to Malay Gandhi, Afnan Tariq, and Henry Li for reading drafts of this.

‍

{{sub-form}}

---

If you’re enjoying the newsletter, do me a solid and shoot this over to a friend or healthcare slack channel and tell them to sign up. The line between unemployment and founder of a startup is traction and whether your parents believe you have a job.