Medication Sensitivity: Why Some Bodies React Differently (and Why There's So Much Trial & Error)

A closer look at why medication is never a one-size-fits-all solution.

photo by Cody Sells

The idea for this Deep Dive came after a conversation with other chronically ill friends. We were lamenting the fact that, though most of us are on meds that are actually helping now, it’s taken years of trial and error to figure out what works for each of us. I’m on a biologic used to treat rheumatoid arthritis and psoriatic arthritis, but before that I was on a couple of different biologics that could also treat Crohn’s disease and ulcerative colitis. Some of my friends had also been on these medications, and found the same ones that didn’t work for me helpful for their own conditions. The same goes with friends on different antidepressants or ADHD meds. It got me thinking: of course we’re all different, but why would medication efficacy be so different from person to person when other over the counter products like ibuprofen or Tylenol seem to work relatively predictably across people.

Here’s what I found:

First, There’s Really No “Average Patient”

I’ve been thinking a lot lately about how much testing a drug needs to go through before it actually goes on the market, and the issue that is inherent in drug testing: there have to be control groups, and sometimes the control groups don’t end up representing the group of people the drug is intended for.

For instance, a drug being tested for ulcerative colitis might be tested on a range of people who have been diagnosed with ulcerative colitis, but for the control to be accurate, they probably have to make sure this group of people aren’t also medicated for depression or anxiety or even arthritis (which is a common side effect of IBD). So the drug is tested for one condition, but the reality of people living with that condition is that they might have other conditions alongside it.

I’m getting ahead of myself here, too, because early Phase 1 drug trials are typically only tested on healthy people because researchers are trying to simply understand how a medication moves through the body.

And, to make matters even more complicated, in 1977 the FDA issued a guidance recommending that women of “childbearing potential” should generally be excluded from early stages of drug research. This guidance was reversed in 1993, but still, women and racial/ethnic minorities have historically been incredibly underrepresented in clinical research.

Now, Let’s Answer That Ibuprofen Question

Why does it seem like you have to go down several rabbit holes to find the right biologics, antidepressants, ADHD meds, and immunosuppressant meds but can just pop and Advil for a headache and trust that it’s going to work?

It’s because ibuprofen belongs to a class of meds called nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit certain enzymes, COX-1 and COX-2 (cyclooxygenases if you want to know the full name), and these enzymes are used by the body to make prostaglandins. Prostaglandins basically signal to your brain when inflammation and fever is present, and makes your nerves more sensitive to pain. When prostaglandins are blocked, it reduces pain and inflammation full stop. Doesn’t matter what is causing the pain/inflammation.

So, ibuprofen doesn’t need to know anything about the source of the pain, just that there is pain. This is why it works whether you’re getting period cramps, a headache, dealing with an ankle sprain, or dinged your shin on a coffee table.

Acetaminophen, which some people prefer (I know plenty of folks who can’t deal with the stomach issues that can accompany ibuprofen), isn’t an NSAID and doesn’t actually have anti-inflammatory effects the way ibuprofen does, but it also deals with prostaglandin signaling and other pathways in the central nervous system. Like ibuprofen, it’s focused on processes involved in the experience of pain, rather than the source of pain itself.

For both ibuprofen and acetaminophen, they’re relieving a symptom rather than treating a cause. I’m sure you already knew that, but it’s a helpful look at why these medications can be more quickly and universally effective.

So What Are Chronic Illness Meds Trying to Do? And What Makes Them Harder to Tolerate?

Biologics and other chronic illness medications are typically trying to do something much different from an over the counter painkiller. And the more specific the target, the more the underlying disease matters.

For instance, let’s use RA as an example. Different rheumatoid arthritis biologics target different parts of the immune system. Some are inhibiting “tumor necrosis factor” (TNF, a protein that promotes inflammation) while others are interfering with IL-6 signaling (an inflammation pathway involved with joint inflammation, fever, and fatigue), some target B cells (immune cells that can trigger autoimmune attacks), or affect T-cell activation (immune cells that amplify immune responses).

The thing is, two people can both be diagnosed with RA and yet have very different diseases on a molecular level. I tried a medication that’s a TNF inhibitor and it didn’t do much, maybe helped my disease from progressing, but when I tried a medication that blocks T-cell activity, it’s done wonders for me.

Researchers are beginning to get a better understanding of this. In a trial known as R4RA, researchers studied people with rheumatoid arthritis who hadn’t responded very well to TNF inhibitors. They took biopsies of joint tissue and compared responses to different biologics: rituximab, which targets B cells, and tocilizumab, which blocks the IL-6 receptor.

They essentially found what we’re talking about: two people can have the same diagnosis without having the same disease biology.

This helps explain something that all of us living with chronic illness has found to be a maddening rite of passage: seeing someone with the same diagnosis as you responding well to a medication that never worked for you.

The same thing happens all the time in patients with neurological conditions, most commonly perhaps in depression. There was an enormous study called STAR*D that focused on antidepressants, and only a small portion of participants achieved remission with the first antidepressant they tried. People who didn’t improve went on to switch meds or add on another, with no second-step option emerging as the universal answer.

So it’s not just about two bodies processing medication differently, it’s actually about if the drug in question is targeting the biological pathway that actually matters enough in a particular person’s illness to have any effect? And since it’s impossible to tell by symptoms alone, and we don’t yet have protocols for studying each person’s individual molecular makeup of their disease, trial and error is the path we have to take.

Now, It’s About What Your Body Does with the Medication

Say you’ve found the right medication for the right targeted biology. Yay! But the medication still has to actually get to the target.

Now we have to get into what’s called “pharmacokinetics,” aka the field that’s concerned with what the body does to a drug.

When you swallow a pill, it’s not like it’s just entering your bloodstream at the number of milligrams written on the bottle. First it needs to dissolve, then it moves through the GI tract, then some portion of it is absorbed through the intestinal wall. It might be metabolized in the gut, or maybe the liver, before it reaches the circulatory system. Then once it does, it has to travel through the bloodstream and distribute into your tissues. Then finally, it has to be metabolized again and eliminated.

That’s a lot of steps! And there’s room for variation at pretty much every step: how you absorb things, how you metabolize things, how you circulate things through your blood, etc. Therefore, the same dose isn’t going to create the same drug exposure in two people, and it’s more complicated than just “higher dose if you weigh more.”

Absorption

Food can actually pretty dramatically change the absorption of some medications, which is why with some meds you’re supposed to take it with food and others you’re supposed to take it on an empty stomach.

Your stomach acidity can matter, too, as well as your gut motility (the movement of food, liquid, and waste through your digestive tract). Plus the actual formulation of the drug can matter (like when things are quick release, slow release, liqui-gels, etc). Also, other medications and moods can interfere with enzymes and transporters in the intestines (why grapefruit juice is a no-no for people on certain statins, etc.)

If you’ve had GI surgery or have a gastrointestinal disorder like IBD or GERD, absorption is going to be affected as well.

Metabolization

If your body metabolizes drugs slower, this is likely what people refer to as a “medication sensitivity.” I’ll tell you why:

Basically, one of the body’s major systems for metabolizing drugs is a family of enzymes called the “cytochrome P450 system” (sounds like a band name kind of, doesn’t it). They’re found primarily in the liver and intestine. If you have lower enzyme activity, it’ll mean a medication is broken down more slowly. This means that a dose of medication will stay in your body longer, or it might produce a higher concentration than intended, and this can increase its effects (as well as its side effects).

On the other hand, someone with higher enzyme activity may metabolize and eliminate the medication so quickly that its intended dose doesn’t stay in the body for long enough to have an effect.

And some drugs actually rely on metabolization for the drug to actually work. This is the case with codeine, an opioid. Codeine relies on one of those enzymes in the cytochrome P450 system, CYP2D6, to produce morphine. Someone with higher enzyme activity can accidentally overdose, whereas someone with low enzyme activity might get very little pain relief. It’s kind of the opposite, since the low-activity patient might typically find themselves more sensitive to other drugs.

FYI: Chronic Illness Affects Your Metabolism, Too

You would perhaps think that your metabolism was somewhat fixed in how it processes and eliminates medications, but it isn’t Disease can actually change it.

Essentially, inflammatory cytokines (which are the molecules involved in immune activity) can alter the expression of some of those drug-metabolizing enzymes we talked about. This gets kind of insane once you actually begin treating the chronic illness, too, because as inflammation gets treated, your body might process the very medication that’s treating the inflammation differently. This has literally happened to me: a drug that didn’t seem very effective for six weeks suddenly became effective because it was helping with its own metabolization behind the scenes. INSANE. This is also why we’re often told to stay on drugs for at least six weeks before switching to a new one.

There Are Lots of Other Factors That Play Into Drug Sensitivity, Too

This list can get really long really quickly, so I’ll do my best to just name the quick hits:

• Liver and kidney function

  • This will affect how quickly particular meds are metabolized or eliminated from the body. Drinking alcohol can affect these functions, which is why certain drugs don’t allow you to drink within a few days of your dose.

• Other meds, supplements, foods, and substances

  • Some are going to inhibit the same enzymes another med relies on for metabolization. Others will increase enzyme activity. Grapefruit, like I said, is famous for this. St. John’s wort is another. Smoking also messes with some important metabolizing pathways.

• Age, sex, body composition, and hormones

  • A no brainer, for sure, but all of these things are going to affect absorption and metabolism.

• Inactive ingredients

  • The fillers, dyes, coating, stabilizers, preservatives, sweeteners, etc found in pills can trigger intolerances or allergies, or affect absorption in other ways. I have friends who can tolerate a generic drug made by one factory, but not another!

• Gut microbiome

  • Of course your microbiome matters. The bacteria in our digestive tracts have their own enzymes and can chemically modify tons of medications.

Trying a Medication Is, and Isn’t, a Shot in the Dark

I have been burned by so many physicians before, so I’m not necessarily defending them, but as I was doing research about all this it really did help me understand what’s actually happening each time I tried a medication that didn’t work for me. I now understand that each time I try a drug, it’s essentially trying to answer a ton of questions at once:

• Is the drug actually targeting the pathway that matters on a biological level for my version of this illness?

• Will enough of it reach the right place in my body to be effective?

• Will my body metabolize it in a way that keeps this drug effective?

• Will the intended effect of this drug outweigh everything else it might be doing to me?

Every time you try a drug that doesn’t work for you, a good doctor is actually ruling out all of the aspects of it that are ineffective in order to pinpoint what exactly can help your disease. Sure, there are bad or inattentive doctors out there who are not doing the proper amount of detective work, and if this is your experience I really hope you can seek treatment from someone who takes your condition a lot more seriously.

Privatized Health Insurance, Big Pharma, and the Medical Industrial Complex

Another big problem with this whole trial and error system is that health insurance companies often won’t approve certain medications until other medications are tried first. This has happened with me and I’m sure it’s happened with you. My doctor had to provide credible evidence that Humira and Enbrel didn’t work for me before I could go on Orencia (they also wouldn’t approve Cimzia, which is what I was supposed to try next, but thankfully Orencia has been great for my biology specifically).

This is where things actually get evil. This practice is called step therapy, or, horrifyingly, “fail first.” An insurance plan requires you to try one or more meds from their “preferred list” before it will cover a different (read: more expensive) treatment. Your insurance company is, in essence, determining the order in which your trial and error happens. Which is messed up. What’s even worse is that the “preferred drugs” on their lists aren’t even typically what are deemed best by doctors. The preferred drugs list comes from negotiations and, essentially, lobbying, by these middlemen called pharmacy benefit managers. So, yeah, your suffering basically becomes part of the proof required to unlock care. And don’t even get me started on how inflated these drug prices are, when they then get subsidized by copay assistance programs and coupons and rebates, all to drive insurance premiums up to make both privatized health insurance and big pharma an even more lucrative business that isn’t actually concerned with getting patients the right treatment as efficiently and accessibly as possible. Ugh!

Anyway, I hope all of this was helpful. It doesn’t change how frustrating it is to be on the never-ending ferris wheel of trying out medications, but understanding what’s really happening has been empowering for me, and I hope it is for you, too.

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Sources

U.S. Food and Drug Administration. Step 3: Clinical Research. Overview of Phase 1–3 clinical trials, including the use of healthy volunteers in many Phase 1 studies.

U.S. Food and Drug Administration. Enhancing Participation in Clinical Trials: Eligibility Criteria, Enrollment Practices, and Trial Designs. Guidance encouraging broader enrollment across demographic groups and among people with comorbidities, organ dysfunction, disabilities, and other characteristics historically excluded from some trials.

U.S. Food and Drug Administration. Promoting Safe & Effective Drugs for 100 Years and Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs. Historical background on the exclusion of women of childbearing potential from early clinical trials and the 1993 reversal of that policy.

Vane JR, Botting RM. “Anti-inflammatory drugs and their mechanism of action.” Review of NSAID inhibition of cyclooxygenase and prostaglandin production.

Humby F, et al.; Rivellese F, et al. R4RA studies of synovial biology and differential response to rituximab and tocilizumab in rheumatoid arthritis.

U.S. Food and Drug Administration. Table of Pharmacogenetic Associations and Table of Pharmacogenomic Biomarkers in Drug Labeling. FDA summaries of clinically relevant gene-drug relationships.

SEARCH Collaborative Group. “SLCO1B1 variants and statin-induced myopathy: a genomewide study.” New England Journal of Medicine, 2008.

Schmitt C, et al. “Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis.” Research demonstrating inflammation-related changes in CYP3A4 activity.

Jani M, et al. “Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of anti-drug antibodies on the long-term treatment response in rheumatoid arthritis.” Research linking anti-drug antibodies and low adalimumab levels with treatment response.

Zucker I, Prendergast BJ. “Sex differences in pharmacokinetics predict adverse drug reactions in women.” Biology of Sex Differences, 2020.

Reker D, et al. “‘Inactive’ ingredients in oral medications.” Science Translational Medicine, 2019. Analysis of excipients across oral drug formulations.

Zimmermann M, et al.; Wang X, et al. Research on gut microbial drug metabolism and person-to-person variability in microbiome-mediated metabolism.