Perfectly Simple

Hope is the thing with feathers –

That perches in the soul –

And sings the tune without the words –

And never stops – at all –

Emily Dickinson, the exquisite American poet—prolific in life, but only published after death—was masterful at cloaking the complex in the simple. Take the above stanza, written in 1861, that soars in her signature rhythm of iambic trimeter. It uses the straightforward metaphor of a bird singing to encapsulate the abstract entity—hope—that binds the entirety of the human spirit. Dickinson was a keen observer of the world around her and she probed nature’s mysteries in the most effortless of lines. No easy task.

Complexity hidden within the simple is a concept to which we are no strangers. The physiological processes within the human body are mind-blowingly complicated. When the body goes bad (as is the case when our good patients bowl through our doors), things become exponentially so. But we often rely on simple interventions. Is it any wonder we have some difficulty understanding exactly how some of these work?

One of the simplest of our analgesics is Tylenol. Acetaminophen. Used for over seventy years, with a mostly benign side effect profile, and proven efficacy in defined groups, it does what it says on the packet. Provides gentle analgesia. Simple. Now, dig a little deeper, and ask the question, but how?

To try and get to the bottom of the pharmacodynamics of acetaminophen, one has to understand pain. We’ve just gone and made it harder. A Los Angeles level of highway spaghetti nerve and neurotransmitter traffic, a knotted interplay between nociceptive pathways and the brain’s interpretation, pain is wildly subjective. Pain is essentially the brain’s opinion. But that opinion is formed by some commonalities among humans: tissue injury (or perceived tissue injury), the soup of mediators and messengers, gated entry to the spinal cord, and multiple central locations from brainstem up.

So how does acetaminophen fit in? The most recent evidence says, we still don’t know. It appears to have, unlike the COX 1 and COX 2 inhibitors, almost no effect at the peripheral sites of injury, and instead exerts its effect centrally. Its two main actions seem to be selective inhibition of cyclo-oxygenase within the brain itself, requiring the low peroxide environment of intact neuronal cells, and an indirect effect on cannabinoid and vanilloid tone, whatever it is these may be. It feels like Tylenol could be an Emily Dickinson poem itself.

(The endogenous cannabinoid system is looking increasingly interesting. We know that placebo analgesics work via a strange combination of personal variability, expectation of therapeutic effect and ritual, priming the endogenous opioid and cannabinoid systems. Fascinatingly, the placebo effect can be blocked by naloxone!)

Another wildly simple drug, causing hugely complex effects, is lithium. Could it get more simple? Three protons, three electrons, four neutrons, just an entry blip in the periodic table, fizzed together in the Big Bang. But here it is, altering the vast complexity of human thought: bringing down mood, stopping people dressing outrageously, curbing their wild spending. Again, its actions are at the same time incredibly simple, yet dizzyingly complex. Lithium essentially replaces sodium (no wonder the body gets confused, I mean look at them). Basically, lithium is sodium that doesn’t work as well, slowing down central neuronal transmission in critical areas, in particular the white matter. But it doesn’t stop there. A barrel of other actions has been documented. There is neuroprotection of gray matter, inhibition of certain dopamine pathways, downregulation of NMDA receptors, promotion of GABAergic neurotransmission and many, many, many (you get the picture) other pathways.

There are thousands of similar examples in therapeutics. Drugs or interventions that on the surface seem reasonably straightforward and comprehensible, but when we dive deep into trying to understand them are anything but.

It seems only appropriate to let Emily have the last say about all of this.

“Faith” is a fine invention

When Gentlemen can see –

But Microscopes are prudent

In an Emergency.