live, love, hurt

Pretty much everyone knows what acetaminophen is. If you don’t, acetaminophen is the active ingredient in the brand names Panadol and Tylenol. Acetaminophen is known by different names–especially outside the United States–and is most commonly called paracetamol and often abbreviated APAP (from here on out). All of these names come from the chemical name, n-acetyl-para-aminophenol. APAP is notable as one of the first non-opioid (non-narcotic) analgesics without anti-inflammatory properties (this honor actually goes to the drug phenacetin, which was widely used but taken off the market in 1983 due to carcinogenicity concerns. APAP is a metabolite of phenacetin). It is a pain-relieving (analgesic), fever-reducing (antipyretic) drug in the aniline class, of which itself is the only remaining member.

Until recently, pharmacologists did not fully understand APAP’s mechanism. That is, exactly how does it relieve pain and reduce fevers? Considering the only other non-opioid analgesics consist entirely of the non-steriodal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, APAP’s mechanism was assumed to be a similar one. NSAIDs work by inhibiting enzymes called cyclooxygenase (COX) which produce chemical messengers called prostiglandins which set off inflammation and pain. While NSAIDs markedly reduce inflammation, there is almost little to no inflammation reduction with APAP usage. Why is this?

There are two varieties of cyclooxygenase: COX-1 and COX-2. Most NSAIDs inhibit both of these types equally. COX-1 inhibition has the unwanted side-effect of reducing protective liners in the stomach which can lead to gastric bleeding (indeed, the number one problem with NSAID use). However, inhibition of COX-2 does not produce this effect. Due to this, a number of drugs were developed that selectively inhibit COX-2 while leaving COX-1 alone, and these drugs were called “COX-2 inhibitors” with drug name suffixes of “coxib,” for “COX inhibitor.” Examples of such drugs include valdecoxib, rofecoxib, and celecoxib. A number of these drugs were developed and were very well-regarded by pain management physicians and chronic pain patients alike for their excellent ability to lower pain and inflammation without marked side-effects and even alleviated the need for opioid use (or at least reduced it). Unfortunately some of these drugs were abruptly removed from the United States market and, aside from celecoxib, no new COX-2 inhibitors have been approved or remain on the US market.

So where am I going with this? As APAP’s mechanism becomes more clear, recent findings have suggested that APAP is strongly selective of COX-2 (so much for the need to remove them from the market). So while APAP does indeed inhibit COX like the NSAIDs, there is strong evidence that APAP works through at least two pathways. The first one is well-researched and well-understood (COX inhibition), and the second pathway is what we’re interested in. So what exactly is going on here?

Recent research suggests that APAP may earn its analgesic and antipyretic properties by indirectly activating the endogenous cannabinoid system. The same way that opioids activate our own natural pain-relief system that endorphins and other natural ligands use, the body also has a natural cannaboinoid system which is responsible for the effects of tetrahydrocannabinol, or THC, which is the main active ingredient found in marijuana. Just like morphine binds to opioid receptors (mu, kappa, delta, and others), drugs like marijuana bind to the cannabinoid receptors CB1 and CB2. A well-known natural opioid is endorphin. There are also natural cannabinoids, and the one floating around our brains is called anandamide. The entire purpose of the endogenous cannabinoid system has yet to be fully elucidated, but we will explore some of the regulatory functions they serve below.

When you take APAP, it is metabolized by the body into a number of different chemicals. Some are active, some are inactive. One particular metabolite is taken in by an enzyme in the body called fatty acid amide hydrolase (or FAAH), which converts it into a metabolite called AM404. AM404 is versatile. It’s effect is as an analgesic and an antipyretic (sound familiar?). AM404 inhibits FAAH, which also metabolizes anandamide (the natural cannabinoid). The net effect is that anandamide uptake is inhibited, and levels of anandamide in the brain increase. AM404 also directly inhibits the formation of COX-1, COX-2, and prostaglandins (sound even more familiar?). AM404 also activates a receptor called TRPV1, which is also where the substance capsaicin (the substance that makes hot peppers hot) binds. TRPV1 is responsible for pain transmission and thermoregulatory actions. When activated, TRPV1 enhances and modulates pain transmission, and also tells the body to cool itself down. However, when TRPV1 is bound to for long periods of time it “shuts down,” preventing it from functioning, thus reducing pain.

So let’s take a step back. We’ve got a lot of things going on. Thanks to AM404–which is introduced by acetaminophen–we have the following things going on:

1. AM404 inhibits FAAH–which metabolizes anandamide–resulting in an increase of anadamide.
2. Anadamide binds to cannabinoid CB1 and CB2, and also activates the TRPV1 receptor. Each of these actions are known to inhibit pain on their own.
3. AM404 also activates the TRPV1 receptor.
4. AM404 also inhibits cyclooxygenase and prostagladins.

All of these processes are working to reduce pain (and fever). So, what does this really matter? By investigating these processes we can create novel analgesic drugs that aim to inhibit FAAH in the same way AM404 does (APAP’s use itself is limited due to its toxicity at higher doses) and giving rise to this exact process. We can also make drugs to target TRPV1, and in fact there are already several in advanced testing phases (both agonists and antagonists are being explored, but I’d personally be interested in a partial agonist–can we activate and overload it without causing the burning sensations?).

Let’s remember, this started by looking closely at the metabolism and mechanism of a drug almost everyone worldwide knows of and has made use of: acetaminophen. First we found out that APAP is most likely a highly selective COX-2 inhibitor, and so that trash about taking Bextra and Vioxx off the market was just that: trash. More importantly–if you’ve managed to follow along–you’ve almost certainly deduced that because acetaminophen introduces AM404, and AM404 causes activations in the endocannabinoid system, and in this fashion acetaminophen acts as a pro-drug for a cannabimimetic metabolite (AM404 itself), this means that Tylenol and Panadol and hugely popular drugs containing acetaminophen are activating the endocannabinoid system–like marijuana–in order to produce it’s primary effect of analgesia. Tylenol’s pain-relieving action involves activation of the endogenous cannabinoid system.

And marijuana is illegal?

In March, I was told by my pain management physician that he’d be leaving the office and indeed Hopkins all together. Long story short, Hopkins wanted him to do a bunch of things to patients purely for the sake of bringing in revenue, and he refused to do so and instead quit, taking several other physicians with him. I was told, at the time, that he’d be there until May and in May I’d get several post-dated prescriptions to cover me until he had his private practice set up in June. That plan–like so many plans–didn’t quite turn out that way.

In May I met–for the last time–with my pain management physician. He refilled all my medications and told me which physician I’d be seeing until he gets set up somewhere. This was now not a certainty as I’d been led to believe before. Now he may or may not continue his practice elsewhere, and I’m somewhat concerned. I take the scripts and bid him farewell.

Thirty days later it’s time for a refill. I don’t have a treating physician anymore. I call the office and they arrange for a one-time 30 day refill of my medications in exchange for a urine sample. Apparently it was horrible of my previous physician to simply trust me and not require urine analyses (UAs) in the past, and some more stuff about why he’s a bad doctor and I should stay there. I’m told to make an appointment with the new physician. The appointment was 52 days away, and I had scripts for 30 days.

Thirty days later it’s time for a refill. I call up and this time I’m told that I’m not allowed a refill. Why not? Apparently it was “made clear to me” that the previous script was a “one-time thing” (which it wasn’t [made clear to me]). I was supposed to get an appointment before those scripts ran out! Wait, I did make an appointment. It was 52 days away. How am I supposed to get one 30 day script when my appointment was more than 30 days away? Well, according to “the system” my appointment was “just created” (likely because someone modified it or something and it changed the date it was edited) and that means I didn’t make an appointment and it’s my fault. I go in and they decide that, for yet another urine sample, I may obtain 14 days worth of my medication. Except that you can’t fill 14 days of fentanyl patches because they come in boxes of 5 and 14 days would be 7 patches and they can only fill them per box, so they only give me 5. I tell the office this. When my urine comes back “clean” they give me another 30 days.

Not quite thirty days later is finally time for my appointment. I come in for my new physician, the one that’s been writing these scripts, and the first words out of his mouth consist of some FUD about my current treatment being all wrong, and it’s very wrong for someone as young as me to be on “two hardcore narcotics” (he specifically and repeatedly used the word “narcotic” over “opiate” or “opioid”–both of which are more appropriate for medical professionals–because “narcotic” is a scary-sounding word) and instead I should look into permanent back surgery. I argue that I have no surgical options given my condition and that I’ve already had every interventional procedure that I could have. He tells me of an orthopedic surgeon I should immediately go see for a second opinion. As it turns out I know this orthopedic surgeon. He referred me to pain management–to the very office I am currently sitting in. When I tell him this I’m still instructed to “go back” to get new radiographs and with new radiographs, a new opinion on surgery. The surgeon had before told me the only thing he could offer me were spinal fusions. I turned him down given my age, which he agreed with, and he sent me to pain management which he deemed, in his own words, “the only reasonable next step.” Two years later my only reasonable next step is backwards, it seems. The new physician continues to try to alarm me about my current treatment, telling me that my medications are “dangerous and addictive.” I tell him I’ve been on them off and on for four or five years and have yet to have any issues with abuse or addiction, and that every UA he’s ordered on me has come back pristine. He tells me that narcotics build up in the body and always eventually cause addiction and that they’ll make me sleepy and surely I must be intolerably constipated and throws in every other classic opioid side effect, trying to get me to admit that there’s a reason to discontinue the therapy. I tell him no, the only side effect I even notice is constipation and I simply have a fiber bar or two every day and don’t even notice the difference. He’s angry, realizing that I’m actually educated about my condition and the treatment and ties up the appointment by telling me I have until August to find “other options” before he discontinues my medications.

One of the best parts of this whole thing is that when I first got there a resident finishing up her fellowship came in and talked to me first. After she went through everything she agreed with my current treatment and, after asking how it was working, thought I should increase my fentanyl dose (which I’ve been wanting to do for months). When the attending came in and shot down all that with his bullshit, she looked rather put off and disappointed. I don’t know if she was disappointed because he didn’t agree with her and thus she must be wrong, or because he was being so obviously obtuse about my treatment and there was nothing she could do to help me. The best part of this was that his own Fellow disagreed with him and thought my current treatment should stand. I liked her. She was a very nice lady. I’m sad I’ll never see her again.

Currently I’m waiting for some results from various tests I had with my rheumatologist. He’s a very smart physician. While he doesn’t know exactly what’s wrong with me (he suspects an extremely mild non-specific “type” of Ehlers-Danlos Syndrome, but it’s a wild shot) he told me he was positive it wasn’t progressive osteoarthritis, which is what my pain clinic has been telling me for two years. They also tell me it “just happens,” even to males in their early 20s. I’m also expected to see the orthopedic surgeon that originally referred me to the pain clinic in the first place. I’m not totally sure I’m going to do this, because I don’t see the point. I’m not going to have surgery, and the last time I saw him my options were “surgery or pain management.” Guess which one I chose.

Monday I’m going to talk to my primary care physician about what she could do for me if I lose my medications. The Monday after that I’m going to get the results of all my rheumatology tests, and maybe have an answer and even treatment. If all of this fails, come August I’ll have no answers and no pain management. I will have to quit my job, move home to St. Louis, and try desperately not to curl up into a miserable ball of existence, wondering why I should continue to bother to live.