New Hope for Novel Analgesics
- September 3rd, 2010
- By Eric Will
- Write comment
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:
- AM404 inhibits FAAH–which metabolizes anandamide–resulting in an increase of anadamide.
- 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.
- AM404 also activates the TRPV1 receptor.
- 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?