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?

When OxyContin® was released, abusers quickly found that crushing the tablet easily defeated the time-release mechanism, causing all of the oxycodone–meant for slow release over 8-12 hours–to be released into the body at once. This caused a surge in abuse of the drug in the late ’90s and well into later decades as well. Zogenix has announced that the release mechanism for its new hydrocodone formulation is the same currently used by Avinza®, a brand-name of controlled-release morphine. Other drugs using the same release mechanism include Ritalin® LA, Focalin® XR and Luvox® CR. The release mechanism is called Spheroidal Oral Drug Absorption System, or SODAS® and is licensed from Elan Drug Technologies. The SODAS® capsules contain tiny extended-release beads that release too much medication if crushed, chewed, snorted, dissolved, or injected, which will likely lead to a sharp increase in abuse of the drug much in the same manner as OxyContin®. However, for those in pain taking their medication as prescribed, it will be a welcomed addition to the pain pharmacopeia.

Under the US Controlled Substances Act, products containing “no more than 15mg of hydrocodone compounded with an NSAID or APAP” are allowed to be treated as Schedule III drugs, but hydrocodone on its own or in amounts more than 15mg are Schedule II, along with morphine, oxycodone, fentanyl, and most other opioids. Due to an additional law, there are currently no hydrocodone-only drugs on the US market today. This drug would change that.

While only in Phase III trials, the drug remains 3-5 years away.

• Zogenix Press Release
• Elan Drug Technologies Press Release

Some time ago, it was noticed that NMDA receptor antagonists (dissociative anesthetics) like ketamine, phencyclidine, and dextromethorphan have the side-effect of reducing the amount of tolerance formed to opioid analgesics. This has far-reaching implications because if you can mediate opioid tolerance, you can control the amount of opioid needed for pain relief.

The NMDA receptor both induces and maintains persistent enhancements of the excitability of neurons to prolonged stimulation, or “wind-up.” Wind-up is a key spinal mechanism requiring activation of the NMDA receptor that both amplifies and prolongs certain types of pain. As a result, wind-up may be one of the events underlying prolonged or chronic pain. Evidence from animal studies indicates that this mechanism is involved in the induction and maintenance of certain types of pain, most notably inflammatory and neuropathic.

Neuropathic pains are at least partly mediated by the NMDA receptor, which may relate to changes in opioid sensitivity. All opioids reduce, or with high doses block the input that causes certain types of pain, probably via activation of the presynaptic opioid receptors to prevent the release of primary afferent transmitters and so prevent pain input from actually activating the neurons that make you feel pain. However, if the pain continues, wind-up overcomes the inhibitions of input and the neurons commence firing, causing pain. As wind-up increases the activity of neurons, a higher dose of opioid will be required to block the increased excitability. Thus, at moderate doses, opioids delay wind-up without inhibiting the process itself. In contrast, NMDA antagonists abolish wind-up. Thus, threshold doses of morphine combined with low doses of NMDA antagonists are able to elicit dramatic inhibitory effects, a synergism that suggests low probability of side effects. Importantly, in a model of neuropathic pain where morphine is inoperative, the co-application of an NMDA antagonist restored the ability of morphine to inhibit the response.

All that medical speak translates to this: the pain input that’s prolonged and intensified by NMDA receptors can be delayed by opioids, but not inhibited. However, NMDA antagonists (mentioned above) completely turn off the prolongation and intensification, allowing opioids to take away that pain. Basically stated, it amounts to the aforementioned. Adding a mild NMDA receptor antagonist (in extremely sub-anesthetic doses) to an opioid enhances the effects of the opioid, allowing smaller amounts of opioid, and thus fewer side-effects.

At least there’s one good use for dextromethorphan.

The spinal action of opioids is an excellent example of how basic research in animals can lead to improvements in the clinical relief of pain. The knowledge gained from basic animal studies showing an opioid inhibition of nociceptive spinal neurons and the direct analgesia following epidural and intrathecal opioids was soon applied to humans. Importantly, the use of various different models of clinical pain states has led to animal studies addressing the extent and mechanisms of plasticity in opioid spinal function, since pathological and physiological and pharmacological events can alter the degree of opioid antinociception. It is noteworthy that opioid receptors originally cloned from rats and mice allowed much in vivo research, and ultimately it was discovered that the animal opioid receptors are identical biochemically, and pharmacologically, to human opioid receptors.

These animals were used to develop pain and suffering relief in humans. If a couple of massively overpopulated rodent had to die for me to be pain free, I have to tell you that I’m not that upset by it.