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 us 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?

I’ve written previously on the many side effects of having chronic pain. You have physical and psychological side effects from the medications themselves, and physical and psychological side effects just from the pain itself. The former link is about the physical medication side effects, and the latter is about the psychological pain side effects. This piece is going to concentrate on yet more physical medication side effects, but just for a moment I’d like to expand on the psychological effects from just being in pain.

According to various medical texts, the brain is not designed to be in pain for a long period of time. In fact, the nervous system in general is not designed to send “pain signals” for very long at all. As such, when chronic pain happens often times the neurons that send these signals “learn” to get better at sending them, in the way that your brain learns for memories. A common myth is that people exposed to pain frequently have a higher “pain tolerance,” when in fact the opposite is true. The more often you’re exposed to pain, the more adept your nervous system becomes at sending pain signals. If the same neurons send the same signals for long enough, something called neuronal plasticity happens: in laymen’s terms, those neurons physically change themselves to permanently transmit pain. There is no definitive way to tell when something like this has happened to someone, but it’s a good bet that when all interventional procedures such as disconnecting the nerves themselves (rhizotomy) still fail to provide pain relief, you have this situation. This is bad. There is no way to reverse this process. Your body is now in constant pain. In medical terminology:

Under persistent activation nociceptive transmission to the dorsal horn may induce a wind up phenomenon. This induces pathological changes that lower the threshold for pain signals to be transmitted. In addition it may generate nonnociceptive nerve fibers to respond to pain signals. Nonnociceptive nerve fibers may also be able to generate and transmit pain signals. In chronic pain this process is difficult to reverse or eradicate once established.

Being in constant pain is not only–you know, painful–but it also wreaks havoc on your body. People with high-intensity chronic pain have significantly reduced ability to perform attention-demanding tasks. Pain appears to strongly capture the attention of people with chronic pain; tests assessing the ability to attend show poorer performance than pain-free people on all tests demanding attention. The exception is found with tasks that are highly demanding of attention, where performance between the two groups is equivalent. In experimental testing, two-thirds of individuals with chronic pain demonstrate clinically significant impairment of attention independent of age, education, medication and sleep disruption. Individuals with the highest levels of pain showed greatest disruption of memory traces, suggesting that pain diminishes working memory.

Now that I’ve gotten some of that out of the way, I have another story about physical medication side effects. Last week I was at work. I work some two hours from my home. Right before leaving, I went to use the bathroom but found it difficult to urinate. I didn’t really give this much thought because I’ve had a “shy bladder” for close to a decade. It’s always been stressful and difficult for me to give urine samples for job applications or other reasons. I left work and when I got home a few hours later, I was still unable to urinate. This worried me. Since I usually get home late I tried a few more times and went to bed. When I got up in the morning and got to work I found myself still unable to urinate. At this point I was still leaning toward a shy bladder and figured that if I drank enough I could sort of force it out. This is the technique I use to give urine samples. A few hours later I was very much surprised to find that this didn’t work.

After consuming a large amount of fluids I felt as if my bladder were going to burst and I was in quite a large amount of pain and discomfort. I immediately ran to the bathroom where I was still totally unable to urinate. I realized at this point I had an emergency condition on my hands and tried to convince my carpool to start heading home immediately. By the time they had gathered their things I realized there was no way I was going to make it two hours back home, and decided to run to the hospital across the street from work.

Upon walking into the ER I told the triage nurse I hadn’t urinated for 22 hours and I was in severe discomfort. After a quick sign in with a list of medications and allergies I was rushed off to a room where she quickly (and not as horrifyingly painfully as last time) inserted a Foley catheter where she promptly drained close to 950mL of urine (a normal liquor bottle is 750mL). I felt much better. After a discussion with the physician about the possible causes he was leaning toward my pain medication, as opioids are a frequent cause (but individually rare (less than 10%) side effect) of urinary retention. After a urine analysis (I didn’t have trouble giving a sample this time–it came out of a tube), blood work, and a couple of non-contrast abdominal and pelvic CT scans all came back normal I was told the most likely culprit was the “vast amount of narcotic medications” and advised it would be best the catheter stayed in a few days. I was not entirely happy with that verdict. As I limped out of the ER (and when you’re a male with a tube up your penis, you limp) I was picked up by my carpool and taken home. After a few days of being told my PCP wouldn’t take out a catheter in the office and to go to the ER I realized I could either spend five hours at the bottom of the ER triage or I could take it out myself. I cut the injection port and let the balloon deflate and gently removed it without issue. Within a few hours (and since) I have been urinating just fine.

This story is obviously personal and represents a few things. The physician determined my situation was a side effect of my pain medication and so informed me in such a way as to say “maybe you shouldn’t be taking those medications.” Well, doc, I’d love to not take these medications but without them I can’t function due to Intractable Pain. Maybe if I was on Disability or some other form of I-don’t-work income I could try it and see what happens, but I have a job and a family to support with that job. So firstly it represents bias against people on pain medications, once again. This is a psychological (or maybe even social) side effect of pain medications. Friends and family may shy away from you because you’re on “narcotics” or worse, assume you’re an addict because you’re dependent. I’ve written extensively on how these differ, but the laypeople just fail to understand. There have even been episodes of Intervention-style shows on television wherein a chronic pain patient was accused by a weeping family of abusing their medications and being an addict. A lot of times on these shows it’s true: they’re quite obviously addicts; however, more than once I’ve seen a pain patient taking their medications as prescribed and enduring their side effects only to have this taken as “addiction.” What’s worse is that I’ve seen these legitimate patients forced into rehab more than once because of a bias against medication.

We are sick people. We are sick people with a serious disease. We have pain that’s caused by a disease or is a disease in and of itself. We take medication for that disease, and we withstand the side effects of both that medication and that disease. My only problem is that some of those side effects are man-made, and in a reasonable and educated world should be put to rest. Educate yourselves.

A long-experienced phenomenon, tolerance is the need to increase the dosage of medication to achieve the same effect. This is most frequently seen in illicit drug abuse. Heroin users quickly have a need to take increasing doses in order to achieve the same “high.” The same goes for other illicit drugs like amphetamines and cocaine. With most drugs tolerance is a complicated process and is not fully understood. In most cases we assume the neurotransmitters (or their receptors) affected by the specific drug type is down-regulated in some way. That is to say, if you take a lot of opioid analgesics your body reduces the amount of naturally-produced (endogenous) opioids, and also decreases the amount of opioid receptors in the body.

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.

This post is mostly to clarify, to journalists, what the difference between drug tolerance, drug dependence, and drug addiction is. Why does some loser like me on a tiny corner of the internet need to clarify this? Apparently, no journalists can be bothered to do any actual research.

I have read time and time again in several prominent publications that all pain medications lead to addiction. No ifs ands or buts, always. Therefore, they are dangerous and evil, we should hate them, and doctors shouldn’t prescribe them.

But who really cares? If these medicines are so widely regarded as dangerous, no one must need or use them, right? This stuff is only used by hard core junkies on the street to get high. These are the narcotics they’re always going after on COPS.

These are all excellent points. It’s too bad none of them are true.

First of all, no one uses the term “narcotic” correctly. In fact, it is so widely misused that the medical profession has completely given up. Now, “narcotic” is referred to as a legal term, and medical professionals use terms like opioids. So, what is a narcotic, really? A narcotic refers to opium, opium derivatives, and their semi-synthetic or fully synthetic substitutes. This means cocaine, meth, LSD, steroids, DXM, and yes, even marijuana are ruled out. None of these are narcotics, no matter how much the police insist upon calling them that. Why does law enforcement do this? I don’t know. Probably because “narcotic” is a scary sounding word. Opium is a milky substance produced by certain species of poppy flowers, and it contains a great many chemicals, called opiates. An opioid is any substance that binds to opioid receptors in the central nervous system (or “any substance which behaves pharmacologically like morphine”). The terms opioids and narcotics are, in essence, synonymous.

So, what are opioid receptors?

The brain works by sending messages between cells to tell those cells what to do. These messages are sent by chemicals known as neurotransmitters. Examples of neurotransmitters include melatonin, dopamine, serotonin, epinephrine (adrenaline), endorphins, and so on. Neurotransmitters that are produced directly by our bodies are referred to as endogenous ligands. These transmitters are made to fit into certain spots on the outsides of cells, like a key into a lock. These spots are called receptors. The ligand for 5HT receptors is serotonin. The ligands for (parts of) NMDA receptors include glutamate and aspartate (specifically, N-methyl D-aspartate). It is thought that all receptors have corresponding ligands, but there are several receptors we know of that we have yet to discover natural ligands for (such as the sigma receptors). A ligand for the various opioid receptors is endorphin.

(Update: A few people emailed me to let me know the ligand for sigma receptors is angeldustin. This isn’t entirely correct. The theorized ligand used to be called angeldustin, but is currently referred to as endopsychosin (never say neuroscientists don’t have a sense of humor). The reason it was called this is because PCP appears to exhibit effects on the sigma receptors, and PCP tends to make you a bit of a nut. The argument goes along the lines of “why would the brain have a natural ability to mimic the effects of PCP on the brain, and in effect make itself nutso.” Some theories of schizophrenia point at the sigma receptors. The antipsychotic drug haloperidol appears to have effects on sigma receptors. We really have absolutely no idea what they do.)

Drugs that act on the brain do so by manipulating neurotransmitters or receptors in one way or another. Some drugs prevent neurotransmitters from being produced, some prevent them from being reabsorbed, and others mimic the transmitters themselves.

In general, there are three ways that a transmitter works on a receptor. In one way, the transmitter binds to the receptor and activates it, causing changes within the cell. These transmitters are called agonists. In the second way, a transmitter binds to the receptor but doesn’t activate it, and these transmitters are called antagonists. In the third way, a transmitter binds to the receptor and partially activates it, and these are appropriately named partial agonists. One interesting property of partial agonists is that they tend to “normalize” receptor activity levels. In the presence of a low amount of neurotransmitter, the partial agonist will increase receptor function. In the presence of a high amount of neurotransmitter, however, the partial agonist will limit receptor activity. This is a type of negative feedback. The best example I can think of negative feedback is a thermostat: when it’s hot, it turns the heat off; when it’s cold, it turns the heat on.

When you take a narcotic painkiller, the drug binds to and activates various opioid receptors in the brain, spinal cord, and gastrointestinal tract. Drugs like this are opioid agonists. The opioid receptors influence many things, most notably pain and mood. Wait, the gastrointestinal tract? Yes, actually, one of their most noted side-effects is constipation, which can be severe. Opioids reduce gut motility, which means it slows down your bowels, which gives your body more time to absorb water from the bowels, which solidifies the stool. If you’ve ever taken Immodium for diarrhea, you’ve taken a very potent opioid (although, one which does not cross the blood-brain barrier and thus it is only active in the gastrointestinal tract, so it does not cause analgesia or euphoria). The effects and side-effects are enourmous and complicated, and if you’re interested in how exactly these things happen, see the Wikipedia article on opioid receptors. We’ll sum it up by saying that opioids invoke pain relief, or analgesia, feeling nice, or euphoria, and, over time, the need to increase the dosage to achieve the same effects, or drug tolerance.

The one we’re mostly concerned about is tolerance. Tolerance occurs because your brain is an amazing thing. When there are larger than normal amounts of opioids in your system for an extended period of time, the brain compensates by down-regulating the receptors. That is, it starts creating less of these receptors, so that the opioids have a lesser effect at the same dose. In order to achieve the original effects (be it analgesia or, in the case of an abuser, euphoria), the dosage must be increased so that more receptors are reached. Other than needing increasing dosages, this is not necessarily a bad thing. This is simply how the brain compensates. This is simply reality. Anyone who takes opioids for an extended period of time will experience tolerance.

So, what does this all entail? Tolerance usually implies dependence. Is this a bad thing? Maybe. Drug dependence means that your brain has become tolerant to this drug to one degree or another, and if you suddenly stop taking it, your brain chemistry is suddenly messed up. This manifests as withdrawal symptoms, which can be severe.

So wait, the journalists are right? Anyone that takes opioids for a while will go into withdrawal? Well, yes, but that doesn’t mean that you’re addicted to the drugs. This just means that, as your brain readjusts itself to the way it was before the drugs were introduced, you won’t be having a great time. This can be avoided by slowly and carefully stepping down your dosage over a period of time. By doing this, the brain adjusts slowly to each new dosage, and withdrawal is minimal or nonexistent. This means that people can take opioids for a week, a month, or even years and, so long as their dose is slowly reduced, they’ll return to their pre-opioid state just fine, and (assuming the reason for taking the drugs in the first place is gone) will be perfectly normal.

Okay, then, what is addiction? Well, many people hold somewhat personal views about this, but I’ll discuss how medical professionals view it. Addiction is defined as a psychological dependence on something. The key difference is that one is “all in their heads,” and one is physical. Whether it’s drugs, sex, food, gambling, whatever. In the case of drug addiction, someone thinks they need a particular drug in order to be normal. You can see the confusion. People who are drug dependent actually do need the drug to be normal. Drug addicts only think they do. They crave the drug. They’ll do anything to get more of it, including selling everything they own, including their bodies. Addicts will continue to do the activity despite harmful consequences to the individual’s health, mental state or social life. Addicts are usually dependent on their drug of choice, and usually experience withdrawal fairly often because of their inability to obtain their drug. This has absolutely nothing to do with addiction. There are several drugs which people may become addicted to, like marijuana, but which do not invoke drug dependence.

(Update: It is worth noting that there is a behavior that is noted as pseudo-addiction, and is defined as exhibiting addiction-like behaviors toward a drug. That is, a patient is obsessed with getting more of a drug, but not because they’re addicted. This is seen often in pain patients whose pain is not being adequately treated. Trust me, if you were in severe pain your entire life, you’d probably be pretty obsessed with obtaining pain relief. This can appear to be addiction, and, very unfortunately, many pain patients which exhibit this behavior will be marked as drug seeking and are doomed to suffer.)

So what makes people become addicted to something? No one really knows. As it is a psychological disorder, it’s hard to pin it down. Anyone can become addicted to anything at any point. The unfortunate thing is that most drugs that people are interested in developing an addiction to tend to be either controlled or illegal. This means they have to turn to the black market, and become criminals in the process. So how many people become addicts? Clinically, for people who are taking prescribed medication as it was prescribed, less than 1% of all patients become addicted. This means that, out of 1,000 pain patients, around 0-10 of those patients will experience addiction. Some people think this is unacceptable, and that it’s better to let those 990-1000 patients simply suffer.

For those of you who aren’t in pain, good for you, that’s a reasonable position to take. Pain is transient, you can tough it out, right? Except when it isn’t transient. Millions of people, including me, are in chronic pain. That means we’re in pain every minute of every day. There are many treatments for many conditions that cause this, but for millions of people the only answer to their pain is to be on opioids long-term. People have a stigma about this because they only time they hear about opioids is when someone ODs on heroin. Because of the <1% of patients, the other >90% have to suffer more. Doctors are terrified to prescribe opioids because of their psychological effects, so they’d rather not treat anyone at all. I think this is stupid, and I don’t understand how, as someone who has promised to “limit suffering,” they can do this. Sure, opioids make you feel good, and in our society that is a Bad Thing™, but for the rest of us who need them to live, please, I implore you, pull your heads out of your asses.