What exactly are we talking about?
By now everyone in America is familiar with the term. Most people though (you'd be surprised to know how many healthcare professionals among them) don't know anything beyond a few drug names, the idea that they're supposed to dull pain, the growing realization that they're very dangerous and the fact that we're experiencing a national crisis related to them.
There are many ways of looking at or thinking about opioids. I’m not going to go into detail here about the basic science (biochemistry and pharmacology) of the drugs – there are plenty of good references out there if you want to put the time and effort into becoming an expert. I’ll admit to a little bias, but I think a pretty good one is Opioid Dependence: A Clinical and Epidemiologic Approach. I wrote the book targeting a general practice physician audience, but it’s not so technical that anyone with a serious interest can’t digest it – in fact it’s being used right now at our local University as a college-level text.
That textbook looks at both basic science and clinical issues from a three-part arrangement of perspectives based on classic epidemiology (historically the study of epidemics) principles. The first part focuses on the opioids themselves, the second part on prescribers, and the third part on individuals who have become dependent on the drugs.
We’ll visit those topics in more detail in the next post, Opioid Basics Part Two: Rise and Resolution of the Epidemic. For now we’ll stay mostly away from the public health side of things and stick to an individual-level focus. And within that 'sandbox' we'll look at opioids from two distinct perspectives: the analgesic (pain-dulling) and the addictive. There are again, a myriad of different perspectives including:
basic biochemistry and molecular biology
biology-pharmacology interface including the complex interactions between the endogenous (natural) opioid system, the immune system, the endocrine system and more
law enforcement / criminal justice
but we'll limit ourselves to what concerns most people: pain and addiction.
We're not going to talk at all in this post (nor any planned posts) on when and how they should be prescribed or used. Hopefully we'll get arount to posting a video here on the site you can watch about that; it's a lot more complex topic than can be covered in a simple post. Suffice it to say here that in America 2018 it's more important to understand when they should NOT.
Opioid Analgesia : How they dull pain
The first thing we ought to talk about is the fact that built in to almost every animal life-form on this planet is a natural ('endogenous') opioid system. Most people are familiar with the term endorphin - the mediators of the so-called 'runner's high.' (Being a former long-distance trail and mountain runner I'm convinced that's a hoax!) Endorphins (and their cousins endomorpins, enkephalins and dynorphins) are formed naturally in the body and activate opioid receptors (think of them as baseball gloves, with the opioid being the baseball) located mostly in the brain and spinal cord.
This natural opioid system is a remarkable, finely tuned and balanced mega-system that interacts with the immune /inflammatory systems, the endocrine (hormonal) systems, and much more within our body. It's involved in mood stability, stress coping, and far more than 'just' pain relief. Each of the individual ligands (the natural molecules, or the balls in the analogy above) and the receptors plays a different role, and that role varies depending on which part of the nervous system it's acting upon, how long it's been active, and a whole lot of other variables including disease states, genetics, and so forth. It's complicated, and after almost a half-century of intensive research we're just beginning to scratch the surface.
Let's focus on the basics though from the standpoint of analgesia (the dulling of pain) though. Opioids (whether endogenous, or exogenous - meaning derived from a plant or a laboratory) act in several different places in the brain and spinal cord, but the most important site (according to our current understanding) where they have the biggest influence from a pain standpoint is in the spinal cord, in an area called the dorsal horn. It's in the dorsal horn where the first pain sensing nerve (the primary afferent) from the skin or bone or organ transmits information to the second nerve (secondary afferent) that then travels up the spinal cord. (All of this is discussed and diagrammed a bit more in "What's the Point [of Pain?])
Opioids act directly on both of those nerves, the primary and secondary afferents, interfering with both their ability to conduct a message on their own (by hyperpolarizing the nerve membrane) and by decreasing their ability to communicate with each other (by reducing neurotransmitter release.) In addition, opioid action at the level of the brain (in the midbrain's periaqueductal gray region, and the rostroventral medulla) sends a message down the spinal cord that further blunts the pain message trying to climb upward. (You might be surprised to learn that this action, which we call descending modulation, actually uses the same neurotransmitter currency that antidepressants do - serotonin and norepinephrine - which explains why certain antidepressants work so well in treating pain also.)
That's not all opioids do to blunt pain though; they also act peripherally to a minor degree - at the level of the skin, muscles, bones, organs. And they work of course in many complicated ways within the brain to alter consciousness, stress and anxiety. Anyone who's worked in healthcare long enough has heard people say it a hundred times - "I still hurt, I just didn't care any more."
Opioid-Induced Hyperalgesia : How they worsen pain
Among the many negative or adverse effects opioids produce (sedation, depression, breathing compromise, nausea, constipation, gallbladder and pancreas problems, immune system problems, bone density loss, etc.) one of the most fascinating, and certainly counter-intuitive problems that chronic opioid use causes is opioid-induced hyperalgesia (OIH.) Whereas analgesia is the lessening of pain, hyperalgesia is exactly the opposite: an increase in pain.
OIH isn't the same thing as tolerance, which just means that the effect of a substance decreases with repeated use. Tolerance usually leads to people wanting and using more of their drug of choice. OIH is a state where people actually hurt worse, with increased sensitivity to pain.
OIH may develop over months, weeks, or even days depending on a number of factors. As far as mechanisms, many different complex and interrelated systems seem to be involved. The AMPA/NMDA system, an important part of the how the brain and spinal cord learns, is involved. The dynorphin/kappa opioid receptor (KOR) system, part of the natural check-and-balance arrangement of the endogenous opioid system plays a role. Research is quickly revealing though that the glial cells of the brain, which make up somewhere between 50-90% of the brain, and in particular the microglia cells may be the most direct and important mediators of the process. Dr. Linda Watkins' lab at the University of Colorado is one of the world's foremost glial research centers and has been instrumental in showing that opioids act directly on microglia (via TLR4 activation) to cause neuroinflammation and hypersensitivity of the nervous system. Think of it essentially as an angry brain and spinal cord.
As a sidenote, many of us in the pain management field have found that people who use oxycodone with any regularity seem to suffer the worst degree of OIH (more on that issue in an upcoming post discussing some of our research currently in the publication stage.)
Opioid Addiction : The Pursuit of Pleasure (at First...)
Switching gears, let's look briefly at how opioids cause addiction - or rather, what we know of the biological mechanisms underlying that process. Just like any chronic condition, addiction is a biopsychosocial problem and despite quite a bit of recent enthusiasm for the 'brain disease' model of addiction, solid evidence from unbiased science (check out Marc Lewis' excellent book The Biology of Desire for a quick, easy and fascinating read on the topic) refutes this overly simplistic concept. So do most experts from the fields of ethics and philosophy. Nonetheless, biology certainly does play a role, and comprises part of the problem.
From a biological perspective, the euphoria (pleasant and rewarding feelings) that opioids confer are a consequence of the drug binding a particular type of opioid receptor - the mu opioid receptor (MOR) which also happens to be the main receptor involved in analgesia. While MOR exist throughout the brain and spinal cord, it's the ones in a part of the brain called the mesolimbic system (including the ventral tegmental area and the nucleus accumbens) that seem to be responsible for the hedonic reward - the euphoria that first hooks people. The exact mechanism behind the euphoria remains unclear at present. Much has been made of dopamine in this process - one of the body's most common neurotransmitters. Like most things in science, what we thought we knew was incomplete and much of it inaccurate; currently dopamine's role is thought to comprise conditioning to an expectation of pleasure. It seems to be the mesolimbic system's signal to other parts of the brain when a cue for something we really want crosses our radar.
Addiction is in essence a habit of pursuing something that we find more rewarding than anything else, and for which we're willing to sacrifice just about anything. At least that's how it starts.
Opioid Addiction : The Scourge of Dependence/Withdrawal
It doesn't generally take too long however before tolerance sets in and people in the throes of addiction begin to require more and more of their drug of choice to enjoy the same hedonic reward they did at first. And before too much longer, they are requiring more and more just to maintain their sense of wellbeing and avoid the harsh symptoms of withdrawal. Unlike substances such as alcohol or sedative-tranquilizers like the benzodiazepines, opioid withdrawal isn't life-threatening, but for those who have experienced it (and I've treated many) they often say they wish someone would put them out of their misery.
Different chemical processes are involved in withdrawal, just like with OIH. The cortisol stress system and the catecholamine (adrenaline-like) system operate in conjunction with the dynorphin-KOR system (as in OIH).
Chills, anxiety and agitation, severe depression, widespread pain, nausea and vomiting, diarrhea, and an overall sense of torment are the classic description I hear. And once addiction has set in, it becomes an all-consuming pursuit of the drug at any cost to keep out of this horrible state. It's not about pleasure or reward any more - that's long gone, and people now generally hate the drug and what it's done to them. But they can't do without it - the cost and the pain just seems too high.
In the case of opioids, since higher and higher doses are required to keep from becoming 'dope-sick,' the risk of overdose and death is constantly increasing. And the grim fatality statistics (115 people die every day in this country from opioid overdose at the time of this posting) are just the tip of the iceberg. Literally tens of millions more lives, and not just the addicts' are ruined by opioid dependence, with the condition spreading ever more rapidly year by year. This is far more than a biological problem.
-Heath McAnally, MD, MSPH
1 Sep 2018
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