Opioid use disorder

Worldwide, opioids are the most common cause of drug-related deaths.
The number of individuals using opioids has drastically increased over time, with an uptick in heroin use, and an even bigger uptick in prescription opioid use, and a large number of people using both. Because of the potential for opioid use disorder and overdose, opioids are regulated substances in many countries.

As a class, opioids share one thing in common—they bind to opioid receptors in the brain, spinal cord, and gastrointestinal tract. Some are endogenous, meaning that they are produced naturally by the body, like endorphins, which are named for “endogenous morphine” due to their similar effects on the body. But others are exogenous, meaning that they come from outside the body, like heroin and morphine, which come from the opium poppy—a flowering plant that oozes a milky white liquid—while others like fentanyl are synthesized in the laboratory.

To understand how opioids work, let’s zoom in on a region of the spinal cord that has opioid receptors. Normally, in the absence of endorphins, nociceptive fibers carry pain signals from the body to the dorsal, or posterior, horn of the spinal cord.

Here they release neurotransmitters,

like glutamate, substance P and calcitonin gene-related peptide. These neurotransmitters cause pain signals to be transmitted to the brain via ascending pain pathways.

Now, let’s say someone goes to play a rigorous game of badminton. Exercise releases endorphins which activate the three major opioid receptors located on neurons, called the mu, kappa, and delta receptors.

As endorphins or other opioids bind to these receptors on the presynaptic terminals of nociceptive fibers, they inhibit the opening of calcium channels, preventing calcium influx, and thereby blocking the release of pain-causing neurotransmitters like glutamate, substance P and calcitonin gene-related peptide. At the same time, endorphins also bind to postsynaptic neurons, opening potassium channels here, leading to hyperpolarization and decreased excitability of the neuron. These effects together reduce the transmission of pain signals to the brain.

If we move up to the brain’s reward pathway, made up of midbrain regions like the ventral tegmental area, nucleus accumbens, and prefrontal cortex, we find another important effect of opioids.

Here, inhibitory neurons normally release gamma-aminobutyric acid, or GABA, at the presynaptic terminal, which in turn inhibits postsynaptic dopaminergic neurons, leading to decreased dopamine release.

But, when there are endorphins or opioids in the area, they bind to the opioid receptors on these inhibitory GABAergic neurons, causing a decrease in GABA release. With less GABA around, there is less inhibition of dopaminergic neurons, leading to a flood of dopamine in the brain’s reward center. This increased dopamine leads to a calming sensation and feelings of pleasure or euphoria, also known as an emotional “high”.

Now remember, the purpose of the reward pathway is to train the brain to repeat activities that cause dopamine-mediated pleasure, so when opioids stimulate this reward pathway, the brain learns to do that behavior again and again.

With exogenous opioids, there are multiple routes to get the drug to the brain.

One way is by ingesting it; that route is the slowest. A faster route would be inhalation because the drug is rapidly absorbed through the lungs; this route is not routinely used medically and is more commonly encountered with substance misuse.

The fastest route is direct injection of the substance into the blood. Typically, the faster the exogenous opioid reaches the brain, the stronger the relationship between the behavior and the reward.

Over time, people can develop tolerance to a drug. Tolerance means that with repeated use, their response to the drug decreases. As a result, even when taking the medication exactly as prescribed, a higher dose may be needed to achieve the same effect as before.

At a cellular level, there are two main reasons for why this happens.

One reason is that opioid receptors become less sensitive to stimulation by a drug, and the other reason is that the neurons may remove opioid receptors from the cell membrane in a process called down-regulation, leaving fewer receptors available for binding. In either scenario, tolerance leads to the need for higher and higher doses of a drug, and often that tolerance remains for a long time even after tapering off the drug.

Alright, so now let’s say that you’re at rest, there aren’t any drugs or anything else stimulating your reward pathway. In this situation, your brain keeps your heart rate, blood pressure, and wakefulness in a normal state, called homeostasis.

Now, let’s say you finally get a text with exam results that you’ve been waiting weeks for. All of a sudden you may feel sweaty and flushed, your heart rate may jump a bit. You’re now above your normal level of homeostasis, because something has changed, right? But it doesn’t stay that way for long, and after the text message, your brain brings things back down to this baseline.

With repeated drug use, a few things start to happen.
Let’s say you take a drug at a specific time and setting, like 3:00 P.M. in the bedroom, every day.

If it’s a depressant, it makes everything go lower: heart rate, blood pressure, and wakefulness.

Your brain, being the smart brain that it is, will pick up on this pattern.

So, the next time it’s 3:00 P.M. in the bedroom, your brain preemptively increases heart rate, blood pressure and wakefulness, since it knows that when you take the drug, everything’s going to decrease again.

Now, let’s say 3:00 P.M. in the bedroom rolls around, but there’s no drug…

In that situation, the brain still increases everything, but the changes aren’t countered with the effects of the drug, and so the person can feel awful;

these are called withdrawal symptoms. These symptoms can persist to the point where a person may need drugs just to feel normal, and if that’s the case, they are considered to be dependent on that drug.

Now, on the flipside, let’s say that you use the drug in an unfamiliar setting, like at 11:00 P.M. at a party. Well in that situation, your body’s not ready for the drug and there’s no physiologic “counterbalance” to help offset the effect of the drug.

When that happens, it can lead to overdose, even on a “normal” dose that the person’s taking, and that’s oftentimes what happens.

The symptoms of opioid withdrawal include dysphoric mood, myalgias, sweating and shivering, yawning, nausea, vomiting, and diarrhea, rhinorrhea, pupillary dilation, and insomnia.

These symptoms can feel really awful, and often prompt people to use opioids again. This is called negative reinforcement, since you’re removing the drug, which causes withdrawal symptoms which reinforces more drug use to avoid those symptoms.