Worldwide, the abuse of opioids and resulting Opiod Use Disorder, are the most common cause of drug related deaths. The number of individuals abusing these drugs has quadrupled in the last 20 years, with an uptick in heroin use, an even bigger uptick in prescription opioid use, and a large group of folks abusing both. Because of their potential for addiction and overdose, opioids are regulated substances in a lot of countries. As a class, opioids share one thing in common — they bind to opioid receptors in the brain, spinal cord, and gastrointestinal tract.
Some opiods are known as endogenous, meaning that they are produced naturally by the body, like endorphin, short for endogenous morphine. But others are exogenous, meaning that they come from the environment, like heroin and morphine because they come from the opium poppy — a flowering plant that oozes out a milky white liquid, while others like fentanyl are synthesized in the laboratory. To understand how opioids work, its necessary to focus on a region of the brain tissue that has opioid receptors. Normally, in the absence of endorphins, inhibitory neurons secrete a neurotransmitter that prevents nearby neurons from releasing the neurotransmitter dopamine.
Say a person goes to play a rigorous game of tennis. Exercise releases endorphins which activate the three major opioid receptors located on the inhibitory neurons, called the mu, kappa, and delta receptors. As endorphins binds to these receptors, they block the inhibitory neurons from releasing neurotransmitters, allowing the dopamine secreting neurons to freely unload dopamine. The dopamine then gets picked up by a third neuron in the same area. When dopamine release takes place in pain processing regions of the brain like the thalamus, brainstem, and spinal cord, the result is feeling less pain. When dopamine release takes place in reward pathway regions like the ventral tegmentalarea, nucleus accumbens and prefrontal cortex, the result is a calming effect that feels good.
That’s how things would normally work, but when a powerful exogenous opioid binds to the opioid receptors, the result is a massive flood of dopamine. This helps with pain control, but it can also cause an incredible state of euphoria within the regions of the brain involved in the reward pathway, which is 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.
In the case of exogenous opioids there are multiple routes to get the drug to the brain. One way is by ingesting it, but that route is the slowest. A faster route would be inhalation, because the drug is rapidly absorbed through the lungs. The fastest route, though, 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. Now over time, people that are consistently using a drug, even when taking them exactly as prescribed, can develop tolerance which means that with repeated use, they have a reduced response, and therefore an increased dose is needed to achieve the original response.
At a cellular level, there are two theories that explain why this might happen. One theory is that opioid receptors might become less sensitive to a drug, and the othertheory is that the neurons may remove opioid receptors from the cell wall in a process called down-regulation, leaving less receptors available for binding. In either scenario, tolerance leads to the need for higher and higher doses of a drug, and often times that tolerance remains for a long time even after tapering from the drug.
When you are at rest, there aren’t any drugs or anything 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 that you get a text message, call or something indicating that there’s some sort of ’emergency’. 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 after the next text message or phone call reveals it to be a false emergency; your brain brings things back down to this baseline.
Perhaps you were to take the drug at a specific time and setting, like 3pm in the bedroom, and, being 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 the pattern. Now, next time, at 3pm in the bedroom, the brain preemptively increases each one, since it knows that when you take the drug, everything’s going to decrease again. Now, let’s say 3pm 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, and these are called withdrawal symptoms.
Withdrawal 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 flip side, let’s say that you use the drug in an unfamiliar setting, like at 11pm at a party. Well in that situation, your body’s not ready for the drug and there’s no physiologic counter-balance to help offset the effect of the drug. When that’s the case, it can lead to overdose, even on a dose that the person’s been normally taking, and that’s often times what happens. The symptoms of opioid withdrawal include anxiety, shivering, tremors, yawning, bodyaches, vomiting, diarrhea, abdominal cramps, runny nose, sneezing, sweating, and an increased heart rate and blood pressure.
These symptoms can feel really awful, and often prompts people to use opioids again;a process called negative reinforcement, since you’re removing the drug, which causes withdrawal symptoms which reinforces more drug use to avoid those symptoms. There is also positive reinforcement from the dopamine-induced euphoria, again leading to more drug use. Together this positive and negative reinforcement leads to opioid addiction also known as Opioid Use Disorder.
Opioid Use Disorder reveals itself in at least two of the following behavior patterns within a year according to the DSM-5:
- Using more opioids or using them for longer than intended
- Being unable to cut down on the use of opioids
- Having opioid use take up a significant amount of time
- Having cravings to use opioids
- Having opioid use affect responsibilities at work, school, or home
- Using opioids even if they cause recurrent interpersonal problems
- Giving up important activities in order to use opioids
- Using opioids in physically dangerous situations
- Using opioids while worsening a physical or psychological problem
- Becoming tolerant to the opioids
- Feeling withdrawal symptoms from opioids
Having 2 or 3 of these symptoms is considered mild, having 4 or 5 is considered moderate, and having 6 or more is considered severe. In addition to ruining a person’s life, opioid addiction can also end it in an overdose.
Most often, an opioid overdose causes severe cardiac and respiratory depression, to the point where a person may have pinpoint pupils and simply stop breathing. In that situation, the most important thing is to perform rescue breathing, giving supplemental oxygen, and administering naloxone. Naloxone is an opioid antagonist that powerfully binds to opioid receptors, and rather than having a direct effect, it blocks other opioids from binding and activating the receptor. This works because at any given moment, opioids are binding and unbinding to receptors which means once an opioid releases its hold on a receptor, the naloxone can simply sneak in and bind more strongly.
When naloxone given intravenously it can reverse the effects of opioids within minutes, potentially saving a person’s life. Generally speaking, high doses of strong opioids carry the greatest risk of addiction and death, and when paired with other substances that can cause respiratory depression, like benzodiazepines, they’re more likely to cause overdose. This is because they can act synergistically to cause respiratory depression.
For people with opioid dependence, the most effective treatment is a combination of therapy with medications. Specific therapies that work include motivational interviewing, which can be used to understand why an individual wants to stop using opioids and identify specific barriers to treatment. Also cognitive-behavioral therapy can help an individual learn about withdrawal, discuss the thoughts, feelings, and behaviors that lead to opioid usage, and create a plan to navigate triggers for usage. Another form of therapy are peer-support programs which use group discussions to help individuals commit to ending the use of opioids and by holding one another accountable.
In addition, the use of medications, which reliably decrease cravings and reduce withdrawal symptoms. Methadone is a full opioid agonist with a long half-life that slowly builds up in the tissues over time, allowing it to reach a steady-state level within a week. Steady-state refers to the situation where the overall intake of the drug is more orless in balance with its elimination, so that the body is exposed to a stable level. In contrast, buprenorphine is a partial agonist that is sometimes given in combination with naloxone, forming an agonist/antagonist combination. Buprenorphine has a ceiling effect, meaning that above a certain dose it does not have any more of an effect, which reduces the chance of an overdose. Another medication called naltrexone, can be used for people who are already abstaining from active opioid use. Naltrexone is a mu-opioid receptor antagonist that blocks the effects of opioids and helps maintain abstinence.
These medications can competitively bind to the opioid receptor without producing the same euphoria as the opioids they take the place of. Since they have opioid effects, though, they can cause side effects like constipation, insomnia, weight gain, hormonal changes, and cardiac arrhythmias. The good news is that over time, an individual can safely taper their use of opioid treatments altogether. This approach is more likely to succeed than simply stopping opioids withoutt hese treatments.
Finally, all of these approaches work best when an individual has a strong network offamily and friends offering support. Opioid use still carries heavy stigma because usage is still tied to a notion of individual choice and moral failure, even though we now know that opioid use is a consequence of biological, psychological, and social factors — all of which need to be addressed to maximize the chances of recovery. The most effective treatment is a combination of therapy and medications, with a lot of love and support from family and friends.