Opioid Use Disorder

[snorts] >> 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. Enjoying our Osmosis videos? Unlock your full potential with an Osmosis subscription. Get unlimited access to every Osmosis feature and resource with a free 7-day trial. 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 a 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 the 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 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. All right. So, now let's say 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 this 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 flip side, 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. There's also positive reinforcement from the dopamine induced euphoria associated with using the drug, again leading to more drug use. Together, this positive and negative reinforcement leads to opioid use disorder. The DSM-5 or Diagnostic and Statistical Manual 5th Edition defines opioid use disorder as causing at least two of the following behavior patterns within 1 year. One, using larger amounts of opioids or using them for a longer time than intended. Two, being unable to cut down on or control the use of opioids. Three, having opioid use or recovery from use take up a significant amount of time. Four, having cravings to use opioids. Five, having opioid use affect responsibilities at work, school, or home. Six, using opioids even if they cause recurrent interpersonal problems. Seven, giving up important activities in order to use opioids. Eight, using opioids in physically dangerous situations. Nine, using opioids even if it's worsening a physical or psychological problem. 10, becoming tolerant to the opioids unless the tolerance is only under medical supervision, and finally, 11, feeling opioid withdrawal symptoms. Having two or three of these symptoms is considered mild. Having four or five is considered moderate. And having six or more is considered severe. In addition to disrupting a person's life, opioid use disorder can also end it through overdose. Without rapid treatment, opioid overdose causes severe respiratory depression to the point where a person may simply stop breathing and experience cardiac arrest. In that situation, high-quality cardiopulmonary resuscitation or CPR is essential and naloxone should be administered as soon as possible. Naloxone is an opioid antagonist that is used to treat opioid overdose. Since naloxone has a higher affinity for opioid receptors than opioid agonists like morphine, fentanyl, and heroin do, it actually displaces the agonist from the receptor and doesn't allow another to bind. When naloxone is given intranasally or intravenously, it can reverse the effects of opioids within minutes, potentially saving a person's life. Generally speaking, high-potency opioids carry the greatest risk of substance use disorder and death. And when paired with other substances that can cause respiratory depression like alcohol or benzodiazepines, they're even more likely to cause overdose because they can act synergistically to decrease respiration. It's clear that opioids have strong addictive potential. So, before starting treatment with an opioid, assess the patient's risk for misuse or opioid use disorder using a validated tool to help identify higher-risk patients and guide safer prescribing. In addition, ongoing monitoring for signs of misuse is essential throughout the duration of the treatment. And opioid use should be limited and well-defined. Opioids have a role in controlling acute pain, for example, but the goal should be to use short-acting opioids at the lowest effective dose for just a few days, and to slowly increase their dose only if needed. When opioids are used for chronic pain, they should be tapered down as soon as possible, ideally in a gradual patient-centered manner. In general, though, chronic pain should be treated with non-opioid approaches. These include exercise and biofeedback, as well as through other types of medications, such as acetaminophen and NSAIDs, like ibuprofen. There are also disease-specific treatments. For migraines, we can use triptans. For neuropathic pain, medications like gabapentin. And for joint pain, we can use topical pain treatments like capsaicin. For people with opioid dependence, the most effective treatment is a combination of therapy and medication. Specific therapies that have been shown to work include motivational interviewing, which can be used to understand why an individual wants to stop using opioids and identify specific barriers to treatment. Cognitive behavioral therapy can help an individual learn about withdrawal, discuss the thoughts, feelings, and behaviors that led to their opioid usage, and create a plan to navigate triggers for potential usage and relapse. Another form of therapy is peer support programs. These use group discussions to help individuals commit to ending the use of opioids by holding one another accountable. In addition, evidence strongly supports 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 about a week. Steady-state refers to the point where the overall intake of the drug is more or less in balance with its elimination, so that the body is exposed to a stable level. In contrast, buprenorphine is a partial agonist that is often given in combination with naloxone, forming an agonist antagonist combination. Buprenorphine has a ceiling effect, meaning that there is no effect above a certain dose, which reduces the chance of an overdose. These medications competitively bind to the opioid receptor without producing the same euphoria as the opioids that they take the place of, making them effective treatment for opioid use disorder. Since these agonists have opioid effects though, they can cause side effects like constipation, insomnia, hormonal changes, and cardiac arrhythmias. The good news is that over time, some individuals can safely taper off their use of opioid treatments altogether. And this approach is more likely to succeed than simply stopping opioids without the assistance of these medications. 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. All of these approaches work best when an individual feels supported, such as by professional, peer, or community 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. All right, as a quick recap. In addition to blocking transmission of pain signals in the spinal cord, opioids stop inhibitory neurons from releasing inhibitory neurotransmitters in the reward pathways of the brain, increasing dopamine and causing feelings of euphoria. Long-term use can cause people to develop tolerance, which is the need for increasing doses to achieve the same effect, as well as dependence, which is the reliance on the opioid to function normally. The most effective treatment is a combination of therapy and medications, along with social support. Helping current and future clinicians focus, learn, retain, and thrive. Learn more.