In Part 1, we discussed how opioids relieve pain by turning off certain neurons in our brain and spinal cord, activating the descending pathway of pain inhibition and deactivating the ascending pathway of pain sensation. In Part 2, we are going to apply these concepts of neurobiology to explain why opioids can be so addictive and potentially dangerous, resulting in the opioid epidemic currently in North America.
The neurobiology of opioid use disorder
Opioid addiction, which medically is termed “opioid use disorder”, is diagnosed when a patient satisfies at least 2 of the criteria shown here within a year. The more criteria that are met, the more severe the opioid use disorder. These criteria essentially measure the extent of the detrimental effect of opioids on a patient’s mental state, physical health, and social life.
The neurological basis of opioid use disorder stems from the mesolimbic reward pathway in our brain. This part of the brain is responsible for motivation and is normally activated by rewarding and beneficial behaviours such as eating food and having sex. Activation of the reward pathway is associated with a sense of pleasure when we perform these actions and thus motivates us to repeat them, which also creates the phenomenon of addiction.
The mesolimbic system is highly complex, so for the purposes of this video we will only focus on two areas of the brain in the reward pathway: the ventral tegmental area and the nucleus accumbens. Dopaminergic neurons in the ventral tegmental area release the neurotransmitter dopamine to activate the nucleus accumbens, which then activates other areas of the brain to create the feeling of euphoria. Usually, these dopaminergic neurons are tightly controlled by inhibitory GABAergic interneurons. However, these interneurons have opioid receptors, and when opioids bind to them, the interneuron no longer releases GABA. Without that “brake”, dopaminergic neurons freely release dopamine which activates the reward pathway to induce pleasure. After repeated use of opioids, the association between pleasure and opioid use is formed, termed “drug liking”, which is what drives opioid use in the early stages of opioid use disorder. This mechanism is almost identical to the way the descending pathway of pain inhibition is activated – also through “removing the brake” by shutting down inhibitory GABAergic interneurons in the brainstem. The rate at which drug liking develops varies between people based on their genetics and environment, predisposing certain people to addiction than others.
However, long-term opioid use disorder is not only fueled by simply enjoying using opioids. The effects of tolerance, dependence, and withdrawal are now also key players. Tolerance is when repeated use of a drug desensitizes the body so that more and more of a drug is necessary to create the same effects in the body.Tolerance can be so extreme that some chronic pain patients who have used morphine for an extended period of time require 100 times the normal dose of morphine for a mild painkilling effect [1]. This is a huge problem – the higher the dose of opioid used, the higher the risk of overdose and death, which we will discuss later.
In this video, we will focus on the most well-studied theory of opioid tolerance, which involves the secondary messenger cAMP. As discussed in Part 1, the enzyme adenylyl cyclase synthesizes cAMP from ATP. There are many cAMP-dependent pathways in the neuron such as those that regulate neurotransmitter release, ion channels, receptor sensitivity and internalization, and gene expression. In a very simplified view, cAMP makes neurons more likely to depolarize and release neurotransmitters. For the purposes of this video, remember that more cAMP activates neurons, while less cAMP shuts them off. The Gα subunit of the mu opioid receptor stops cAMP synthesis by interacting with and inhibiting adenylyl cyclase. As cAMP is degraded without being replenished, this results in a decrease in cAMP levels, which, combined with the changes in Ca and K channels, shuts neurons off.
However, chronic use of opioids eventually no longer decreases cAMP. Why does this happen? The body always wants to be in a balance, or homeostasis. It’s not normal for cAMP in neurons to always be so low, so neurons try to compensate by increasing the activity of adenylyl cyclase pre-emptively to synthesize more cAMP, overshooting cAMP levels above normal. When opioids are administered, the subsequent decrease in cAMP is cancelled out by the pre-emptive increase, so neuron cAMP levels are at a relatively normal value.
In order to overcome the anticipatory increase in cAMP, a patient would need a higher dose of opioids to lower cAMP levels below normal and inhibit neurons. This is the main reason why tolerance occurs. At the same time, changes in gene expression from repeated opioid use can also cause receptor structural changes, internalization, and uncoupling, through pathways that may or may not involve cAMP. These changes effectively decrease the amount of functional receptors and make the neuron less sensitive to opioids, which further contributes to tolerance.
Opioid Withdrawal
Withdrawal symptoms are also related to the compensatory increase in cAMP. If a patient with opioid use disorder stops using opioids, the compensatory increase in cAMP is not cancelled out by opioid use, so certain neurons become overactive to cause withdrawal symptoms. Opioid withdrawal symptoms can be attributed to overactive neurons in three areas: the ventral tegmental area, the locus ceruleus, and the gut. As we go through these areas, you will notice a common theme – opioid use results in symptoms opposite of the normal function of these neurons due to neuron inhibition, while withdrawal results in symptoms that are more extreme versions of the normal function of these neurons due to neuron overactivation.
The locus ceruleus is located in the brainstem and its function is to keep us awake and alert or make us feel stressed. It also is involved in activating the sympathetic nervous system, our “fight or flight” response, which when activated causes sweating, pupil dilation, and increased heart and breathing rate. The locus ceruleus has opioid receptors, so when opioids bind to neurons in the locus ceruleus, they shut them down to cause common side-effects of opioid use such as drowsiness, sedation, dry skin, pinpoint pupils, and slowed heart and breathing rate. As you can see, these are all opposite of the functions of the locus ceruleus. However, these neurons slowly begin to become tolerant to opioids by pre-emptively increasing cAMP levels, and so opioids are less able to create these symptoms. During withdrawal, when there aren’t any opioids to cancel out the increased cAMP levels, neurons in the locus ceruleus go into overdrive to cause jitteriness, anxiety, excessive sweating, wide dilated pupils, and extremely fast heart and breathing rate. These withdrawal symptoms are all extreme versions of the functions of the locus ceruleus.
Certain neurons in the intestines cause gut movement to push contents out. When these neurons are inhibited by opioids, gut movement slows down to cause constipation, a common side-effect of opioid use. This side-effect is taken advantage of by certain anti-diarrheal drugs such as loperamide, which activate opioid receptors. During withdrawal, gut movement becomes so rapid that contents are propelled out of the intestine before sufficient water is absorbed, resulting in a common opioid withdrawal symptom: diarrhea.
Finally, the GABAergic inhibitory interneurons that are keeping the dopaminergic neurons in the ventral tegmental area in check also become tolerant to opioids, which means the opioids do not cause as much pleasure as before, and perhaps the absence of opioids during withdrawal causes GABAergic neurons to go into overdrive to create the feeling of discomfort.
To avoid these distressing withdrawal symptoms, patients will continue to use opioids, no matter the negative consequences to their lives – which fits the diagnostic criteria for opioid use disorder perfectly.
To summarize, the progression of opioid use disorder starts off with the brain associating pleasure with opioid use from repeated stimulation of the mesolimbic reward pathway. Long-term use causes tolerance through increasing cAMP pre-emptively, creating the need for more and more drug to cause the same effect. Taking the drug away results in withdrawal symptoms as there are no opioids to cancel out the compensatory increase in cAMP. Thus, the opioid user becomes dependant on increasing doses of opioid to continue feeling somewhat “normal”. If opioids are not used for a few weeks, tolerance and withdrawal symptoms eventually disappear as the body stops overcompensating to return to homeostasis, but this is such an excruciating process that going cold-turkey is rarely effective.
Overdose
As tolerance forces patients to use higher and higher doses of opioids, their risk of overdose also increases. An overdose is deadly because it causes respiratory depression, which means you stop breathing. To understand why this happens, we should look at how breathing is controlled by the brain. The pre-Botzinger complex in the brainstem has neurons that constantly generate signals rhythmically which get sent to the diaphragm and other respiratory muscles to keep us breathing. If, for some reason, you stop breathing, you don’t inhale more oxygen or exhale carbon dioxide, so blood CO2 levels rise and blood oxygen levels fall. However, the body has a feedback loop that forces you to breath again. The levels of high CO2 and low oxygen in your blood can be detected by chemoreceptors to activate the pre-Botzinger complex and kickstart breathing. That’s why people can’t die by just holding their breath. However, both the chemoreceptor neurons and the pre-Botzinger complex also have opioid receptors, and at extremely high doses of opioids like during an overdose, these respiratory neurons are shut down. Without them, your brain no longer “forces” you to breathe, and so you don’t, and then you die.
Unless…the overdose is reversed. You may have heard of a drug called naloxone. Naloxone’s structure is very similar to morphine, allowing it to bind to opioid receptors – in fact, naloxone is even better at binding to receptors than morphine, so it kicks morphine and other opioids off the receptor. However, naloxone’s slight structural differences make it unable to activate those receptors after binding. This is a very useful characteristic because naloxone can prevent opioids from binding to receptors to exert their effects such as respiratory depression. This is what we call a receptor “antagonist”. Without the opioids binding to and inhibiting those respiratory neurons, the drive to breathe returns. In some cities with an opioid crisis, like Vancouver, naloxone kits are available in certain drug stores. If you are in a community where opioid overdose is common, perhaps consider keeping one. You just might end up saving someone’s life.
The Opioid Crisis
I’d like to remind viewers that the point of this video is not to say that opioids are terrible drugs. They are the best at reducing pain, and if used correctly can greatly improve the quality of life for people suffering from debilitating diseases such as cancer. The problem right now is that many people who are currently addicted to opioids may have started their addiction by being unnecessarily prescribed opioids by their doctor for their non-cancer pain. 4 out of 5 heroin users in the United States reported that they started their addiction by using prescribed opioids. [3]
This overprescription crisis is often attributed to Purdue Pharma, the maker of Oxycontin, a long-lasting formulation of oxycodone. This drug company aggressively promoted the use of Oxycontin for all kinds of pain through crazy marketing strategies and misleading research articles in the 1990’s. Never before was a drug as heavily promoted as Oxycontin, with the marketing team using Oxycontin-branded plushies, wrenches, clocks, hats, and even mixtapes. Around the same time, the infamous correspondence by Porter and Jick in the New England Journal of Medicine claimed opioid use was safe. Despite having flaws such as the fact that patients were only prescribed a low dose of opioids in the hospital and not monitored after leaving the hospital, this correspondence and other flawed articles were used by Purdue Pharma to justify its claim that only 1% of patients on Oxycontin develop opioid use disorder. With this false sense of security, doctors soon began to prescribe more opioids than necessary. As a result, oxycodone use in the US skyrocketed by 500% between 1999 and 2011 and overall opioid use increased by 400%. In reality, Oxycontin was just as effective as morphine but just as addictive as well. It’s probably not a coincidence that in the US the increase in opioid use was accompanied by a 600% increase in the number of patients seeking medical treatment for their opioid use disorder, and the 400% increase in opioid-related overdose deaths. In 2007, Purdue Pharma and three executives were eventually fined $600 million for misrepresenting the risk of Oxycontin, and they stopped advertising for Oxycontin in 2018, but the damage was already done. Both opioid prescription rates and opioid use disorder rates have remained high ever since. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2622774/)
The most recent spike in opioid overdoses you may have heard in the news is related to a synthetic opioid called fentanyl, which is almost 100 times stronger than morphine. To give you an idea of how strong that is, only 2 mg of fentanyl can cause overdose and death. Illicit drugs such as cocaine and methamphetamines, as well as other illicit opioids like heroin and oxycodone, are now being laced with fentanyl because just a tiny bit of it can boost the effectiveness of the product, creating larger highs but also more overdoses.
What can we do to stop this crisis? Preventing patients from becoming addicted to prescription opioids is a good start. The healthcare system needs to address the problem of opioid overprescription by educating physicians and patients alike and carefully monitoring opioid use. At the same time, there needs to be better support for patients at high risk of or already diagnosed with opioid use disorder. Current medications are available that pharmacologically treat addiction, such as methadone and buprenorphine, but at the same time these people also need help in other aspects of their lives too – a stable home setting, financial status, and social network. Availability of naloxone kits can also save more people.
Ultimately, the goal is to make a non-addictive but still effective analgesic that isn’t easily tolerated. While there are still lots of things we don’t understand about opioids, research is done every day to get us closer to that goal. Thanks for watching, and see you next time on Medicurio.
Opioid drugs are a well-known class of drug due to both their ability to kill pain and kill people. Watch part 2 of this two-part series to learn how opioid drugs can cause addiction and overdose, as well as a bit of the history behind the opioid epidemic in North America.
Watch Part 1 here: https://youtu.be/s60KzN4GJdQ
*Two great articles about the opioid crisis:*
The Promotion and Marketing of OxyContin: Commercial Triumph, Public Health Tragedy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2622774/)
The Prescription Opioid and Heroin Crisis: A Public Health Approach to an Epidemic of Addiction (https://www.annualreviews.org/doi/full/10.1146/annurev-publhealth-031914-122957)
*Mechanism of cAMP*
Two key functions of cAMP have been discovered in neurons. The first is the activation of ion channels to let positive charge into cells, called a “pacemaker current”, which depolarizes the neuron to activate it. Increased cAMP makes it easier for ion channels to open. Without cAMP, it is harder for these channels to open, resulting in less positive charge entering the neuron to depolarize and activate it. The second function of cAMP in neurons is to increase neurotransmitter release. Certain neurotransmitters are released via a protein kinase A dependent pathway, which is initiated by cAMP. Without cAMP, these neurotransmitters are not released. These two functions combined point to cAMP acting as a neuron activator, and thus when opioids decrease cAMP levels, neuron function is also inhibited.
*Methadone and Buprenorphine Mechanisms*
Methadone (Dolophine) is a long-acting opioid receptor activator that does not cause as much euphoria as morphine. Patients with opioid use disorder patients can enroll in a “methadone maintenance” program, in which they receive a dose of methadone every day. This prevents withdrawal symptoms and unsafe activities obtaining and administrating illicit drugs, helping patients get their lives back on track. Its ability to activate NMDA receptors may also be a reason why this drug is effective at eliminating addiction, tolerance, and withdrawal, but the true mechanisms are still being investigated.
Buprenorphine is a partial agonist of the opioid receptor. This means at low doses it can activate the receptor, but at high doses it inhibits the receptor. Thus, the risk of overdose is limited with buprenorphine and thus can also be used to wean patients off of opioids, albeit slower than methadone.
References:
Kosten TR, George TP. 2002. The neurobiology of opioid dependence: implications for treatment. Science and Practice Perspectives, 1(1): 13-20
Kolodny A, Courtwright D, et al. 2015. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annual Review of Public Health, 36: 559-574
Williams JT, Christie MJ, Manzoni O. 2001. Cellular and synaptic adaptations mediating opioid dependence. Physiological Review, 81(1):299-343