Opioid agonists, like naltrexone, buphrenoprhine or methadone, are medication used in opioid use disorder. Are pharmacokinetic concepts like onset of action, receptor activation and avidity clinically relevant for opioid agonists? How is methadone therapy supervised? Who can prescribe opioid agonists? How is misuse of therapeutic agonists prevented? Find out the answers by watching this video presented by Dr. Stephen Holt, Co-Director at Yale Addiction Recovery Clinic, USA.
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Okay, having explained the benefits of treatment of opioid use disorder in the previous Medmastery lesson, let's review the different options in some detail. Different chemicals have different pharmacokinetics, this means that they will have varying rates of onset based on modes of use. For example, inhaled or injected drugs exert their effects more quickly than sublingual drugs, that need to go through the oral mucosa, and sublingual drugs work more quickly than swallow drugs, that need to go through the gastrointestinal system.
A substances lipophilicity also impacts its rate of onset. For example, heroin is very lipophilic, so it crosses the blood brain barrier and enters the brain much more quickly than its hydrophilic counterpart, morphine. Different chemicals also have different pharmacodynamics for example, they will also vary in the degree to which they activate the opioid receptor once they bind to it.
Activation describes the biological response that occurs when a chemical binds to a receptor. Full agonists will activate it strongly, partial agonists less so, and antagonist will not activated at all. Let's use a graph to help us understand the differences between a full agonist, a partial agonist and an antagonist. The y axis here shows opioid activation, the x axis shows opioid dose.
Looking first at full agonists, you can see that as we increase the dose, opioid activation increases in an almost linear fashion. If we keep going up on the dose, we'll start to see respiratory depression, and ultimately, death. This is the same for all opioid agonists, including methadone, oxycodone, or heroin. In contrast, our partial agonist buprenorphine has a ceiling effect as you go up on the dose. Essentially, once you get to around 24 milligrams of buprenorphine, there's no further effect, no risk of respiratory depression, and no risk of death.
Naltrexone is our opioid antagonist. It strongly binds to the opioid receptor, but fully blocks its downstream effects. And so, to summarize, while all three of these medications are first line in the treatment of opioid use disorder, only methadone and buprenorphine are considered opioid agonist therapy, while naltrexone is considered opioid antagonist therapy. You may have heard of naloxone. Naloxone is an intravenous form of naltrexone that is rapidly delivered to the brain, it can also be delivered intramuscularly, subcutaneously and even intranasally, and it's used to rapidly reverse an opioid overdose. Due to its very short acting pharmacokinetics, it is not considered a maintenance treatment for OUD. Which brings us to another key pharmacodynamic concept known as avidity.
Avidity describes how strongly a substance binds to a receptor, almost as if there's some kind of glue holding them together and whether it can be displaced when something else comes along. Think of this as a competition among compounds, regardless of what they do when they get there. It turns out that while heroin is a potent activator of the receptor, it's actually easily displaced by a variety of other medications, most notably naloxone and naltrexone, which have a very high avidity for the receptor. Likewise, if a person has naloxone or naltrexone in their system when they use heroin or any opioid, that opioid can get to the brain, but it won't be able to activate the opioid receptors due to the antagonists iron grip.
Buprenorphine is somewhere in the middle in terms of its avidity. It has stronger avidity than full opioid agonists but would still be displaced by both naloxone and naltrexone. Returning to our prior schematic, we can add in a column for avidity. We see that heroin and oxycodone are actually relatively weak and easily displaced by a number of medications. These basic concepts of speed of onset, activation, and avidity explained the therapeutic properties of our OUD medications. Let's talk about the opioid agonist methadone in more detail.
Well, methadone has a very slow onset of action. Once it's in the brain, it basically saturates all the opioid receptors and suppresses any cravings. When the receptors are saturated, a patient who injects a bag of heroin will get very little if any effect, so heroin loses its allure. While the prevention of withdrawal is typically achieved with a dose of 30 to 40 milligrams per day, to fully saturate the receptors and stamp out any cravings treatment doses are typically in the 80 to 120 milligram per day range. Important side effects of methadone that are common to all opioids include constipation, hypogonadism, pruritis, and respiratory depression. Respiratory depression is of particular concern when methadone is combined with benzos.
The most important methadone specific side effect is QT prolongation, which is dose dependent. Most methadone programs will check the QT interval regularly while titrating up the dose and then annually once at a steady state. Importantly, methadone is usually only available via licensed methadone dispensaries, it's not available as a prescription. Instead, patients need to present to their program every morning to get a single dose, usually in liquid form that they need to drink right in front of the staff.
Over time, patients that do well in their program are granted take homes, which are basically extra doses that they can take home with them, maybe up to 14 days of doses, so they don't need to come in daily. The other opioid agonist we will discuss is buprenorphine. Buprenorphine is available in a number of forms, including sublingual tablets, sublingual films, a monthly injectable subcutaneous form, and even implantable cartridges that are replaced every three months. The sublingual forms typically contain naloxone along with buprenorphine, which may seem counterintuitive, since naloxone, as you may remember, is an opioid antagonist and buprenorphine is an opioid agonist.
So how can they be given together? Naloxone is not well absorbed sublingually so it doesn't get into the bloodstream when taken in this form, and therefore will not block the action of buprenorphine. It's like giving buprenorphine alone. But if the patient decides to dissolve the tablet or film and inject it for a quicker effect, then Naloxone will go along for the ride and will block the effects of any opioids including buprenorphine, this can lead to opioid withdrawal symptoms.
So ultimately, the purpose of the naloxone, buprenorphine combination is to discourage misuse by injection. Unlike methadone, buprenorphine can be prescribed in any clinicians office by a physician, physician's assistant, or a nurse practitioner. Some countries require additional training in order to prescribe buprenorphine in the primary care setting, though this is typically just a one time, eight hour course. The bupren nalox tabs and films are available in 2,4,8 and 12 milligram doses, and most patients are maintained on a dose between 8 to 16 milligrams per day.
The injectable form given subcutaneously in the abdomen, lasts for over a month, and is a great way to guarantee adherence and keep patients safe until their next visit. Again, because buprenorphine has a higher avidity for the opioid receptor than all of the full opioid agonists a patient taking 16 milligrams of bup a day can't accidentally overdose on IV, heroin or fentanyl, regardless of how much they consume and that is a very good thing. Buprenorphine can cause some of the same opioid related side effects I have already mentioned, although typically to a much lesser extent.
There really aren't any buprenorphine specific side effects, nor are there any significant contraindications. It's even safe during pregnancy and has become the preferred drug for OUD in this setting. Patients on opioid agonist therapy whether it's methadone or buprenorphine report feeling normal when they take their meds. This figure shows how patients getting into opioids for the first time feel when they use heroin early in the natural history. Over time, however, they get less and less of a euphoria with each use, until eventually they aren't getting any pleasurable effects at all. They're merely trying to stave off the miserable effects of opioid withdrawal.
Telling such a person to just shape up and quit is genuinely ridiculous at this point. Opioid agonist therapy helps to bring the patient back to feeling normal, so that they can re- engage in treatment and move on with their lives, all with a simple once daily dose of medication.
Finally, let's discuss the opioid antagonist naltrexone. It's available as a daily 50 milligram pill or a monthly injectable. It's best for patients who have already detoxed off opioids and for those who wish to truly be opioid free. You wouldn't want to administer naltrexone while any opioids are still in the brain, as naltrexone would immediately displace those opioids, creating a very fast, very acute opioid withdrawal state. As such, it's best to wait at least five to seven days after the last dose of any opioid before starting oral or injectable naltrexone.
Research has shown that methadone, buprenorphine and naltrexone are all equally effective at keeping patients alive and keeping them in treatment, provided the patient has detox off opioids for at least a week before starting treatment with naltrexone.