The over-prescription of opioid pain relievers such as oxycontin and the widespread availability of potent synthetic opioids such as fentanyl has led to an epidemic and opioid overdoses are now the leading cause of accidental deaths in the US.

At the same time, certain advancements have played a crucial role in managing the opioid crisis in the US, which has seen entire communities ravaged by addiction and thousands of lives lost.

The conventional approach to treating opioid addiction primarily relies on medication-assisted treatment (MAT), which combines medication with counselling and behavioural therapy. In this article, we take a look at conventional ways of treating opioid use disorder and recent research that can further improve these.

There are three medications that are approved for the treatment of opioid use disorder in the US: naltrexone, methadone, and buprenorphine.

Naltrexoneis an opioid receptor antagonist. It blocks other opioids from getting to the receptor, and turns the opioid receptor off. 

“Naltrexone can protect a patient from overdose if they do relapse, and it can reduce opioid craving,” explains Dr. Arthur Weissman, a clinical assistant professor of family medicine at the Jacobs School of Medicine and Biomedical Sciences in Buffalo, New York, who has a special interest in addiction medicine. “The evidence that it reduces opioid overdose death rates is not as convincing, but it can still be an option in the right patient.” 

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Methadone is a full opioid receptor agonist; it turns the receptor fully on, while buprenorphine is a partial opioid receptor agonist, so it turns the receptor partly on. 

“Agonist therapy—methadone or buprenorphine—works by stabilising the parts of the brain that have become very ‘sick’ in opioid use disorder,” Weissman continues. “When a patient is appropriately medicated with buprenorphine or methadone, they do not feel ‘high’, they do not experience withdrawal symptoms, and they do not experience craving (an intense desire to use the drug). They feel normal.”

A 2021 research report indicated that buprenorphine and methadone are extremely effective in controlling opioid use disorder. The overdose death rate drops by two-thirds and there are substantial decreases in criminal activity and disease transmission (like HIV and hepatitis), and substantial improvements in employment and social function. 

Sublocade and Brixadi – game-changers in the opioid crisis?

Non-injectable forms of buprenorphine, which have been available for about 20 years as sublingual films and tablets, have more diversion potential—patients diverting their prescribed medications into the illicit market. The recent development of injectable treatments is a positive advance in managing this issue. There is no possibility of diversion of injectable buprenorphine because it must be administered in a clinical setting under medical supervision.

Sublocade, an extended-release buprenorphine injection, was approved by the US Food and Drug Administration (FDA) in November 2017 and was developed by Indivior, a pharmaceutical company specialising in addiction treatment.

More recently, a new brand of extended-release injectable buprenorphine, known as Brixadi, produced by Braeburn, was FDA approved in May 2023. While Sublocade is a once-a-month injection, Brixadi comes in weekly and monthly versions, and in more dosing strengths, which offer greater flexibility in treating patients. For people in recovery who are unable to tolerate the higher doses of extended-release buprenorphine, these lower doses and a weekly injection may help maintain their medication adherence.

“There is perhaps less stigma attached to a patient being prescribed buprenorphine than being on methadone,” observes Weissman. “Though for some patients, buprenorphine does not have enough of an agonist effect, which is particularly relevant in the fentanyl era because fentanyl is so potent and so potentially lethal. There is no precipitated withdrawal when starting methadone, because it is a full agonist.”

Also, with injectable buprenorphine there is some risk of adverse reactions at the injection site, like pain or bleeding, or allergy to components of the injection itself. However, Weissman adds that there is evidence that Sublocade gives higher and more consistent blood levels of buprenorphine, which may provide a therapeutic edge for some patients, particularly in the fentanyl era.

Future outlook for alternatives

Combining buprenorphine with an opioid receptor antagonist such as naloxone (for reversing overdoses) has been a standard MAT practice for some time, and new formulations and delivery methods are being developed to improve patient compliance and reduce the risk of misuse.

In the age of precision medicine there is also a push towards novel therapies that can target different aspects of addiction and potentially offer more personalised treatment. Along with opioid receptor modulators, researchers are developing drugs to modulate neurotransmitter systems (such as dopamine, serotonin, and glutamate), which play a role in addiction. Pharmaceuticals that target immune responses or inflammation associated with opioid misuse are also in development, and identifying genetic and epigenetic factors that contribute to opioid addiction susceptibility will lead to more targeted therapies.Top of Form

However, these advances are of limited value if they are not made widely available, says Weissman.

In the US, we do not do a good job of making treatment available – only 11% of US patients with opioid use disorder are on agonist therapy,” he observes. “There are some encouraging developments, however, like the X-waiver is gone (this was a requirement that US prescribers do up to 24 hours of an onerous training program before they could prescribe buprenorphine for opioid use disorder), and naloxone (for reversing overdoses) just became available over the counter. The bad news is that the opioid overdose death rate is still accelerating, despite our efforts.”