by Emma Dolen
figures by Allie Elchert

Imagine a dystopia where a person with diabetes needs to drive a few hours every day to get their insulin at a special insulin clinic. Let’s pretend that they only need insulin once a day. They set their alarm for bright and early and get in the car to travel to the clinic before it closes for the day and before they start experiencing the adverse effects of a blood sugar spike. At the clinic, they are monitored closely as they take their insulin to ensure that they are not sneaking any out. After they finish their insulin, they hop in the car and drive back home or to work. If they miss their alarm or there is traffic getting to the insulin clinic, they might not get there before the clinic closes. Then they have to risk going a day without insulin or will risk taking black-market insulin. Every so often, the clinic checks to make sure that they are managing their diabetes outside of just taking insulin. If they are not exercising regularly or are maintaining a poor diet not conducive to treating diabetes, the clinic will refuse to give them their insulin. Also, if this hypothetical person lives in Wyoming, they might need to drive to another state to get to the insulin clinic.    

Fortunately, this Orwellian nightmare does not exist for the treatment of diabetes. People with diabetes can typically refill their insulin prescription at the pharmacy for up to three months at a time. They do not need to drive for hours or to a different state to fulfill their prescription at a special insulin clinic. Doctors will monitor the health of people with diabetes, and may suggest modifications to their exercise plan or diet, but patients will not lose access to insulin based on poor adherence to a prescribed exercise and diet plan. Replace “diabetes” with “cancer” or “heart disease” and it seems just as absurd. However, if we replace “diabetes” with “opioid use disorder” in the above-mentioned hypothetical, we get the reality for treatment in the United States. 

The Treatment Gap

Opioid use disorder (OUD) is the official diagnosis for someone who is dependent on opioids and cannot control their opioid use, leading to negative life consequences. Put simply, OUD is the medical term for being addicted to opioids. Opioids like oxycodone, heroin, and fentanyl are highly addictive, and abuse of these drugs is a huge problem in the United States. The origins of the opioid epidemic are dramatic and disconcerting: think aggressive marketing tactics used by pharmaceutical companies, overprescribing of doctors, and weak oversight by regulatory agencies. Thirty years after its onset, the opioid crisis is still raging on, and people are often unable to access adequate treatment for OUD. In 2022, over 6.1 million people in the United States suffered from OUD and only 18.3% of them received the gold standard of care: medication-assisted treatment. Medication-assisted treatment has shown greater ability to prevent relapse than non-medication treatment and has reduced the overdose rate of those with OUD by over 50%. The data is clear, yet patients still must jump through hoops to get medication-assisted treatment. Why? Well, the most successful medications for treating OUD are, in fact… opioids. 

The Opioid Paradox

When a person experiences pain, a signal has to be transmitted from the cells at the site of the pain to the brain to tell the person, “Ouch! That hurts!” The mu opioid receptor sits on the outside, or membranes, of these cells and affects the way that cells talk to and transmit messages to one another. When activated, these mu opioid receptors inhibit the transmission of pain through the spinal cord to the brain. When opioids bind to the mu opioid receptors of a cell, that cell passes on a message to other cells saying, “Hey, we are not in pain anymore” (Figure 1). Heroin, fentanyl, and other commonly abused opioids bind the mu opioid receptor in the brain and spinal cord to strongly block pain and cause euphoria. However, the problem arises when the brain adapts to this new state as over time, the mu opioid receptor activates the cellular messaging less effectively and the cell requires more opioid to continue sending the message to decrease pain and increase pleasure. This tolerance to opioids develops quickly, and the same person must take more of the opioid to get the same effect as before. The baseline state of the person has changed. Not only do they require more opioid to get an effect, they now need that opioid to feel “normal” at all. Furthermore, without the opioid, they will experience withdrawal. This is because the use of opioids at higher and higher doses changes the brain, and when the flow of opioids suddenly stops, the brain’s natural reward system drops below baseline and the person is unable to feel pleasure from natural rewarding activities. In addition, they may be violently sick, endure agonizing body aches, profusely sweat, and experience extreme anxiety. It is more than a slight discomfort. It is excruciating. And it can last for days. It is simple to make the pain stop – just take more opioid. And the cycle continues.

Figure 1. Opioids bind to mu opioid receptors in the brain and spinal cord, leading to pain relief.

The two most effective medications for long-term treatment of OUD are methadone and buprenorphine. These two drugs are also opioids that bind to the mu opioid receptor. However, unlike heroin and fentanyl, they do not cause euphoric effects. Opioids like heroin, oxycodone, and fentanyl have short half-lives, meaning they exist in the body only for a short time before being excreted (Figure 2). Heroin levels peak quickly and then fall rapidly, with half of it cleared out in just minutes. Therefore, a heroin user would need to continually take in more heroin throughout the day to stave off withdrawal. On the other hand, OUD-treatment opioids methadone and buprenorphine have long half-lives, meaning they stick around in the body for longer before being excreted. At first glance, this might seem a bit backwards – why would an opioid used to treat addiction be one that actually sticks around in the body longer than other opioids? Well, longer availability in the body means a longer sustained effect, with less need to take more opioid.  

Figure 2. Methadone stays longer in the body, allowing for less frequent opioid administration.

Methadone and buprenorphine activate the mu opioid receptors more slowly than other opioids, and reduce cravings for even longer. Because of this, methadone and buprenorphine do not produce euphoria in people who are already opioid-dependent. Think of it like choosing an afternoon snack. Candy might immediately satisfy your sweet craving, but you will probably be hungry in another hour. While Greek yogurt might not taste as good as the candy, it will probably satiate you until dinner. In a similar way, opioids like heroin and oxycodone may lead to instant gratification, but methadone and buprenorphine will stave off withdrawal for longer periods of time without causing euphoria.

OUD Obstacle Course: The Barriers to Accessing Treatment

While both exhibit relatively slow half-lives, methadone and buprenorphine work slightly differently. Buprenorphine is a partial activator of the mu opioid receptor and the intensity of its effects is limited, even at high doses. Simply put, a person can get a lot higher more easily on heroin or oxycodone than they can on buprenorphine. Methadone, on the other hand, is a full activator of the mu opioid receptor. Yet because of its longer half-life, a person who is used to stronger opioids, like heroin or oxycodone, will not experience the euphoric sensation from methadone that they are accustomed to experiencing from heroin or oxycodone (Figure 3).

Figure 3. Because methadone and buprenorphine have longer half-lives, they are able to stave off withdrawal for longer periods of time. Furthermore, because buprenorphine only partially activates the mu opioid receptor, it produces much less of a high than heroin, even at high doses.

Methadone is often more effective for those with severe OUD because it prevents withdrawal better than buprenorphine. However, methadone has a higher risk for abuse potential than buprenorphine and therefore is tightly regulated. Methadone for OUD cannot be dispensed at a pharmacy; it can only be distributed at an opioid treatment facility and patients can typically only receive one dose at a time, requiring them to come back to the facility daily. Furthermore, there are not enough facilities licensed to administer methadone, with some states only having a handful of sites, and others having none at all. If patients cannot make it to the clinic one day, they will likely suffer from withdrawal, leading them to turn to illegally acquired methadone or other opioids. Although it does have the potential to be abused, studies have shown that the most common reason for illicit methadone use was due to a missed medication pick-up. The dystopian world described earlier? It exists – not for accessing insulin for diabetes, but for accessing treatment for OUD. 

Rethinking Access to OUD Treatment

We possess medications that reduce the risk of death for individuals with OUD by over 50%. If this was any other disease, increasing access to life-saving treatment would be indisputable. Yet persistent stigma and outdated policies have created barriers, limiting the availability of these crucial treatments. Perhaps the future will not hold such hurdles for OUD treatment. Last spring, Senator Ed Markey introduced the Modernizing Opioid Treatment Access Act, aiming to expand access to methadone for OUD treatment by permitting physicians to prescribe it for unsupervised use. This would be a major shift from the current norm, where only specific opioid treatment clinics can administer methadone, and those with OUD must go to the clinic daily to receive it. The bill has yet to pass in either the United States House or Senate, and has sparked great controversy. However, some federal changes are starting to take effect. Beginning in April 2024, opioid treatment clinics will be granted increased flexibility for treating patients with methadone. Clinic doctors will be able to prescribe increased doses of methadone and will no longer be bound by the strict rule of “one dose per visit,” enabling patients to receive multiple days of medication without the need for daily clinic visits. Doctors unaffiliated with opioid treatment clinics will still be prohibited from prescribing methadone for OUD. While caution is warranted in increasing opioid prescriptions, individuals with OUD deserve evidence-based treatment. The optimal path forward is not self-evident, but ensuring access to life-saving treatment for OUD is imperative for fostering a healthier and more hopeful future for those with OUD. 

Emma Dolen is a Ph. D. student in the Chemical Biology program at Harvard University.

Allie Elchert is a Ph.D. candidate in the Biological and Biomedical Sciences program at Harvard Medical School, where she is studying transcription regulatory processes in yeast.

Cover image by GDJ on pixabay.

For more information: 

  • Check out this opinion piece by the New York Times for a more in-depth analysis of treatment for OUD.
  • This article summarizes multiple studies that compare the outcomes of medication-assisted treatment for OUD vs. placebo.   
  • For a concise description of opioids and medication-assisted treatment, read this.

Leave a Reply

Your email address will not be published. Required fields are marked *