Quitting opioids cold turkey, without the help of medication, is a recipe for severe withdrawal and relapse — there’s no dispute.

Opioid use disorder (OUD) rewires the brain so profoundly, triggering such intense cravings and withdrawal symptoms, that willpower and good intentions almost inevitably fall short.

Medication, by contrast, can prevent withdrawal symptoms and suppress cravings, dramatically lowering a patient’s odds of relapse, overdose, and death.

The FDA has approved three medications for the treatment of OUD: methadone, buprenorphine, and naltrexone.  But which of the three government-approved medications works best?

In the fentanyl era, the answer may be more nuanced than in the past, when heroin and pain pills dominated.

However, the supporting research was largely conducted prior to the rise of fentanyl, the ultra-potent synthetic opioid that has infiltrated the illicit drug supply and driven up opioid overdoses and deaths.

Experts who treat OUD on a daily basis say fentanyl has, to some extent, changed the treatment equation.

Buprenorphine, the key component of SuboxoneⓇ, remains a safe, effective medication for addiction to all opioids, including fentanyl, and for many patients, a better long-term choice than methadone.

While methadone remains a viable alternative to buprenorphine, Naltrexone (Vivitrol), meanwhile, is fading from relevance for fentanyl-dependence, though the drug remains useful for alcohol addiction and in certain populations with OUD.

“Suboxone has been shown to be the superior treatment for OUD,” says Brian Dawson, M.D., chief medical officer of Ideal Option and an addiction medicine specialist.

“Compared to methadone and naltrexone, it has a more protective effect against overdose. However, methadone is an effective therapy for some people who are not transitioning to Suboxone well.”

Here, we discuss the pros and cons of the three FDA-approved OUD medications.

Buprenorphine

For OUD patients, buprenorphine offers a win-win, satisfying the brain’s need for opioids without delivering a high. The upshot: a lower risk of overdose or relapse and much better odds of getting your life back.

Buprenorphine is classified as a partial opioid agonist, which means the drug locks onto the opioid receptors but produces milder effects than full opioid agonists, such as methadone, oxycodone, heroin, or fentanyl.

If you use another opioid while on buprenorphine, you won’t experience euphoria. Buprenorphine binds so tightly to the opioid receptors that other opioids can’t worm their way in.   

Buprenorphine is usually taken in the form of Suboxone, a combination medication that includes a small dose of naloxone, aka Narcan, known for reversing overdoses. (Buprenorphine staves off withdrawal and cravings while naloxone discourages misuse of the medication.)

A dose of Suboxone, a film that dissolves under the tongue, occupies the opioid receptors for about 24 hours. Almost immediately, the drug reverses withdrawal symptoms such as vomiting, nausea, anxiety, restless legs, and chills. Taken daily, Suboxone also suppresses cravings.

Patients report they suddenly “feel normal again,” stability that allows them to get through the day, address any underlying mental health issues, and focus on recovery.

Compared to methadone, Suboxone has a much lower potential for abuse and overdose.

What’s more, the medication can be prescribed at an outpatient medical clinic. Patients usually start out being seen twice per week for close monitoring and support during the initiation phase, and then transition to less frequent visits as they gain stability and progress in their recovery.  Ideal Option patients who are stable in treatment are typically seen once per month. 

By contrast, most methadone patients typically need to visit a clinic every day to receive their dose and be observed taking it.

Patients on Suboxone may need the medication for years, depending on their addiction history, but most can wean to a low dose, the way a depression patient might continue with antidepressants to maintain stability.

Since its approval in 2002, buprenorphine has demonstrated no significant drawbacks, other than discomfort during the necessary abstinence period prior to starting the medication.

To avoid “precipitated withdrawal,” a severe form of withdrawal caused by starting buprenorphine too soon, patients dependent on opioids such as oxycodone or heroin must abstain for at least 24 hours before taking buprenorphine. Most motivated patients can withstand the withdrawal symptoms they experience during this period, especially if accompanied by a supportive friend or family member.

However, because fentanyl takes longer to clear the body, initiation onto buprenorphine may require an abstinence period of up to 36 hours.

For patients unable or unwilling to tolerate this 36-hour abstinence period, one option is to start buprenorphine with a very low initial dose that is too low to cause precipitated withdrawal, and then gradually increase the dose each day until the patient reaches the therapeutic dose of buprenorphine before discontinuing their fentanyl use. This method, which can take from 5 to 8 days, is known as the “low-dose initiation” method, or sometimes called, “microdosing” buprenorphine. 

Alternately, some patients heavily dependent on fentanyl do better with a two-step transition — from fentanyl to a stable dose of methadone to Suboxone. At Ideal Option, providers discuss the two options with OUD patients dependent on fentanyl and, if needed, will refer patients to a methadone clinic for the first step. Then, after three or four weeks on methadone, the patient will transition to Suboxone.

Either way, ending up on Suboxone is ideal for OUD patients.

“Suboxone is definitely a better long-term maintenance medication compared to methadone,” says Dr. Dawson.

Methadone

Available since the 1970s, methadone is better known than buprenorphine and, when dispensed by methadone clinics, has helped many patients avoid overdose and use of illicit opioids.

However, compared to Suboxone, methadone has some significant downsides.

Methadone doesn’t bind tightly to opioid receptors, so it can be knocked off these receptors by pain pills, heroin, or fentanyl, paving the way for overdose.

“Methadone can be overridden by other opioids,” explains Dr. Dawson.

In addition, as a full-agonist opioid, methadone can cause euphoria and sedation, and taking too much can result in respiratory depression and serious heart problems.

For these reasons, methadone is tightly controlled. Most patients must visit a methadone clinic every day. Such supervision is helpful for patients who don’t have support from family or friends but can be a barrier for patients with more stability, those with a job, and those without transportation.

Even taking the prescribed amount of methadone can make patients feel drowsy.

“On methadone, it’s harder to wake up and drive the kids to school, hold a job, and generally manage your life,” says Dr. Dawson.

Methadone, taken as a tablet, liquid, or an injection, is generally safe when dispensed at a methadone clinic and taken exactly as directed but can lead to overdose, even death, when bought off the street.

For most OUD patients, Suboxone offers a safer, more practical path to recovery. However, the fentanyl crisis has highlighted an important benefit of methadone: Patients can transition to the drug directly from fentanyl, without having to endure a preceding abstinence period.

Naltrexone

Unlike buprenorphine and methadone, naltrexone is not an opioid agonist. Rather, it works by blocking the effects of opioids in the brain, preventing euphoria and reducing cravings.  The medication is available as either a pill, which is taken orally once daily, or as a monthly injection called Vivitrol.

Naltrexone is not dependence-forming or dangerous but has a significant disadvantage: “It’s only effective in people who have been abstinent from opioids for several weeks,” says Dr. Dawson.

OUD patients typically receive monthly Vivitrol injections, but as the extended-release formulation wears off, patients may experience cravings that put them at risk for returning to opioids.

Relapse can be particularly dangerous for naltrexone patients, whose opioid tolerance diminishes during the abstinence period. This makes patients more susceptible to deadly overdose.

“That’s why Suboxone is more commonly prescribed for OUD,” says Dr. Dawson.

The OUD patients most likely to benefit from naltrexone are those with a short, modest history of opioid use, not a fentanyl addiction or long-term use of heroin or pain pills.

Naltrexone has helped OUD patients who did not use opioids while in jail or inpatient treatment and who seek to maintain opioid abstinence afterward.

Still, starting on Suboxone after jail or rehab may be a better option for many patients. (And taking Suboxone while in jail or inpatient treatment is certainly better.)

No matter what medication an OUD patient chooses, medication is not an express ticket to recovery from addiction.

Medication-based treatment works best when combined with counseling, behavioral therapies, and peer support. It’s critical for patients to address any mental health conditions that may have fueled, or contributed to, opioid addiction in the first place.