Medication for anything only works if the patient takes enough. This is emphatically true for people taking medications for opioid use disorder. If they don’t get enough buprenorphine or methadone, they are likely to experience cravings and revert to using risky, often dangerously adulterated opioids.
Yet far too often—thanks to undue fears and stigma, misinterpretation of evidence and misguided regulations—buprenorphine is prescribed at inadequate doses while the advantages of methadone are under-utilized.
“If a patient is provided an inadequate dose then the medication won’t work,” said Sam Snodgrass, PhD, a behavioral pharmacologist with his own addiction history, who is on the boards of the addiction support organizations Broken No More and GRASP.
“If someone has high blood pressure and they take an anti-hypertensive medication at an inadequate dose, it won’t control their high blood pressure,” he told Filter. “If we are provided buprenorphine but at an inadequate dose, then we will continue to use street drugs when we run out … or we will continue to buy buprenorphine off the street to supplement what we are prescribed. The result is that we may very well drop out of treatment and people will then say, as they do now, that the medication doesn’t work—when the problem isn’t with the medication, but with the dose.”
Buprenorphine dosing has become highly standardized. Prescribers tend to opt for the lowest possible dose—not necessarily the most effective. The risk-averse attitude behind this approach is misguided, because buprenorphine is relatively safe even at higher doses—and these higher doses are often necessary to optimize effectiveness.
While higher doses can be prescribed off-label, what many experts identify as buprenorphine’s “ceiling effect” means that even these may not have the desired outcome.
What many clinicians now consider high-dose buprenorphine—24 mg a day, the maximum dose for OUD indicated by the FDA label—has essentially the same level of effectiveness as about 60 milligrams of methadone. Researchers determined this in the 1990s, in the studies that led up to the approval of buprenorphine to treat opioid use disorder. However, many buprenorphine patients get far less than 24 mg—and many need higher doses still.
“There are people who will do fine on 24 mg of buprenorphine,” said Yngvild Olsen, MD, MPH, medical director of the Institutes for Behavior Resources/REACH Health Services in Baltimore. “But there are people whose opioid use disorder is so severe that, for various reasons, they just don’t stabilize on maximum doses of buprenorphine.”
So in practice, buprenorphine often may not be “holding” patients—preventing their craving for opioids. And while higher doses can be prescribed off-label, what many experts identify as buprenorphine’s “ceiling effect” means that even these may not have the desired outcome.
“Buprenorphine has a ceiling effect due to its partial-agonist activity which contributes to its better safety profile,” said Andrew M. Peterson, PharmD, PhD, executive director of the Substance Use Disorders Institute at the University of the Sciences in Philadelphia, and the John Wyeth Dean Emeritus. “However, where that ceiling occurs varies by patient and it is difficult to predict who will need what dose,” he told Filter.
Peterson cited a 2008 meta-analysis that concluded:
“The review of trials found that buprenorphine at medium (8 mg ‐15 mg) and high doses (16mg) can reduce heroin use effectively compared with placebo, although it is less effective than methadone, especially if methadone is prescribed at adequate dose levels of between 60 mg and 120 mg per day.”
“There is a small handful of patients who need higher doses, but it has very little added effectiveness going above 24,” said Olsen.
Snodgrass, however, has doubts about the validity of evidence for burprenorphine’s ceiling effect, as we’ll see in the second half of this article.
Clinically, the proper dose is whatever is adequate; no value-judgements should apply. Fear-mongering about over-prescribed patients selling it on the street will only prolong the crisis.
One advantage of methadone is that it certainly has no ceiling effect and can therefore be prescribed in high-enough doses. Patients may need higher-than-average doses for a number of reasons. These include if a person has a rapid metabolism, genetic factors and their history of opioid use—the type of opioid they used, as well as duration of use and route of administration.
For patients who benefit from higher doses, many experts believe that methadone, a full opioid agonist, is a better option than buprenorphine.
Buprenorphine, unlike methadone, is a partial opioid agonist, which means the molecule binds to and activates opioid receptors in the brain, but not 100 percent, explained Olsen, whose book on opioids with Joshua M. Sharfstein, MD, The Opioid Epidemic: What Everyone Needs to Know—is due out next month.
Methadone is only dispensed in the US through dedicated clinics, which have invasive requirements of patients, such as daily attendance.
“Because of that, there is a plateau of buprenorphine’s effectiveness,” she said. This plateau is also the main factor behind a key advantage of buprenorphine, however: its safety profile. It is far less likely to cause respiratory depression and death than full agonists.
A major regulatory problem is that methadone is only dispensed in the US through dedicated clinics or opioid treatment programs (OTPs), which have invasive requirements of patients, such as daily attendance.
While patients are given take-home prescriptions for buprenorphine right away, methadone must be dispensed and consumed (until OTP patients “earn” some “take-homes”) in the clinic.
Olsen, who runs both an OTP and a buprenorphine clinic, sees the value in the comprehensive, specialized services provided by an OTP. But the stringent regulations for OTPs—including the requirement for drug testing—are too much to ask of patients during an opioid-involved overdose crisis. Many proponents want there to be no regulations outside of basic primary care for either methadone or buprenorphine.
The Drug Addiction Treatment Act of 2000 first provided for patients to be prescribed buprenorphine by a limited number of waivered physicians. “When DATA 2000 was first passed, many methadone patients were attracted to the idea of going once a month,” said Joycelyn Woods, director of the National Alliance for Medication Assisted Recovery. Instead of going through the rigors of the OTP, they would simply pick up their buprenorphine prescription monthly from a physician.
However, patients were warned that if they needed more than 60 mg of methadone, they would not be “held” by buprenorphine, Woods told Filter. And pharmacological factors make it difficult to switch from methadone to buprenorphine (switching from buprenorphine to methadone is simpler).
Still, some patients did leave methadone and their OTP for the convenience of buprenorphine, setting the stage for their relapse. This led to years of on-again, off-again acrimony between the American Association for the Treatment of Opioid Dependence (AATOD) and the American Society of Addiction Medicine (ASAM), with AATOD on the side of methadone and OTPs, and ASAM on the side of office-based treatment with buprenorphine.
“While we advised these patients to return to methadone, we continue to receive calls from buprenorphine patients saying that they just don’t feel right,” said Woods. “Sometimes I think that perhaps they don’t believe their doctors, who tell them they should probably be taking methadone.”
That said, the thought that scares Woods the most is that buprenorphine prescribers, who unlike OTPs do not have to provide comprehensive care, are not fully informed. “I would not be surprised that some DATA 2000 practices don’t even know that buprenorphine has a ceiling.”
For methadone, “I consider 100 mg to be the higher range of the therapeutic dose range,” said Olsen. But she noted that studies show population-level, rather than individual, results, and that it’s important for clinicians to take individual characteristics into account. Some patients need higher doses still–some even more than 200 mg a day.
Asked what percentage of OUD patients need “high” doses of methadone or buprenorphine, Olsen replied, “I’m not sure anyone has a good answer to that. The people most likely to know who is getting higher doses are the payers and PDMPs [prescription drug monitoring programs].” What’s more, the people getting higher doses aren’t necessarily the same people who need them.
As for determining whether a patient needs 12 mg, 24 mg or some other daily amount of buprenorphine, clinicians theoretically face a challenge, conceded Olsen. “Addiction is a complex interaction between genetics and environment, and it also depends on the type of opioids that people are using, and the context in which their addiction is active.”
However, in practice, it’s not that difficult. “If someone is still having opioid withdrawal, or even cravings, then you titrate the buprenorphine dose up,” said Olsen. Adjusting to the optimum level should take no longer than two-to-four weeks.
“We know you’re not going to feel 100 percent, but our goal is to get you safely to a dose where you won’t have any withdrawal.”
With methadone, increasing the dose may take longer because of the risk of respiratory depression, said Olsen. Federal regulations mandate that the initial dose should be low, so it’s rarely high enough during the first few days or weeks to quell cravings.
Even though she knows 40 mg of methadone isn’t typically enough to “hold” OUD patients, Olsen said she would not be comfortable starting a patient higher. “I would need some more data on the safety of starting out with higher doses.”
But the initial lower doses will still help, and will definitely prevent the most severe withdrawal symptoms. “We get people started on a dose of methadone on day one,” said Olsen. “That 30-to-40 mg is going to help keep the edge off.”
She tells patients, “We know you’re not going to feel 100 percent, but our goal is to get you safely to a dose where you won’t have any withdrawal.” Depending on the individual, Olsen tries to reach this as quickly as possible. It may take three-to-four weeks.
“When I talk to my methadone or buprenorphine patients who are still using opioids like heroin, they’re not getting any euphoria from them,” said Olsen. “What is driving them to use are all the triggers that activate part of the limbic system”—the part of the brain that governs basic emotions and drives. “But physiologically, they aren’t getting any effects; the methadone and buprenorphine block the physiological effect.”
Prescribing 16 mg or less of buprenorphine is common practice. This is based on two studies, explained Snodgrass. One of the studies established that there is a ceiling effect for buprenorphine dose. The other determined the degree of receptor-binding at different doses.
The first study asked the question “How much do you feel the drug?” and the patients (there were only four) rated their answer along an analog scale of 0 to 70, said Snodgrass. The researchers measured the patients’ reactions to the medication for three hours; at the end of those three hours a ceiling effect was reached and there were no differences for the 8, 16 and 32 mg doses.
However, the researchers also measured the blood level of buprenorphine at different doses, for 96 hours. They found that for up to four hours, there were no differences in levels between the 16 and 32 mg doses. After those first four hours, however, the blood level for the 16 mg dose dropped precipitously, said Snodgrass; by 12 hours, there was no difference between blood levels for the 16 mg dose and the baseline of 0 mg. For the patients on 32 mg, however, blood levels remained significantly higher for up to 60 hours.
“It thus follows that 16 mg is not a high enough dose to keep us stable over a 24-hour period. It is an inadequate dose.”
“However, plasma levels after the 32 mg dose of buprenorphine remained significantly elevated in comparison to baseline up to 60 hours after drug administration,” according to the study. “At 96 hours after administration of 32 mg buprenorphine, the plasma concentrations were comparable to those produced by therapeutic maintenance doses. These observations suggest that opioid effects of extended duration may be achieved by administering high doses of buprenorphine without increased medical risk.”
Snodgrass noted that this means “yes, there was a ceiling effect but that ceiling effect was measured for only three hours.” If the researchers had continued to measure the effect over a longer period of time, “they would have seen the 8 mg and 16 mg doses drop while the 32 mg dose would have remained at that ceiling,” said Snodgrass. “It thus follows that 16 mg is not a high enough dose to keep us stable over a 24-hour period. It is an inadequate dose. But the dose of 32 mg holds us for 24 hours. We remain stable. And really, isn’t that the purpose of the medication?”
The receptor-binding study demonstrated that there were no significant differences in the binding of mu opioid receptors for 16 mg and the 32 mg doses of buprenorphine:
“Relative to placebo, BUP 16 mg reduced μOR availability 85–92%, and BUP 32 mg decreased μOR availability 94–98%. μOR binding potential of BUP at these two higher doses was more consistent across ROIs (Regions of Interest), although the thalamus showed slightly less reduction. Significant dose-dependent decreases in μOR availability were demonstrated for whole-brain estimates and all ROIs. Least square post hoc testing indicated that, for all ROIs, mean μOR availability significantly differed between all doses except for the 32 vs 16 mg comparisons (which never differed from one another).”
However, noted Snodgrass, these data were obtained four hours after administration of buprenorphine. As the ceiling-effect study showed, the blood level for 16 mg drops quickly after four hours.
In the receptor-binding study, the researchers also determined blood levels over time, and found a significant difference based on dose:
“For BUP plasma levels, there were significant effects of Dose, F(3,96)=22.48, p<0.01, and Time, F(8,96)=9.66, p<0.005, but no significant Dose × Time interaction (p<0.07).” Further: “Least squares post hoc testing indicated that mean BUP and nor-BUP plasma levels significantly differed from one another at all doses except between 2 mg and placebo.”
If the researchers had measured receptor-binding for longer than four hours, said Snodgrass, they would have most likely seen a drop in the binding at 16 mg, while the 32 mg dose would have produced more stable receptor-binding over a longer period of time.
“The primary measure of clinical efficacy is time in treatment,” said Snodgrass, noting that neither ceiling effects nor receptor-binding are measures of clinical efficacy. On the measure of time in treatment—retention—higher doses (over 16 mg) of buprenorphine provide greater clinical efficacy.
Two meta-analyses showed this. The first found:
“As with MMT [methadone maintenance treatment], there is growing evidence that higher doses of buprenorphine (16–32 mg) are more efficacious than lower doses; however, because of the pharmacology of buprenorphine, doses above 32 mg do not provide additional efficacy.”
However, this meta-analysis provides no data concerning clinical efficacy above 32 mg, noted Snodgass. “There is the assumption that because of the pharmacology there would be no advantage to higher doses.”
In the second meta-analysis, “The higher dose group used a buprenorphine dose of 16 mg or more per day. The lower dose group used a buprenorphine dose of less than 16 mg per day.” It found: “The higher dose group showed significantly better retention in treatment compared with the lower dose group (69% vs. 51%, t = 3.06, df = 19, P = .006).”
And it concluded:
“Our meta-analysis reported that the buprenorphine dose range of 16 mg or more per day is associated with significantly improved retention in buprenorphine maintenance treatment compared with lower doses. Therefore, buprenorphine dose may play an important role in improving treatment outcomes for buprenorphine maintenance treatment.”
The highest buprenorphine dose in use in the United States for OUD patients is 32 mg, said Snodgrass, and “this isn’t used enough.” He noted that in Italy, a study conducted with doses up to 56 mg of buprenorphine—the average dose was 28 mg, but the dose was titrated based on clinical response—showed a retention rate of 92 percent after 30 months. That’s far higher than has been shown for cohorts on lower doses. In one study, only 45 percent of privately insured buprenorphine patients were still in treatment after one year.
A 2015 US-based study concluded:
“Given the linear trend of higher [buprenorphine] dose related to increased retention, future studies should investigate if … doses greater than 32 mg should be considered to increase retention, and perhaps to further reduce opioid use during treatment.”
“History has taught that for about 20 years it was common to have [methadone] dose ceilings of 40 mg per day, but it is now well established that this is inadequate to maintain the necessary plasma concentrations to be effective; the effective range is between 60 mg and 120 mg or higher per day for most patients. The current study suggests the possibility of [buprenorphine] at a dose of 32 mg or higher having a potential impact on improving treatment retention and outcome. Thus, further investigations of the safety, efficacy, and clinical utilities of higher doses … should be considered.”
The bottom line, for Snodgrass, is that providers should not ignore the potential benefits of higher buprenorphine doses. “When you see a study reporting low retention rates for buprenorphine, ascertain the dose used in the study,” he urged. “I think you will find the dose used was 16 mg or less.”
As we learn more about buprenorphine, a point on which we should all agree is that adequate doses of the medication must be given if we’re serious about cutting overdose deaths. We already know enough about methadone: Doses can be adequate for all patients.