These questions concern basic aspects and issues that are generally unclear to patients. Some apply broadly to the treatment of drug dependence, while others are specific to buprenorphine (BPN). Buprenorphine is currently used under the names Subutex or Subuxone (combined with naloxone).
What is it and how does it work?
It is a chemical substance that acts on the system of “switches” (receptors) in our brain that normally serve to operate the system of “internal opioids,” or “internal morphines.” In part, it acts similarly to morphine and heroin, that is, on the same switches; in part, however, it acts in a different way. Thanks to this combination, it can be used, like methadone, in the treatment of dependence on morphine and heroin (opioids in general).
BPN binds tenaciously to a large number of receptors, and when heroin arrives, it prevents it from binding to the same switches; in other words, it is difficult to “dislodge.” While bound, it stimulates the cells.
The medication is designed to be taken sublingually. In this way, it is absorbed slowly and can be used for therapeutic purposes, something that would not be possible with other routes of administration.
Why is it used as a treatment? Isn’t it an opioid too?
It is not the opioid itself that causes drug dependence. Dependence develops because certain opioids, and through certain routes of administration, disrupt the brain’s endogenous opioid system and create a kind of permanent “gap” in opioid stimulation. The brain responds to this by keeping alive, in a violent and persistent manner, the desire to use the very substances that produced the stimulation in the first place.
This generally corresponds to an uncontrollable desire to use a substance identified as “good,” without which the person feels unable to function properly and without which the brain seems switched off and disorganized. This subjective experience does not correspond to the actual situation, in which the person is essentially disorganized all the time, but becomes agitated and desperate in the absence of the substance.
This damage does not concern the most immediately reversible part of the problem, namely so-called “physical” withdrawal. Rather, it concerns the brain signal that remains altered, together with a whole series of hormonal, psychological, and behavioral reactions. The way out constantly suggested by the brain is to resume or continue using the substance, while at the same time the same brain is desperately trying to break this bond and avoid repeating the behavior.
When this damage is to be treated, substances such as BPN or methadone are used. They do not have exactly the same type of action on the brain, but at the same time they act on the same switches, allowing them to enter the “broken” mechanism.
The essential difference is that therapeutic substances enter the brain “slowly,” so there is no peak phase—the flash, rush, or “hit,” as it is variously called—corresponding to rapid accumulation in the brain immediately after administration. By avoiding this phase, the opioid action does not risk triggering a mechanism of drug dependence.
A simple demonstration of this is the absence of spontaneous cases of opioid addiction caused by therapeutic opioids, despite their widespread use, including among people already dependent on opioids. Moreover, when people discontinue treatment, relapses occur with heroin; despite the proven efficacy of the medication, they generally do not show a tendency to resume the medication itself, demonstrating substantial neutrality toward it: it is viewed as a possible therapeutic tool, but not as a “drug.”
But doesn’t someone who receives BPN treatment for years become dependent on BPN?
A misunderstanding about the nature of dependence arises from the word itself, which obviously does not simply mean “to depend on,” but is shorthand for “drug dependence”: being tied to a toxic substance through uncontrolled behavior.
A person with drug dependence does not simply “depend on the drug.” The drug is merely the thing that causes harm but toward which the person is driven by their own brain, as a consequence of damage that does not tend to repair itself adequately. The drug caused the damage, so to speak, but the dependence maintains itself.
Someone who depends on the therapeutic effect of BPN obviously becomes a patient who depends on a medication to maintain a state of health and avoid experiencing the disease. Since there are currently no definitive cures for drug dependence that allow a person to stop needing treatment within a short period of time, “depending” on treatment should be regarded as fortunate rather than problematic.
It would be more accurate to say that one can “rely on” an effect that is not random but “depends” on the treatment, and that continues to depend on the treatment even after years—which is fortunate, because the effect does not wear off over time.
Is treatment with BPN different from treatment with methadone?
Absolutely not. The principle on which the treatment is based is the same: creating and maintaining the conditions that allow the person to rehabilitate and preserve this state of personal and social balance, while gradually eliminating the compulsive desire to use heroin.
In both cases, this objective is achieved by reducing the desire to “get high” and by blocking the effects of doses that may nevertheless continue to be taken in the meantime.
In practice, it is a pincer movement between “not feeling” the drug and “not wanting to use,” which brings the person’s brain back to a condition of freedom and control over their behavior.
The new feature of BPN is that, in addition to treating withdrawal and reducing the desire to use, it also “blocks” the effects of heroin. So, if the person no longer feels heroin, this is extremely important for stopping use. Is that true?
BPN does have this property, but it is not a new development. Methadone at doses above 60 mg does exactly the same thing. “Narcotic blockade” is a therapeutic technique that dates back approximately forty years.
The particular feature of BPN is that it produces blockade already at the initial doses, that is, those usually required to suppress full withdrawal. This does not happen with methadone, which produces blockade but only above the doses—approximately 10–60 mg—usually sufficient to “cover” withdrawal.
This blockade depends on the fact that with 8 mg of BPN, a large proportion of the “switches” involved in heroin action have already been occupied by the medication, so that at around 16 mg the blockade is almost complete.
This relationship between dose and the number of switches already “blocked” means that above a certain dose—16 mg—increasing the dose no longer produces an increase in opioid effect, and above 32 mg the blockade itself is already complete.
Receptor blockade over time can improve outcomes, provided that the initial results have already been positive. In other words, heroin use that has already decreased tends to decrease further after the first few weeks if the doses are sufficient to produce complete receptor blockade.
Is BPN therefore an agonist or an antagonist?
All opioids can act as “antagonists” of other opioids at certain doses. In the tug-of-war between two substances, the one that occupies the positions in the brain more tenaciously wins, preventing the other from occupying them and producing its effects.
There are “pure” antagonists, which do nothing other than this and do not themselves produce opioid effects, such as naltrexone.
BPN, however, produces its own effect while occupying these positions, and is therefore an agonist. It is called a partial agonist because it is less potent than methadone, for example. Thus, once it has occupied all the positions available to it, it produces a maximum effect that is nevertheless limited compared with the maximum effect that methadone can produce.
Why is it said that taking BPN can precipitate withdrawal? How is that possible?
The effect of any substance that acts on opioid receptors depends on the conditions existing at that moment: whether the person is tolerant and, if so, to what degree.
Someone who regularly takes methadone at moderate doses, or large quantities of heroin (grams) and is tolerant, can develop withdrawal after taking a dose of BPN.
BPN immediately binds to a large number of opioid “switches,” including those already occupied by heroin or methadone, and “dislodges” them. The difference is that the effect BPN produces is weaker, so the person suddenly moves into a state of “decrease.”
It is somewhat like replacing iron weights on one side of a scale with feathers.
In some cases of intoxication in which a person was already accustomed to lower doses, BPN can theoretically dislodge methadone, partially replacing its effect and thereby avoiding the need to treat the intoxication while nevertheless precipitating acute withdrawal, as a large dose of a pure antagonist such as Narcan would.
Is BPN easier to discontinue? What is its real advantage over methadone?
There is no need for a medication that is easy to discontinue; rather, what is needed is a medication that is better tolerated and safer.
The true advantages of BPN over methadone, at equivalent efficacy, are fewer side effects and a lower risk of fatal overdose, at least in people who take it regularly.
If someone is accustomed to a dose of 8–16 mg, taking a higher dose does not produce greater opioid effects. Instead, it produces a longer-lasting blockade because the medication accumulates while waiting to be eliminated, thereby prolonging its antagonist effect.
Could everyone taking methadone switch to BPN?
The issue is one of efficacy.
BPN works up to a certain level of potency because it is intrinsically less powerful. However, because it binds very effectively to brain receptors, it occupies many of them and therefore produces a good opioid effect. Good, but limited.
Methadone binds less effectively but is more potent once bound. Therefore, increasing the dose increases the number of receptors “recruited” and increases the effect, up to doses of several hundred milligrams.
In practice, someone who does not respond well to 16 mg of BPN should not expect an immediate reduction in craving simply by increasing the dose. Someone who does not respond to 100 mg of methadone, however, may experience this effect by gradually increasing the dose to 200, 300 mg, and so forth.
In theory, 8–16 mg of BPN are comparable in efficacy to 60–80 mg of methadone.
It should be kept in mind that the majority of people with opioid dependence respond to a methadone dose of approximately 100 mg, and therefore this majority would not, at least initially, respond equally well to a full dose of BPN.
An absolutely incorrect procedure is to reduce the methadone dose in order to start BPN, because this means moving to a less effective treatment—whether the less effective treatment is methadone or BPN makes little difference.
Some people believe that the blocking effect of BPN compensates, in terms of efficacy, for the stronger dose of methadone. This is incorrect reasoning: as we have seen, methadone also produces a blocking effect, so there is no need to create it by using another medication.
Rather, people taking moderate-to-low doses of methadone may gain this additional effect by switching to BPN—for example, by moving from 60 mg of methadone to 16 mg of BPN. Methadone produces blockade above approximately 60 mg, whereas BPN already does so at 8 mg.
In conclusion, the question to ask is: if, at equivalent doses—and therefore presumably equivalent efficacy—there are advantages to switching from one medication to the other, is the switch appropriate? Otherwise, it makes no sense.
Why is BPN chosen for some people and not for others?
In general, it is known that people with less severe dependence and better social functioning respond to lower doses, and therefore BPN can be selected for them from the outset.
Moreover, choosing BPN also produces substantial opioid blockade, which would not occur with doses of approximately 60 mg of methadone or less.
This reasoning is theoretical, however. If it does not correspond to what happens in practice—if the person does not respond adequately to a full dose of BPN—then treatment will obviously be switched to the other option, theoretically more effective because it is also suitable for moderate-to-severe cases.
If the person responds well to BPN, its ultimate advantage over an equally effective methadone treatment lies in its side-effect profile and the corresponding quality of life.
Why is it taken sublingually? Is it true that it can also be injected as a drug?
It is taken sublingually because, if taken normally by mouth and swallowed, it produces almost no effect because the liver filters it out.
Under the tongue, it does not immediately pass through the liver and reaches the brain, where it is distributed.
If it is reduced to powder, dissolved, and injected, it becomes something resembling morphine, with the same risks, including the potential to produce drug dependence, at least in people who were not already dependent.
For this reason, BPN is being replaced in many settings by Subuxone, a formulation that is less suitable for this type of misuse.
Because of a particular feature of its composition, Subuxone continues to work when taken sublingually, whereas it does not work properly when injected. Naloxone is mixed with BPN—hence the name—and when it enters gradually it does not interfere with BPN’s effects (as occurs with sublingual administration). When it enters rapidly, however, it temporarily occupies the receptors and eliminates the immediate effect.
A delayed effect is still produced, but this is of little interest to someone attempting to use the medication as a drug.
Is a BPN overdose possible?
Overdose is possible, particularly in people who are not tolerant, that is, people who are not regularly using heroin and are not receiving methadone maintenance treatment.
This occurs through the same mechanism as with methadone, namely accumulation during the first few days. It is therefore not the “immediate” overdose associated with rapid substances such as heroin, which either occurs immediately or does not.
BPN overdose may occur after the first few days, preceded by episodes of prolonged or profound sleep—practically a coma—and by states of sedation or confusion, sometimes characterized by behavior oscillating between drowsiness and agitation.
The critical period can last for many hours. Even if the person is still breathing or can be awakened, a doctor should be called or the person should be taken to an emergency department because the condition may worsen, leading to coma and respiratory arrest.
Naloxone (NARCAN) is generally ineffective, at least at usual doses, because it is not strong enough to displace BPN from the receptors.
Among opioid overdoses, this is one of the more difficult situations to treat. However, it is much less likely to occur because the opioid effect of BPN does not increase as the dose rises beyond approximately 16 mg: there is a “ceiling” effect because the receptors are already occupied.
Obviously, BPN administered intravenously produces more rapid effects. Depending on the circumstances, these may range from withdrawal in someone tolerant to stronger or high-dose opioids, to fatal overdose in someone who is not tolerant or only minimally tolerant, similarly to what could occur with heroin.
Is there a risk in combining BPN with other substances?
Yes, there is a risk.
In particular, tranquilizers and alcohol can make BPN more potent and therefore make overdose much more dangerous than it would otherwise be.
What happens if someone “mixes” methadone and BPN?
It is a poorly controllable combination.
Initially, the person may feel nothing because methadone does not bind to receptors already occupied by BPN. However, it remains in the system, and when BPN leaves, methadone can occupy those receptors and produce an effect depending on the dose. This can therefore result in a delayed overdose.
Is BPN or methadone preferable as a first attempt in someone who has never tried either?
There are different approaches.
Broadly speaking, someone who tries BPN and responds well may experience fewer side effects, and initial safety is greater with BPN. However, the probability of achieving a successful outcome, regardless of the severity of the case, is greater with methadone.
Initial results with BPN may improve over time because the more pronounced “antagonist” effect that develops over time can refine an already positive initial response.
Methadone, when maintained for weeks at moderate-to-low doses out of necessity or caution, may be “overcome” by more substantial doses of heroin, thereby interfering with the therapeutic effect.
Either medication can be used as an initial treatment, always under medical supervision.
If the physician is more concerned about protecting a patient whose apparent severity seems limited but may actually be substantial, treatment will begin with methadone and may subsequently be switched to an equivalent dose of BPN, if an equivalent dose exists.
Alternatively, the physician may begin with BPN, which is often more acceptable to the patient because it conflicts less with their preconceptions, despite being substantially similar to the other treatment.
Conclusion
In conclusion, these are the two most effective treatment regimens for opioid dependence.
In the hands of a physician, they constitute medical treatment. In the hands of a patient, when obtained on the street or passed illegally from one person with opioid dependence to another, they instead become a means of continuing the dependence with less harm to the individual, but with greater risks of intoxication.