by Mark S. Gold, M.D., Professor, Washington University School of Medicine – Department of Psychiatry
Opioid use disorder (OUD) is a chronic, relapsing, and acquired disease. Opioid use stimulates it’s own taking until loss of control and continued use cause numerous consequences. OUD is often associated with loss of life, employment, relationships, and health. We are in an opioid overdose, opioid use, and opioid dependence epidemic.
While we often focus on reducing overdose and reversing those overdoses that occur, many overdoses are patients with OUDs who are not in treatment. Medication for Addiction Treatment (MAT) and opioid use disorder treatment programs are essential parts of our response to overdose initiatives .
Deaths from overdose are increasing during the covid19 crisis as EMTs, Emergency Rooms, and General Hospitals are inundated with COVID cases, and people with OUDs are staying away. 47,600 people died from drug overdoses involving opioids in 2017.
Between 2012 and 2018, the number of fentanyl-induced fatal overdoses rose dramatically, accounting for a majority of overdose deaths. We have moved from a prescription opioid to heroin and now are in a fentanyl crisis. Centers for Disease Control data show that fentanyl is still the primary cause of fatal overdoses.
Patients who think that they bought heroin are surprised to learn that it was all or partially fentanyl. While treatments have improved, many patients treated in medications for addiction treatment (MAT) programs or health providers’ offices with MAT often relapse.
The first sign of a slip or relapse may be a change in schedule, missed clinic appointments, missed group, or individual counseling. But, today, without actual visits, patients may just slip and overdose. Some patients cease their MAT course, and others drop out of treatment altogether.
We are improving access to treatment and OUD treatment options and outcomes. But, we do lack, for example, prospective, long-term, oncology-like, 5-year studies on the subject.
The prestigious American Society of Addiction Medicine (ASAM) has recently updated its guidelines for the treatment of OUDs . The use of MATs has been studied for years, and they do a very good job at bringing the practice of Addiction Medicine up to date with this publication ( The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update. J Addict Med. 2020;14(2S Suppl 1):1-91. doi:10.1097/ADM.0000000000000633 ).
We know the use of MATs lower the risk of fatal overdoses by approximately 50% . Right places to start MATs are anywhere we find a patient looking for treatment, whether in the emergency department or the physician’s office.
The guidelines help everyone understand that location of treatment is less relevant than starting treatment in a licensed program or clinician primary care or another prescriber. More primary care physicians need to become “waivered” to prescribe this medication, which requires some training and an exclusive license.
Opioid Use Disorders and Buprenorphine
Luckily we have more than one MAT option for patients with OUDs. When I was in training at Yale, we had methadone (a full opioid agonist) . Since the 1970s, we have added to the list of safe and effective MATs for OUD:
Buprenorphine (a partial agonist)
Buprenorphine plus Naloxone (Suboxone)
Naltrexone (an opioid antagonist)
We will focus in this article on Buprenorphine. Buprenorphine is a partial agonist at an opioid receptor that neuroscientists call the mu-opioid receptor. What makes it unique is that it has a very high affinity for this mu receptor, making it an opioid blocker by competing and displacing heroin or fentanyl or other full opioid agonists.
This high affinity means that Buprenorphine is difficult (but not impossible) to dislodge from the mu-opioid receptor. This tight binding or high affinity helps to explain its ability to block the subjective and physiological effects of heroin or other opioids.
Its high affinity is also the primary reason that Buprenorphine can precipitate withdrawal when given to individuals physically dependent on opioids. This blockade of the mu-opioid receptor by Buprenorphine is not absolute and with difficulty can be overcome by higher doses of heroin or with more potent mu opioids, like fentanyl.
On the one hand, the goal of clinical treatment is to engage the patient with OUD and start a MAT as soon as possible. On the other hand, giving a dose can cause opioid withdrawal. So, we usually wait to administer Buprenorphine until signs of opioid withdrawal emerge.
In this way, it is like giving clonidine for detoxification. Thus, the most common way we start buprenorphine induction is to wait and follow the signs, symptoms, and ratings for opioid withdrawal.
Buprenorphine at dose >8 mg/day has been reported to suppress opioid withdrawal for 24 hours in opioid-dependent subjects. However, to contain the use of illicit opioids during treatment, higher doses of Buprenorphine are more effective.
Buprenorphine doses >16 mg/day were more effective than doses <16 mg at retaining subjects in treatment. Buprenorphine binds to opioid receptors, producing prompt blockade of other opioids. Buprenorphine has what we call low intrinsic activity resulting in less euphoria and lower diversion potential than other mu agonists. Buprenorphine is a partial agonist and simply cannot produce a 100% response like a full agonist (i.e., fentanyl) can.
Buprenorphine still has intrinsic reinforcing effects as a partial agonist and can be misused and diverted. Accidental use of Buprenorphine can result in an overdose or death among children and young adults who take it by accident.
Buprenorphine has a street value and is bartered and sold. So, the intentional diversion of Buprenorphine is not uncommon. Sometimes it is taken to self-treat opioid withdrawal symptoms, but, clearly, other times, it is taken for recreational use.
Injected Buprenorphine became the primary drug of abuse  in France. Suboxone, a combination of Buprenorphine and Naloxone, decreases diversion and intravenous use. The rationale is that Naloxone taken orally or sublingually has only low bioavailability.
In contrast, if the medication is crushed up and then injected, Naloxone attenuates the opioid agonist effect and precipitates withdrawal in people dependent on opioids. The effectiveness of the combination buprenorphine-naloxone combination in deterring intravenous misuse is debated.
But, it appears that adding Naloxone reduces but does not abolish, intravenous abuse. Pain management providers prescribe Buprenorphine without Naloxone and also, can be given for OUDs but only in sublingual film or tablet form. Except in pregnancy or very severe liver impairment, prescription of isolated Buprenorphine is discouraged, given the potential for intravenous abuse.
Suboxone is the trade name for Buprenorphine combined with Naloxone, an opioid antagonist. It is one of the primary drugs used for medication-assisted therapy (MAT) for OUDs and the most commonly prescribed.
Subutex was the first version of Buprenorphine to be prescribed as a MAT for opioid dependence. Suboxone is a combination of buprenorphine/naloxone in a sublingual film preparation. Suboxone is available in many different forms, including sublingual tablets (generic) or film which dissolves under the tongue.
There are generic alternatives as well as various brand names, including Zubsolv (buprenorphine and naloxone) sublingual tablets and Bunavail film (buprenorphine and naloxone) buccal film. This Buprenorphine formulation has the highest potential for diversion of all formulations .
Suboxone works by tightly binding to the same receptors in the brain as heroin, morphine, and oxycodone. In one way, it is providing a replacement. Still, it also blunts intoxication with these other opioid drugs, prevents opioid cravings, and it allows many people the time to get additional treatment and make changes to a life of relative normalcy and safety.
Return to premorbid or pre-OUD function is possible. A key goal of Addiction Medicine experts is to work to make Suboxone much more widely available. Suboxone is an opiate medication and, of course, can be abused.
It is not commonly abused and not like heroin or oxycodone or fentanyl. That is because it is only a “partial” agonist of the mu or primary euphoria or opioid receptor. It is difficult to overdose on Suboxone alone.
Compared to other opioids, Suboxone is much less likely to slow breathing. When people do overdose on Suboxone, it is due to polydrug use– mixing Suboxone with alcohol or sleeping pills or anxiolytic sedatives such as benzodiazepines, medicines.
FDA-approved buprenorphine products approved for the treatment of opioid dependence include :
Bunavail (Buprenorphine and Naloxone) buccal film
Cassipa (Buprenorphine and Naloxone) sublingual film
Probuphine (Buprenorphine) implant for subdermal administration
Sublocade (Buprenorphine extended‐release) injection for subcutaneous use
Suboxone (Buprenorphine and Naloxone) sublingual film for sublingual or buccal use, or sublingual tablet.
Subutex (Buprenorphine) sublingual tablet
Zubsolv (Buprenorphine and Naloxone) sublingual tablets
ASAM recommends Buprenorphine for patients with OUD-opioid use disorder, who are able to give informed consent and have no specific contraindication for this treatment .
Opioid Use Disorders- Buprenorphine, Suboxone, and New Buprenorphine Formulations
While experts recognize that alcoholics anonymous and other primarily psychosocial treatments are treatments of choice for alcohol use disorders, OUDs treatment outcomes and priorities are different. Psychosocial interventions, so essential to alcohol use disorder treatment, do not address the early goals of craving reduction, withdrawal reversal, and overdose protection. Patients with OUD are thinking about withdrawal distress and getting opioids. In most cases, it is MAT first and second.
When overdose reversal or an emergency room crisis brings an OUD patient an opportunity for treatment, we try to initiate it there on the spot. Efficacy of MATs in this OUD treatments, and thus making evidence-based OUD treatments more accessible is urgent.
Psychosocial interventions alone are difficult to manage for both the OUD patient and physician. When a MAT is added to these interventions, opioid use and relapses are decreased.
Compared with psychosocial intervention alone or placebo, researchers have shown that MATs reduce opioid use, overdose, morbidity, and mortality. Adherence to OUD medications reduces relapse and overdose risk.
Going to the treatment program, counseling and group, having urine drug tests, and taking MAT medications are core components of effective OUD treatment. It starts with and can be as simple as following the post-evaluation treatment plan.
Buprenorphine and Buprenorphine + Naloxone works and is also safe as a first-line MAT. Rarely, do we hear of someone who is taking their Buprenorphine as prescribed, dying of an opioid overdose. Buprenorphine overdose is rare.
However, considerable diversion of oral and transmucosal opioid maintenance medications has been documented. Delivery systems that reduce risks of nonadherence through diversion or altered self-administration may increase Buprenorphine’s effectiveness for clinical stabilization via increased treatment exposure.
Some alternatives to treatment, for OUD patients, can be hazardous. Discontinuation of MAT, dropping out of a treatment program, or detoxification from opioids carries a significant risk of relapse. MATretention in OUD treatment with FDA-approved medications, such as methadone or Buprenorphine, reduces both all-cause and overdose mortality, and patients who are adherent to medications for OUD use cumulatively fewer illicit opioids.
Therefore, medication adherence is a critical factor in buprenorphine treatment outcomes. However, prescribed sublingual or buccal doses are under the patient’s control, and the decision for dosing each day is subject to changes in motivation, mood, and stress or changes in medication access, in the case either of theft or of being distant from the place where one’s medications are stored.
Buprenorphine, Approved for clinical use in 2002 by the Food and Drug Administration (FDA), in combination with counseling and behavioral therapies, is safe and effective, especially when given as part of a whole-patient approach to the treatment of OUD. When taken as prescribed, the FDA has concluded that Buprenorphine is safe and effective.
Unlike a methadone treatment program, licensed for methadone and located in a specific clinic, Buprenorphine can be prescribed in physician offices, significantly increasing treatment access. Buprenorphine can be given after overdose reversal and in the Hospital Emergency Department.
In general, we recommend waiting two hours after a naloxone reversal to ask the patient to answer the questions on the Clinical Opioid Withdrawal Scale (COWS). The COWS score allows you to pick a dose, treat, and follow according to withdrawal severity.
Remember, too, that it makes sense to always ask about and test for methadone. If the individual has methadone in their system, waiting longer before giving Suboxone is logical. Treatment of withdrawal with Suboxone should be followed over time with the COWS, and marked improvement in withdrawal symptoms should occur within 20 to 30 minutes of buprenorphine dose administration.
The E.D. should be critical to the successful treatment of OUDs. E.D. experts are bundling assessment of opioid use disorder (OUD), administering Buprenorphine, counseling regarding overdose, naloxone distribution, providing buprenorphine treatment, and providing an OTP referral for patients with OUDs.
Three Phases of Buprenorphine Treatment:
The Induction Phase is the medical initiation of buprenorphine treatment. Phase 1 usually begins with a visit to a qualified physician’s office or certified OTP using approved buprenorphine products.
Buprenorphine is administered to a person with a diagnosis of an OUD and who is in the early stages of opioid withdrawal. We try to give it to people who have abstained from using opioids for 12 to 24 hours.
Buprenorphine can also cause acute withdrawal in those patients. It is not generally a problem but can be avoided by giving Buprenorphine to patients who are in the early stages of withdrawal and who do not have methadone or other opioids in their bodies. The clinician documents the objective signs of withdrawal and begins treatment with a dose of 2 to 4 mg buprenorphine. This initial dose may be increased in increments of 2 to 8 mg.
The Stabilization Phase begins after an OUD patient has successfully discontinued or significantly reduced their opioid use, no longer has opioid cravings, and is described as stable and without side effects. The buprenorphine dose may need to be individualized during this stabilization phase.
Following initiation, the buprenorphine dose is titrated to alleviate symptoms. Clinical evidence suggests that 16mg per day is more effective than lower doses. We do not generally use doses higher than 24mg per day as there is little evidence that they improve outcomes, and higher doses may increase the risk of diversion .
The Maintenance Phase is defined by the patient being stable, doing well on a steady dose of Buprenorphine, and is starting to be able to think about their life, goals, and engage in treatment . There is no ideal length of time for the maintenance phase. Rather than an absolute time, the best guidance is to individualize treatment and consider as long as possible as the ideal.
The treatment works but must be initiated. Many patients who have been rescued from an overdose are not given a MAT . It may be worthwhile to consider starting Buprenorphine and asking  what is the worst thing that could happen” after giving a patient Buprenorphine?
Not recognizing that: The patient has other opioids on board that will be displaced from the receptors by Buprenorphine, and you can precipitate severe withdrawal . ASAM’s newest guidelines recommend that Buprenorphine should not be initiated until there are objective signs of opioid withdrawal, as this method reduces the risk of precipitated withdrawal .
Another possibility was that the patient was experimenting with opioids and did not meet the criteria for an opioid use disorder. Physicians can receive Buprenorphine training and waiver through The American Society of Addiction Medicine, which offers this training curriculum . Treatment of OUDs is most effective in combination with counseling and psychiatric services, which can include different forms of behavioral therapy, medications, and self-help programs.
In the United States, the treatment of opioid dependence with medications is governed by the Certification of Opioid Treatment Programs, 42 Code of Federal Regulations (CFR) 8. This regulation created a system to accredit and certify opioid treatment programs (OTPs).
OTPs provide medication-assisted treatment (MAT) for people diagnosed with an opioid-use disorder. MAT patients also must receive counseling, which can include different forms of behavioral therapy.
All of the behavioral health, psychiatric, and addiction medication-assisted treatment is limited by lack of insurance parity, access, and stigma. The ability to get Buprenorphine from your physician or health professionals is by itself de-stigmatizing.
The properties of the medication also reduce diversion and concern that we are not treating the OUD but rather replacing one opioid with another. Buprenorphine is available in many formulations. But, the most common formulation prescribed of Buprenorphine and Naloxone (Suboxone) is in a 4:1 ratio of agonist: antagonist.
As an opioid antagonist with high first-pass hepatic metabolism, Naloxone does not affect the sublingual use of Buprenorphine but blocks intravenous or intranasal abuse of Buprenorphine. Reducing deaths, overdoses, drive for opioids, and stabilizing the OUD to the point that counseling and therapy can progress, has increased acceptance of Buprenorphine as being treatment and solution, rather than being part of the problem.
In seeking to respond to the opioid crisis and OUD, we have tried to lower barriers to treatment and use digital and telephone tele-addiction medicine. Other options, including changing the laws around methadone to expand access, have also proposed by MAT experts .
Diversion and Abuse of Buprenorphine
Buprenorphine and Buprenorphine+Naloxone are opioids, and diversion can and does happen. Diverted Buprenorphine has less street value, is less reinforcing than diverted full agonist opioids that cause greater euphoria, respiratory depression, and overdose.
Buprenorphine’s opioid effects are still appealing to users who do not have an opioid dependency . Suboxone takes Buprenorphine and adds Naloxone to decrease the likelihood of street sales and diversion, but intravenous abuse occurs.
SUD patients know that sublingual tablets can be crushed and injected. Usually, the naloxone effect dominates and can block the euphoric effect. But, the blockade is only relevant up to a point.
For abusers with OUDs, intravenous use can bring on opiate withdrawal symptoms. Still, this is not commonly the reason for buying buprenorphine or buprenorphine + naloxone on the street.
Cicero and others have shown that people buying diverted Buprenorphine are usually trying to self-medicate , prevent opioid withdrawal, and not generally trying to experience euphoria. According to ASAM’s recent guidelines, clinicians should take steps to keep vigilant and reduce the chance of buprenorphine diversion when possible.
Recommended strategies must be tempered by COVID 19 realities. But, generally, diversion reduction strategies suggested by ASAM are: include frequent office visits (e.g., weekly in early treatment); drug testing, including testing for Buprenorphine and metabolites; and recall visits for medication counts .
Length of Time in Treatment and Detoxification
According to ASAM’s new OUD treatment guidelines , treatment duration should be as long as possible or needed. Some patients may want to transition to an injectable or to injectable Naltrexone.
Buprenorphine taper and discontinuation can be perceived as too slow by some patients, but it is actually a slow process with close monitoring over months. Patients who discontinue buprenorphine treatment like those who leave the treatment program should be made aware of the increased risk of death if they return to illicit opioid use.
Patients should be encouraged to remain in treatment if possible, to prevent slips, relapses, and overdoses. It is generally a good idea to aspire to have a program-wide follow-up plan for all patients in residential or outpatient treatment for an OUD to have ongoing monitoring for a year past the point of discontinuation.
Addiction Medicine has made significant progress in developing evidence-based treatments for OUDs, opioid overdose, and rescues. MAT treatment works and saves lives.
Sadly, OUDs and opioid overdose and deaths of despair have increased and brought much-needed attention to the evaluation and treatment of OUDs. Treatments include EMT and community treatment for an overdose with naloxone-Narcan, and evidence-based treatment of OUD with Buprenorphine, buprenorphine-naloxone, methadone, and naltrexone .
MATs are now an essential part of an intensive residential or outpatient programs. They are also the central part of the treatment in methadone or OTPs. All of the MATs have a role in the treatment, and throughout a patient with an OUD’s life, several different medicines may be indicated.
Our work in the laboratory  suggested that Buprenorphine would be an ideal MAT for fentanyl use disorders and withdrawal. Unfortunately, patients with OUD often come into treatment in an emergency. They have numerous emergencies, emergency room treatment, and inpatient and outpatient treatments.
Doing an evaluation and treating the co-morbidity helps. That means providing medications plus medical, infectious, family, vocational, preventative, psychological, and psychiatric services. Fewer survivors of opioid overdose find treatment than we would like.
This may be partially explained by well-documented challenges of oral rather than extended-release injectable MATs. While beyond the scope of this review on Buprenorphine, injectable, and long-acting Buprenorphine.
Probuphine (Buprenorphine) implant for subdermal administration and Sublocade (buprenorphine extended‐release) injection for subcutaneous use are long-acting alternatives that can be used in stable patients. Buprenorphine is prescribed more than other MAT treatments for OUD.
But, that does not mean that only Buprenorphine or Buprenorphine + Naloxone is a logical choice for a particular patient. Patients with OUD have a chronic and relapsing life-long disease for which we do not have a cure.
But, which treatment is best for which person, is not well understood. We also do not pay much attention to treatment resistance  and offer the same treatment approach, many times to the same person, even though they relapsed.
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Dr. Mark S. Gold is a teacher of the year, translational researcher, author, mentor and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine and food.
This blog post was originally published by Addiction Hope. Addiction Hope supports and brings hope to its vibrant online community through education and resources. It promotes ending addictive behavior, developing healthier coping skills and living a value-driven life of health and well-being.