Tox and Hound – We Have A MOUD* Disorder

by Howard Greller

A 37-year-old man with a history of asthma and hypothyroidism presents to your emergency department complaining that he hasn’t been feeling well for a few days. He reports having chills, nausea without vomiting, some loose stool, diffuse body aches, some rhinorrhea, and feeling ill at ease. In your detailed history, it is revealed that the patient has an alcohol use disorder, drinking upwards of a liter of vodka a day, and hasn’t had a drink since the onset of illness. His vital signs are T 99.6°F, HR 105, BP 137/63, RR 12, O2 sat 99% RA. Your exam reveals a thin, tired appearing anxious male. His exam is notable for mild diaphoresis, some clear rhinorrhea, slight mydriasis, and visible tremor. Labs are unrevealing and his rapid flu swab is negative. Your diagnosis is a viral illness that has precipitated alcohol withdrawal. You give him some analgesia, fluids, and your benzodiazepine of choice.

Take a moment. This is a case that is probably playing out as you read this, across hundreds of emergency departments around the country. In your mind, was there any hesitation about giving the benzodiazepine? Now, take the same patient, and change one line:

In your detailed history, it is revealed that the patient has an opioid use disorder, using upwards of a bundle of heroin a day intranasally, and hasn’t used since the onset of illness.

Would you do anything differently? What would you give this patient? Would you have any hesitation to provide this patient with therapy for their opioid withdrawal? Would you opt for an inferior agent like clonidine (or the markedly more expensive lofexidine), in the hope that the theoretical co-localization of imidazoline and mu-opioid receptors (MOR) will somehow magically make the patient better?^​1​

Why wouldn’t you give them buprenorphine (Bup)?

How I Stopped Worrying and Learned to Love the Bup

Benzodiazepines, as indirect GABA agonists, are an incomplete solution to the ETOH withdrawal problem (I have never written a more difficult sentence in my entire life). They work in most cases and are definitely first-line agents, but they fail to address both sides of the neurotransmitter imbalance in this scenario (essentially, diminished GABA and increased glutamate). They’re the best choice that we have because the “ideal” agent, ethanol, is really difficult to administer properly, with a number of unintended consequences, including inducing its own metabolism and making the patient intoxicated.

Unlike benzos for ETOH, there IS a complete, all-in-one pharmacologic solution for opioid withdrawal. Enter buprenorphine. Bup is an agent that directly addresses the issue of opioid withdrawal by directly working on the same receptor as the offending opioid. Bup has a few pharmacokinetic properties that make it ideal for use in opioid withdrawal. First, it is a partial agonist, which means that it binds very well, but only partially activates the receptor (although for analgesia, it may be a full agonist, which is kinda cool).^​2​ So, at low doses it acts kinda like a full agonist. But as you increase the dose, you reach a plateau above which there is no further activation of the receptor. This makes it far safer than using a full agonist like methadone. It also has a long half-life, typically allowing for once-daily dosing. And finally, it has a very high affinity for the mu-opioid receptor (MOR), higher than most opioids, meaning that it can block full agonists from doing their thing. This pharmacokinetic profile creates a margin of safety, namely a ceiling effect for respiratory depression (of course, when not combined with another respiratory depressant, like a benzo), and protection from competition by full agonists. With Bup, you treat the acute withdrawal symptoms, diminish craving (which is the intangible variable that leads to most of the negative behaviors associated with addiction), and provide a margin of safety regarding the most concerning toxicity with these agents (respiratory depression or use of another agent). That not good enough for you? It also allows people to function normally without the troublesome sedation that accompanies a full agonist like methadone.^​3​

There are really only two challenges to using it. First, the patient has to want it. Build rapport with your patients and ask them if they want it. Like asking their preferred pronouns. The second challenge is based on its pharmacokinetics. If you give a low dose to someone who still has a full agonist onboard, Bup will displace that opioid, leading to precipitated withdrawal. The good news is that most of the time, for this scenario, you can just give more Bup to treat them. It is important to note that the combination product that contains buprenorphine and naloxone (e.g., Suboxone™) is NOT the cause of this withdrawal. The naloxone in that product is not orally bioavailable and is there just to prevent diversion and intravenous use.

So we have two types of treatments. One, benzos, provides incomplete protection against withdrawal and is widely used by EM physicians. And the other, Bup, offers complete protection but is rarely used by EM physicians. Why do we have an issue with one kind of substitution over another, especially when one option is even more suitable? Now I know you have no issue, but this is a problematic scenario across a Nation that continues to lose lives to a preventable cause of death at a rate that is greater than the peak of the AIDS crisis. Let’s explore some of the (flawed) reasoning behind not using buprenorphine for opioid withdrawal.

Opioid withdrawal isn’t fatal, so what?

This is a false dichotomy. Sure, the underlying physiology between different withdrawal states leads to some having more acute risks than others. But that is certainly not an argument for ONLY treating potential life threats. This is one of the most disturbing arguments that I hear made. There are countless conditions that are “not fatal”, that we hand out treatment like Halloween candy for, even in the face of poor therapeutic efficacy. How many times in the last week have you given someone a “muscle relaxer” or a decongestant? Were they going to die of their low back strain or nasal congestion? Of course not. Did you hesitate to treat them? Again, of course not. And those that view substance use disorders as self-inflicted harms or a “moral failing” that don’t “deserve” treatment make my blood boil. Because, you know, that’s different from all the other well thought out, rational, good decisions that lead people to use the emergency department . . . Imagine a scenario where we said – “Sorry, you didn’t use your seatbelt, so those rib fractures you got from your MVC? Too f’in bad – no analgesia for you – maybe when you’re miserable at home it’ll remind you to wear your seat belt next time.” Love to see those Press Gainey scores . . .

There are multiple harms associated with addiction. There are the direct harms from use, such as overdose and its consequences (e.g., hospitalization, intubation, iatrogenesis, etc.). There are the harms associated with use, such as injection-related complications like skin and soft tissue infections, thrombophlebitis, and endocarditis, infectious diseases (e.g., hepatitis, HIV, etc.) And then the societal harms related to obtaining the drugs, such as behavioral issues, crime, and poverty. To not treat someone with an OUD is to perpetuate those harms.

Having someone leave your emergency department without an intervention for their OUD can be deadly. There have been a number of recent studies that show that patients that present to the emergency department for a substance-related encounter are at high-risk of subsequent overdose death, one showing a 6-fold fatality rate greater than the general ED population. The study by Weiner et al. showed that both the short term and at one-year mortality (5.5%) of patients treated for a non-fatal overdose was high. Of those who died (635 patients), a significant number occurred within the first month (20.5% – 130 patients), and with the highest risk period being within the first two days (4.6% – 29 patients) post-discharge.^​4,5​ Name any condition where you would feel comfortable discharging a patient without therapy or follow up with a risk of dying a preventable death within 48 hours that is that high. I’ll wait here.

But . . . they need . . .

1. . . . to do this in a monitored hospital setting / detox / rehab facility.
   Actually, no. There is good evidence that this (including the induction itself) can be done, with the right patient, at home. The COWS score is an easy to administer gauge of withdrawal severity.^​6,7​ Honestly, the patients that need this are very likely much better at gauging their withdrawal severity than we are . . . Detox (loosely and frequently defined as behavioral therapy, often without medication) and rehab are not treatment. In fact, they often lead to a loss of tolerance and an increase in overdose mortality after completion of inpatient opioid detox.^​8,9​ People that participate in a rehab program are very likely to relapse as well, and many will die.^​9,10​
2. . . . only a short course of this.
   No, again. This is a chronic illness in which complete abstinence is uncommon (AKA “iterative relapse”). Once we stop clinically shaming patients, use appropriate patient-centered language, and start treating OUD like other chronic diseases (e.g., HTN and diabetes), our mindset will change. Bup is thyroid hormone replacement, not treatment for otitis media.^​11​
3. . . . counseling.
   Provide it if you have it, and the patient wants it. Behavioral approaches help engage people, provide incentives for the reduction of use, modify the attitudes and behaviors related to use, and increase life skills to combat triggers of craving. Counseling likely doesn’t change continued use, morbidity, or mortality. Better yet, help them engage with a peer recovery advocate, which seems to help with decreased drug use and increased engagement.^​12​ But of all the available therapies, medication matters most.^{​8,11,13,14​}
4. . . . to be enrolled in a residential program. Like the one I saw advertised on the highway.
   If it works for an individual, wonderful. But the evidence doesn’t support these programs as a therapy in any long-standing manner. Plus, there are entire industries that have sprung up to take advantage of people with OUD without adherence to any rigorous principles of care, often using forced abstinence or other dangerous approaches.^​15​
5. . . . more than just another drug, because “you’re just replacing one addiction with another.”
   Do you say the same thing to a patient who received a liver transplant? You’re just trading one problem for another? Wow. The longer we talk, I really worry about your bedside manner . . . .

Let me summarize this for you. Patients with OUD who are treated with Bup overdose less and die less. They have fewer of the previously mentioned addiction harms and have less interaction with the legal system.^​16​ The driving force behind addiction, and the behaviors that it engenders, is a desperate need to avoid withdrawal combined with unremitting craving. This cycle of competing demands makes normal functioning nearly impossible and leads to the behavioral problems that contribute substantially to the morbidity and mortality of this condition. You aren’t trading one addiction for another. You are trading an addiction for a chance at life.

X-waiver = prescribing for home. Not treatment in the hospital.

But I need to do that X-waiver thing, and ain’t nobody got time for that . . .

Here’s where I’ll make it easy. You only need an x-waiver to prescribe Bup.

You do not need it to treat withdrawal in the ED. You do not need it to initiate therapy for OUD in the ED. You do not need it to treat pain in the ED. You do not need it with a mouse. You do not need it with a house. You do not need an x-waiver in a can. You do not need it Sam(HSA)-I-Am.

Here’s the relevant language from SAMHSA. Sorry for the legalese. I’ve attempted to translate.

Neither the Controlled Substances Act, as amended by DATA 2000, nor Drug Enforcement Administration (DEA) regulations Administering or Dispensing Narcotic Drugs, 21 Code of Federal Regulations (CFR) 1306.07 impose any limitations on a physician or other authorized hospital staff to maintain or detoxify a person with buprenorphine as an incidental adjunct to medical or surgical conditions other than opioid dependency.”

Translation: There are no limits to maintain someone on a medication they may already be on. Seems reasonable. Additionally, you can “detox” them (aka treat their OUD) if they’re hospitalized for another reason.

A patient with an opioid dependency who is admitted to a hospital for a primary medical problem other than opioid dependency, such as myocardial infarction, may be administered opioid agonist medications such as methadone and buprenorphine to prevent opioid withdrawal that would complicate the primary medical problem.”

Translation: So, if the patient is already on Bup, they can continue on Bup. If you start them on Bup in the ED, and they get admitted to the hospital for anything other than opioid dependence, they can continue on Bup.

A DATA 2000 waiver is not required for practitioners in order to administer or dispense buprenorphine or methadone in this circumstance. It is good practice, however, for the admitting physician to consult with the patient’s substance misuse treatment provider, when possible, to obtain treatment history.”

Translation: Yes. It is a good idea to involve others, but not required.

However, according to DEA, an exception to the registration requirement, known as the “three-day rule” (Title 21, Code of Federal Regulations, Part 1306.07(b)), allows a practitioner who is not separately registered as a narcotic treatment program or certified as a waivered DATA 2000 physician, to administer (but not prescribe) narcotic drugs to a patient for the purpose of relieving acute withdrawal symptoms while arranging for the patient’s referral for treatment, under the following conditions:”

Translation: Here’s the magic. In the ER, if you are not x-waivered, it doesn’t matter. You can use Bup to treat acute withdrawal symptoms. There are limits to this, sort of . . .

Not more than one day’s medication may be administered or given to a patient at one time”

Translation: Okay. Fine. Get them to the right dose, and Bup is dosed daily. So that works.

Treatment may not be carried out for more than 72 hours

The 72-hour period cannot be renewed or extended”

Translation: You can do this up to three days in a row (the so-called “three-day rule”). If there is no one who can provide a prescription for Bup, then the patient can come back up to three times to get treated, while you try and arrange for follow up (or a prescription. . . ) Ever have a patient come back to the ER for an antibiotic injection? What? You don’t do Peds shifts? Must be nice . . .

The intent of regulation 21 Code of Federal Regulations (CFR) 1306.07(b) is to provide practitioners with flexibility in emergency situations where they may be confronted with a patient undergoing withdrawal. In such emergencies, it is impractical to require practitioners to obtain a separate registration. The 72-hour exception offers an opioid dependent individual relief from experiencing acute withdrawal symptoms, while the physician arranges placement in a maintenance or detoxification treatment program.”

Translation: Flexibility. In treating withdrawal. Relief.

This provision was established to augment, not to circumvent, the separate registration requirement. The three-day (72-hour) emergency exception cannot be renewed or extended.”

Say what you will, but this is the sticky wicket. No one seems to be clear as to what this non-renewal or extension means. Most of the concern on a Federal level is a worry about diversion. But here again, the data shows that most Bup that is diverted is used for its intended function – preventing or treating the symptoms of withdrawal.^​17,18​ Diversion isn’t going to happen to medications that you directly give to a patient, only those that you prescribe. So, if a patient shows up to your ER in withdrawal, even after they’ve had their three-days of Bup, what are you going to do . . . ?

Many organizations and individuals, including myself, think that the waiver should be eliminated.^​19​ After all, there is a certain irony that we can prescribe a three-month supply of oxycodone (please don’t) but can’t prescribe the treatment for the addiction that can result. But in the meantime, until the law catches up with science, just get waivered.

Be like France. Or Baltimore.

When Bup is used to treat OUD, even on a large scale, there are declines in overdose deaths. In France, where Bup was made widely available to use without restriction, they saw a reduction of more than 50%. Even with the additional restrictions currently in the U.S., a coordinated effort to get prescribers waivered can save tremendous numbers of lives. In Baltimore, with the restrictions that accompany use in the US, they saw a decline of about 37%.^{​20–22​} The ER is a fantastic point of initiation of therapy for a number of reasons if not only for the fact that that’s where the patients are (with apologies to Willie Sutton).^​23,24​ And while you are at it and they are there, this is a perfect time to provide them with a naloxone kit and a discussion about harm reduction strategies. We do it all the time when we discuss seatbelts, medication safety, safer sex practices, etc. Why not with opioid use? The naloxone kit is the condom of the opioid era.

JUST DO IT

There are a number of really excellent approaches to this, from some really smart people. This post is not to give credence or primacy of any one particular regimen or protocol over any other. If you are not doing this, and interested in starting, in addition to the already cited literature, take a look at these excellent resources.

• ED – Initiated Buprenorphine from the group at Yale
• This paper by Herring, Perrone, and Nelson is a one-stop-shop for the how-to.^​25​
• Reuben Strayer has a great suggested pathway at EMUpdates. And take a look at his talk about just this subject. He’s also written extensively on this, and this white paper from AAEM on the management of OUD in the ED is an invaluable resource if you need help.^​26​
• ACEP also has a good page on the use of buprenorphine in the ER
• The National Academy of Sciences put together a report about this, and here are the highlights and conclusions.
• Shatterproof is an organization dedicated to creating a universal standard of care for addiction.

Conclusion

I think that there is no argument regarding the power and benefit of buprenorphine for the treatment of opioid withdrawal and opioid use disorder in the ER. It has the following strengths:

• Specific, direct and rapid treatment with simple maintenance
• Decreases craving
• Decreases risk of subsequent iv use
• Decreases risk of overdose death

So the only question that remains is not will you incorporate this into your practice, but when?

* There are many different names for the use of medication to manage opioid use disorder. MOUD (“MOOD”) – medication for opioid use disorder. MAT – medication-associated treatment, medication-assisted treatment, or medication for addiction treatment. OAT – opioid agonist therapy. There’s even OA-MAT – opioid agonist medication-assisted treatment. I chose MOUD because it worked with the title, not because of any particular preference. I think OAT is probably the most accurate and bias-free, and my personal choice.