Editor’s Note: This is the sixth part of an ongoing series on what emergency physicians can do to combat the opioid epidemic.

Plenty has been written and said about buprenorphine recently, and that’s not a bad thing.^1–3 It’s a medication that can be started from the emergency department under the correct circumstances. It’s also a medication that a lot of us probably weren’t very familiar with, so many likely benefited from a crash course on bup. Of course, it is important to remember that medication-assisted therapy (MAT) involves more than just buprenorphine. In fact, there are two other medications patients can choose: methadone and naltrexone. Are emergency physicians likely to start patients on either of these medications from the emergency department? Absolutely not, although from what I’m told, some emergency departments have been using intramuscular methadone for opioid withdrawal for quite some time. Either way, given the emphasis on treatment of opioid use disorder (OUD) with medications, there is a fair chance we’ll start seeing more patients on these agents. As such, it is important that we have a basic understanding of them and how they could affect emergency physicians’ practice.

Also, it is worth noting that while we’ll continue to use the term MAT because most of us are familiar with it, the term is falling out of favor because some feel it inappropriately deemphasizes the role that medication plays in recovery for this population.

Methadone

Methadone has been the mainstay in the treatment of OUD long before buprenorphine became the cool kid on the block. While there is a ton of stigma associated with it and the word swirls with all sorts of negative connotations, methadone has been very successful in treating patients with OUD.⁴ It is a full agonist without a ceiling effect like buprenorphine, which means that it can be particularly dangerous. This is one reason it is so tightly regulated, at least for addiction. While it can be prescribed for pain, it cannot be prescribed for addiction. Patients must go to a properly licensed treatment center (e.g., a methadone clinic) where it can be dispensed under a physician’s supervision.

At the clinic, methadone is generally dispensed once a day, although toward the end of pregnancy, patients may receive twice-per-day dosing. If you’re boarding a patient with an OUD, don’t be fooled if they tell you that they get the medication three times per day, which a few of my floor patients have tried in the past. If the center is open or has an on-call number, you can verify the dose and frequency.

What about just doing a quick search of the prescription drug monitoring program (PDMP)? This seems easier than trying to hunt down the methadone clinic and awaiting a return call. Unfortunately, this won’t work. Since methadone is dispensed by these facilities, no prescription is ever written. While this may seem like semantics, it means this information is never loaded into the PDMP, so it won’t be there when you search. Sensing this was a problem, the ACEP Council passed a resolution in 2018 to have methadone included in the PDMP.⁵

As mentioned previously, methadone must be respected. It is potent, with a very long half-life, which means it can easily cause respiratory depression. Commonly, this occurs on days two through four if the medication is titrated too quickly. Fortunately, it doesn’t necessarily require large doses of naloxone to reverse it. In fact, 0.04 mg of naloxone may be enough.⁶ Patients can recrudesce, and this does not always happen quickly. I’ve had a quite a few who went down even four hours after their first dose of naloxone. These patients will require prolonged observation and possibly a naloxone infusion.

Keep in mind that the standard urine drug screen does not pick up methadone and can’t be relied on to rule out a methadone overdose. It won’t pick up buprenorphine or fentanyl either, making this test even more useless.

Methadone also causes a prolonged QTc. Does this mean everyone on methadone needs an ECG? No, it does not, and at low doses, such as 20–40 mg/day, methadone probably does not have a significant effect.⁷ However, some patients are on doses of more than 100 mg/day. In this case, you may want to consider an alternative to medications in the emergency department that cause QTc prolongation or at least obtain an ECG prior to ordering these medications.

What about your patient on methadone that is NPO? I’d recommend cutting the oral dose by at least half.^8,9 For patients on methadone with acute pain, the dose should not be increased in the emergency department. In future columns, we’ll tackle acute pain control in patients on MAT.

Naltrexone

Naltrexone is completely different than methadone or buprenorphine; it is a complete antagonist at the mu receptor. Think of it as extended-release naloxone. While there is an oral form, almost all patients will be on the injectable form, which is meant to last a month to help with compliance. With its high binding affinity to the mu receptor, it works by preventing patients from getting high if they try to use while on the medication. There is no euphoria associated with it, and at least initially, it won’t help with cravings.

Patients must abstain from all opioids for at least seven to 10 days prior to receiving naltrexone. If they do not, the drug can precipitate severe opioid withdrawal. Unlike naloxone, which should improve after 40 to 60 minutes, or buprenorphine, which can be overcome by giving more buprenorphine, this effect of naltrexone can last a long time. Remember the injectable form can last 30 days, but the withdrawal should not last nearly this long.

While precipitated withdrawal is the main complication we worry about with naltrexone, there are also reports of agitated delirium following the administration of it in patients who recently used an opioid.^10,11 Otherwise, it is very safe unless patients try to overcome the blockade with either very large doses or very potent opioids, or they relapse but now have very little tolerance.

It’s important to mention that there are other indications for naltrexone. It is used in patients with alcohol use disorder due to the effects of mu receptors on our reward system. There is also a weight-loss pill that is a combination of bupropion and naltrexone. This isn’t a huge problem, unless someone doesn’t obtain a complete history and prescribes it to an opioid-dependent patient. We’ve had at least one patient to whom this happened, and it took large amounts of fentanyl and multiple antiemetics to improve her symptoms. We’ve also recently noticed a few physicians using low-dose naltrexone for chronic pain.^12,13

What About Lofexidine?

You may have also heard of a new, recently approved drug indicated for opioid withdrawal, lofexidine. It’s actually been used in Europe for years. Alas, it is just an α-2 agonist, very similar to (and much more expensive than) clonidine. It is not used for MAT. 

Dr. Waller is a fellow at The National Center for Complex Health and Social Needs and managing partner at Complex Care Consulting LLC. Dr. Schwarz is associate professor of emergency medicine and medical toxicology section chief at Washington University School of Medicine in St. Louis.

References

1. Waller RC. Buprenorphine explained. ACEP Now. 2018;37(6):13-14.
2. Kaufman M. Suboxone 101. ACEP Now. 2018;37(10):36-37.
3. Boggs W. ED-initiated buprenorphine cost-effective for opioid dependence. ACEP Now website. Accessed Dec. 12, 2018.
4. Sees KL, Delucchi KL, Masson C, et al. Methadone maintenance vs 180-day psychosocially enriched detoxication for treatment of opioid dependence: a randomized controlled trial. JAMA. 2000;283(10):1303-1310.
5. 2018 Annual Council Meeting. ACEP website. Accessed Dec. 12, 2018.
6. Kim HK, Nelson LS. Reversal of opioid-induced ventilatory depression using low-dose naloxone (0.04 mg): a case series. J Med Toxicol. 2016;12(1):107-110.
7. Martin JA, Campbell A, Killip T, et al. QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel. J Addict Dis. 2011;30(4):283-306.
8. González-Barboteo J, Porta-Sales J, Sánchez D, et al. Conversion from parental to oral methadone. J Pain Palliat Care Pharmacother. 2008;22(3):200-205.
9. Methadone. Palliative Drugs website. Accessed Dec. 12, 2018.
10. Wightman RS, Nelson LS, Lee JD, et al. Severe opioid withdrawal precipitated by Vivitrol. Am J Emerg Med. 2018;36(6):1128.e1-1128.e2.
11. Boyce SH, Armstrong PA, Stevenson J. Effect of inappropriate naltrexone use in a heroin misuser. Emerg Med J. 2003;20(4):381-382.
12. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663-672.
13. Low dose naltrexone reduces the symptoms of fibromyalgia. Stanford University website. Accessed Dec. 12, 2018.