Buprenorphine is an effective first-line treatment of opioid use disorder (OUD), but because it is a partial opioid agonist, starting buprenorphine (a process known as induction) can lead to precipitated withdrawal in patients with residual opioid agonist in their system. Carefully following induction procedures can minimize this risk, but precipitated withdrawal is always a possibility. In this article, we’ll review buprenorphine induction procedures that minimize the risk of withdrawal and discuss how to manage withdrawal if it occurs. 

Avoiding withdrawal

The standard induction procedure involves two steps. The first step is ­to quantify opioid withdrawal symptom severity using a validated scale. In the hospital, the most commonly used scale is the Clinical Opiate Withdrawal Scale (COWS; www.tinyurl.com/427amss2). Patients undergoing home induction can use the Subjective Opiate Withdrawal Scale (SOWS; www.tinyurl.com/3wrb8frt). The second step is to start medication once the severity reaches a certain threshold (COWS or SOWS >8–10). This threshold indicates that the amount of residual opioid in the patient’s system is low enough that taking their first dose of buprenorphine won’t trigger additional withdrawal symptoms. 

An alternative method for starting buprenorphine, termed microinduction, involves the gradual introduction of buprenorphine in very small doses while the patient continues taking opioid agonists. Buprenorphine is titrated up to an effective dose, usually over the course of a week or two, and then the opioid agonist is stopped. The main advantage of microinduction is the very low risk of precipitated withdrawal. The downside is that the procedure is relatively slow, leaving the patient undertreated and at higher risk of overdose during the week or two that it takes to complete.

See CATR Apr/May/Jun 2024 for more on buprenorphine induction procedures.

If withdrawal occurs: Three options

Despite our best efforts, precipitated withdrawal will occur in a small subset of our patients. It is uncomfortable, sometimes intensely so, and can cause significant distress. While the research on how to treat precipitated withdrawal is sparse, there are three generally accepted approaches.

1) Symptomatic treatment

Opioid withdrawal symptoms include: 

• Abdominal cramping
• Anxiety
• Diarrhea
• Insomnia 
• Muscle aches
• Nausea
• Tachycardia
• Vomiting

Symptomatic treatment focuses on alleviating these symptoms through a combination of medications, each chosen to relieve a particular symptom. See “Symptomatic Treatment for Precipitated Opioid Withdrawal” table for a rundown of medications that can be used to treat opioid withdrawal symptoms. The list may look familiar, as they are the same medications that are used to treat opioid withdrawal in patients who do not want medications for OUD (MOUD).

2) More buprenorphine

Giving the patient additional buprenorphine might initially appear counterintuitive, but it can ease withdrawal symptoms and make the patient feel somewhat better. The approach, akin to “ripping off the Band-Aid,” floods opioid receptors with buprenorphine, and at a high enough dose it can provide adequate agonism to relieve at least some withdrawal symptoms. Evidence for this approach is restricted to a handful of case reports, but the studies indicate that an additional 8–16 mg of buprenorphine, given once precipitated withdrawal takes place, leads to symptom relief in one to two hours (Spadaro A et al, Am J Emergency Med 2022;58;22–26). This may seem like a high dose to give all at once, especially considering that guidelines typically recommend not to exceed 8 mg of buprenorphine in the first 24 hours (Treatment Improvement Protocol 63. SAMHSA; 2019). However, recent studies have shown that doses of buprenorphine as high as 32 mg are safe and well tolerated (Herring AA et al, JAMA Netw Open 2021;4(7):e2117128). 

3) Switching to an opioid agonist

In cases where symptomatic treatment is insufficient or the patient is not amenable to taking additional buprenorphine doses, switching to opioid agonist treatment, namely methadone, can be effective. Studies have shown that buprenorphine and methadone both reduce morbidity and mortality associated with OUD (Santo T et al, JAMA Psychiatry 2021;78(9):979–993). Pivoting to methadone treatment may be a way of keeping your patient on MOUD after an unpleasant initial experience with buprenorphine.

If you decide to switch to methadone, it’s important to consider the potential for QT prolongation. Whenever possible, obtain a baseline ECG, a set of blood chemistries, and replete potassium and magnesium in patients with potassium <4.0 or magnesium <2.0, which will lower the risk of a prolonged QT progressing to torsades de pointes. If these tests aren’t immediately feasible, at the very least assess the patient’s cardiac risk factors, monitor them as closely as you can, and obtain the labs and ECG as soon as possible.

To dose: 

• A typical first dose is 20–30 mg
• 10 mg can be added if the patient is still in withdrawal (total of 40 mg in the first 24 hours after beginning treatment) 

Remember that methadone must be prescribed by a federally regulated opioid treatment program (OTP) beyond the initial 72 hours. If you are going to start the patient on methadone, be sure that they will have access to an OTP going forward.

Choosing between the three

Studies on treatments for buprenorphine-precipitated withdrawal are small, often lack control groups, and are frequently limited to case reports. No direct comparisons of different treatment strategies have been conducted. As a result, any of the three available options can be considered reasonable, each with its own pros and cons.

Symptomatic treatment focuses on alleviating discomfort but does not help the patient initiate MOUD. Adding more buprenorphine can relieve symptoms and expedite the induction process, but patients may be understandably hesitant to take additional doses. Switching to methadone effectively treats OUD but can complicate follow-up arrangements.

It’s also important to note that symptomatic treatment can be combined with either of the other two options—patients can still receive medications for symptom relief even if they are given additional buprenorphine or switched to methadone. 

Involve the patient in decision-making

Whenever possible, involve the patient in choosing a treatment path.

• Explain the risks and benefits of each approach
• Outline what each approach entails
• Ask which one they prefer 

Because we have so few data, there really is no wrong choice.

Acknowledge patient experience

It is important to acknowledge the discomfort patients feel. Unfortunately, none of the strategies are likely to fully eliminate precipitated withdrawal symptoms once they start. But emphasize that the discomfort is temporary and that it should resolve in eight to 24 hours. After that time, patients will have started buprenorphine and can be titrated up to an effective dose with no fear of further precipitated withdrawal (Spadaro et al, 2022).

Carlat Verdict 

Precipitated withdrawal can occur when buprenorphine is given while the patient still has an opioid agonist in their system. Various strategies can be used to minimize the risk of precipitated withdrawal, but it will inevitably happen from time to time. When it does, offer symptomatically targeted treatments, give additional buprenorphine up to 16 mg at a time, or switch to methadone. Reassure the patient that the discomfort is temporary, and don’t discontinue MOUD.