#498 Opioid Withdrawal with Dr. Ashish Thakrar

September 15, 2025 | By Zina Huxley-Reicher

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Transcript available via YouTube

Grow your management tools for opioid withdrawal in the hospital. Investigate how to decide between methadone and buprenorphine, additional medications to manage symptoms and how and when to use short-acting opioids for management of withdrawal. We’re joined by Ashish Thakrar, MD at the University of Pennsylvania. 

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Show Segments

• Intro, disclaimer, guest bio
• Guest one-liner
• Case from Kashlak; Definitions
• Symptoms of opioid withdrawal
• Medications for the management of opioid withdrawal
• Buprenorphine precipitated withdrawal
• Starting Buprenorphine: Experiences and Strategies 
• Titrating Methadone: Dosage and Adjuncts
• Adjunctive short-acting opioids
• Emerging Trends in Drug Supply: Xylazine and Medetomidine
• Outro

Opioid Withdrawal Pearls

Short-acting opioid agonists can be used in the hospital setting, if needed, to support other approaches to opioid withdrawal treatment. 

Opioid withdrawal symptoms can be broken down into physiological and subjective symptoms. The onset of symptoms varies depending on whether withdrawal is from a short or long-acting opioid.

Utilize methadone or buprenorphine as the backbone of opioid withdrawal treatment.

Compared to people who are using heroin or oxycodone, some who use fentanyl regularly are at higher risk of buprenorphine precipitated withdrawal because fentanyl is highly lipophilic. 

Precipitated withdrawal is defined as an increase in COWS score of >6 over one hour; it is often a time-limited (3-5 hours) withdrawal that clinicians can provide medications to decrease a patient’s symptom burden.

If starting methadone, titrate most patients to 40 mg on the first day. This can be given as a single dose or as 30mg+10 mg >=4 hours later. Addiction experts sometimes use higher doses. 

Alpha-2 agonists, such as clonidine, are helpful in the inpatient management of opioid withdrawal. Other adjunctive medications can be tailored based on a patient’s specific withdrawal symptoms.

Opioid Withdrawal with Dr. Ashish Thakrar Notes 

Opioid Withdrawal Symptoms 

Opioid withdrawal plays a significant role in why many individuals can stay stuck in the cycle of addiction, as many patients want to avoid withdrawal, resulting in continued use. It’s essential to be able to treat withdrawal effectively.  Common symptoms of opioid withdrawal include two major categories of symptoms: physiologic and subjective symptoms. 

• Physiological: pupil dilation, runny nose, watery eyes, hypertension, tachycardia, goosebumps, diaphoresis, vomiting, diarrhea 
• Subjective: nausea, irritability, restlessness, anxiety, insomnia, muscle aches, opioid craving. 

Timeline

The onset of opioid withdrawal can vary depending on whether it is from a short or long-acting opioid. For short-acting opioids such as oxycodone or heroin, the onset of symptoms is often 6-12 hours from last use, and tends to peak within the first day, and generally lasts about 3-4 days.  Long-acting opioid withdrawal tends to start after 2-3 half-lives of the medication.  The timeline for fentanyl withdrawal is more challenging to determine for individuals who are using it chronically, as it acts both as a short- and long-acting opioid depending on duration of use. Less research looks into the timeline, but onset seems to be about 6-12 hours, and peak withdrawal may be 2-3 days from last use, and untreated, it can last 5-6 days from last use. (Sharma, 2024)

There is considerable individual variability in patient symptoms, and these can occur at different time points. Essential to note that an individual may have withdrawal symptoms from numerous substances. Dr. Thakrar notes that he finds that symptoms such as pupillary response, diarrhea, and yawning may be more specific to opioid withdrawal rather than withdrawal syndromes for alcohol or benzodiazepines. 

Measuring Withdrawal 

There are different ways to manage opioid withdrawal. The Clinical Opioid Withdrawal Scale (COWS) can be helpful clinically to determine the severity of opioid withdrawal. Dr. Thakrar notes that there can be large variability in COWS scores based on the person who is doing the assessment, but despite that, it is the most commonly used and so likely the best scale to use at this time. 

Aligning with Patient Goals

Use open-ended questions to determine the patient’s priorities are at that moment (it is helpful not to assume it is always management of their withdrawal). If a patient describes opioid withdrawal as their primary concern, discuss the plan to aggressively and safely treat opioid withdrawal as soon as possible.  Identify a shared priority and align with the patient’s goals. History taking can be iterative, adjusting to what is needed acutely for the patient, and can expand as the patient starts to feel better. Approaching patients in this way can help to address the disproportionately high rates of patient-directed discharges in this population (Ti, 2015; Alrawashdeh, 2023; Simon, 2020). 

Medication Options for Management of Opioid Withdrawal

Dr. Thakrar thinks about management of opioid withdrawal in four buckets: 

1. The foundation and backbone of all management plans is methadone or buprenorphine
2. In almost all cases patients should be given an alpha-2 agonist such as clonidine
3. Next, non-opioid adjuncts to treat targeted withdrawal symptoms should be included in the withdrawal management plan.
4. Finally, we should consider short-acting opioid agonists as an additional adjunct.   

Dr. Thakrar recommends starting by asking a patient if they have a sense of whether they would like to continue either methadone or buprenorphine long-term after this hospitalization to help guide medication selection for their withdrawal management. Most patients will have had some experience with one or the other of these medications and so will have some sense of what they may want. It is essential to note that an individual does not have to want to continue these medications long-term to receive these medications for opioid withdrawal management in the hospital. Dr. Chan reminds us that it is important to have the local context for outpatient management of opioid use disorder, as it may vary greatly whether patients have access to methadone or buprenorphine, depending on where you are practicing in the country – this can be important as you are having these conversations and making decisions with patients. 

Methadone and buprenorphine are extraordinarily effective for OUD treatment. Buprenorphine doses of 16mg and greater have an estimated NNT of 2 for retention in treatment when compared to placebo (Raleigh, 2017; Mattick, 2014). 

Buprenorphine Precipitated Opioid Withdrawal

The unique combination of buprenorphine as a partial agonist at the mu-opioid receptor and its tight binding affinity is the reason that it can cause precipitated withdrawal. This phenomenon happens when buprenorphine is given to a patient who has a full opioid agonist in their system – the buprenorphine outcompetes the full opioid agonist and so they experience a sudden deactivation from full to partial agonism, which we clinically see as severe opioid withdrawal. The definition of precipitated withdrawal is agreed upon as a rise of COWS score by at least 6 points in one hour (Dunn 2023). Buprenorphine precipitated withdrawal is time-limited and only lasts 3-6 hours when treated (Spadaro 2023). Expert opinion is to give more buprenorphine and utilize adjuncts such as clonidine, antiemetics, anti-diarrheal, benzodiazepines,  and, if available, ketamine to help manage precipitated withdrawal. 

There is a discrepancy between the rates of precipitated withdrawal observed in research study settings, where a 1% rate is reported in buprenorphine initiations, and the experiences that patients report (D’Onofrio, 2023). Patients report that it is happening a lot more (30-35% of people report experiencing it) as the drug supply has shifted to fentanyl (Varshneya 2022). Real-world studies of buprenorphine initiation find precipitated withdrawal about 15% of the time. (Thakrar 2024) 

It is important to note that rates of precipitated withdrawal have increased in the era of the predominance of fentanyl in our drug supply.  The biochemical reasons that we may see increased rates of precipitated withdrawal in patients who are primarily using fentanyl include that fentanyl is lipophilic, and with chronic use, stores of fentanyl can build up. As a result, fentanyl continues to enter the bloodstream for many hours after last use and remains active at the mu-opioid receptors. 

The second reason is that fentanyl is also active in the beta-arrestin pathway. This pathway leads to the internalization of the mu-opioid receptors and thus, desensitization (Zhao, 2005). 

When discussing this with patients, it is essential to both listen to and understand the very real concerns patients have about experiencing precipitated withdrawal, and to reassure them that this is a time-limited experience that we can and will treat if they experience it. 

Starting buprenorphine 

Dr. Thakrar notes that the method of buprenorphine initiation is an evolving area of clinical practice and we are still figuring out the optimal way to start buprenorphine and when. We have a strong evidence base behind the traditional or standard induction, and less evidence behind some of the more novel induction strategies such as low-dose or high-dose buprenorphine inductions (Curbisders Addiction Medicine #22). He recommends assessing for risk of precipitated withdrawal using these three considerations: 

1. The larger environment – is there a high rate of precipitated withdrawal in your area, are lots of patients experiencing this? Or is no one in your local area experiencing this? 
2. The clinical context – do you have time to manage a patient’s opioid withdrawal in other ways before starting buprenorphine or do you need to start right away? 
3. The person in front of you – how nervous is the patient about the potential for precipitated withdrawal? Have they experienced it before? How well do they tolerate withdrawal? 

With consideration of the above, you can then use this to help guide how you decide to start buprenorphine. Dr. Thakrar thinks that most patients should utilize the standard induction strategy which involves waiting at least 12 hours since last use, waiting for the appearance of physical exam findings indicative of withdrawal and then starting with a 2mg dose of buprenorphine followed by additional 2-4mg doses every hour or so until you get to 8 mg total dose. After this, patients should take 8 or 12mg doses q8-12h to reach 16-24mg total daily dose by the end of Day 1.

Other induction strategies include low-dose induction of buprenorphine (continuing full agonist opioid such as methadone while slowly increasing doses of buprenorphine), high-dose induction (start with high doses of buprenorphine 8-24 mg dose to start), or utilization of short-acting opioids for withdrawal management while allowing more time for fentanyl clearance before starting buprenorphine. Practice varies widely across the country in terms of preferred induction strategy – understanding what addiction providers in your local area are utilizing can be helpful to guide these decisions. 

Starting methadone

Methadone is a full opioid agonist; it has an onset of action of 1 hour, peak effect is generally within 3-4 hours, and a half-life on average of 24 hours. Dr. Thakrar recommends starting with 30-40mg of methadone.  Due to its long half-life, it can take 5-7 days for methadone to reach steady state, so individuals must balance the risk of aggressive withdrawal treatment and the risk of dose-stacking 2-3 days after starting the medication.  Often these starting doses are not enough to fully manage a patient’s withdrawal symptoms and so this is why utilizing medications from each of the 4 buckets is critical. A patient should not only receive methadone but should also be getting an alpha-2 agonist or other PRNs that directly target a patient’s withdrawal symptoms.Short-acting opioid agonists, like hydromorphone or oxycodone, should be considered. These additional opioids provide time to increase the methadone dose safely. 

For individuals with less experience with methadone. Dr. Thakrar recommends using 40mg on day 1, 50mg on day 2, 60mg on day 3, and then slowing the titration.  Experts such as addiction medicine specialists with extensive methadone experience may go higher on day 1; consider consulting a specialist if using a more rapid methadone titration protocol. (Curbsiders Addiction Medicine #1)

Alpha-2 Agonists

Alpha-2 agonists such as clonidine or lofexidine represent a key piece of opioid withdrawal management. Lofexidine is the only medication that has FDA approval for opioid withdrawal, although many hospitals do not carry this medication, and so clonidine is used more frequently for this purpose. Generally recommended doses of clonidine are 0.1-0.3 mg every 6-8 hours. Dr. Thakrar recommends scheduling this medication instead of leaving it as PRN with hold parameters for blood pressure. 

Medications for the management of withdrawal symptoms

Additional medications should be utilized to target withdrawal symptoms that patients may be experiencing. These may include antiemetics such as ondansetron for the management of nausea, NSAIDS and acetaminophen for the management of body aches, loperamide for the management of diarrhea, and benzodiazepines for the management of anxiety. These medications can be scheduled or ordered as PRN (as needed) medications, depending on the patient’s experience of symptoms. 

Short-Acting Opioid Agonists

When utilizing short-acting opioid agonists in the hospital for management of opioid withdrawal,   Dr. Thakrar recommends starting with hydromorphone 6-8mg (PO) or oxycodone 15-20mg. In his expert opinion, he schedules the medication Q4H and holds for sedation, rather than leaving it as PRN as he finds that PRN medications are often not given.  The dose should ultimately be tailored to the patient’s use pattern and medical co-morbidities. Of note, it is legal to use short-acting agonists for the management of withdrawal in the hospital, but it is not allowed for outpatients to use full agonists for OUD (21 CFR -II – 1306.7). Short-acting opioids should always be a short-term plan for the management of withdrawal. (Thakrar, 2023)  Dr. Thakrar cites three main patient contexts in which he utilizes short-acting opioids:

• Methadone titration – utilize short-acting opioids for a few days to bridge the withdrawal management gap while safely titrating up to a higher methadone dose to decrease dose-stacking risk. 
• Bridge to standard buprenorphine initiation: Utilize short-acting opioids to manage withdrawal to provide additional time to allow for fentanyl clearance before buprenorphine initiation to reduce precipitated withdrawal risk. For example, if a patient has previously needed to wait 48 hours from last fentanyl use, they can utilize short-acting opioids as a scheduled bridge for 48 hours, then hold the opioid for 10 hours and start buprenorphine.
• Low-dose buprenorphine initiation:  utilize short-acting opioids to provide the full agonist opioid during a low-dose buprenorphine initiation (see episode 22 for additional information on this initiation method. 

Emerging Adulterants and Their Impact on Withdrawal: 

Xylaxine, an alpha-2 agonist, has been an adulterant in the opioid supply for multiple years in many parts of the US. It is used in veterinary medicine as an anesthetic. One of the bigger complications we have seen with xylazine are wounds. Additionally, there are some differences in withdrawal symptoms in patients who have been primarily using xylazine, although no adrenergic hyperactivity.  (Curbsiders Addiction Medicine #26)

Medetomidine, a racemic mixture of dexmedetomidine and levomedetomidine, is a newer adulterant in the US drug supply and is a more potent alpha-2-agonist. We have seen more adrenergic hyperactivity in withdrawal syndromes which may require ICU stay to treat with dexmedetomidine (CDC MMWR). 

Links

1. Yale Addiction Medicine Grand Rounds: Buprenorphine-Precipitated Withdrawal Among Hospitalized Patients Using Fentanyl by Dr. Ashish Thakrar
2. Community-based Drug Checking – PA Groundhogs

Goal

Listeners will gain comfort in the use of various options for management of opioid withdrawal in the fentanyl era.

Learning objectives

After listening to this episode listeners will…

1. Describe the symptoms of opioid withdrawal and their timeline.
2. Describe pharmacological management of opioid withdrawal utilizing methadone, buprenorphine, short-acting opioid agonists, and additional comfort medication adjuncts. 
3. Identify and manage buprenorphine-precipitated opioid withdrawal.

Disclosures

Dr. Ashish Thakrar reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Huxley-Reicher Z, Thakrar A, Roy P,  Surani Z, Cohen SM, Chan CA “#498 Opioid Withdrawal with Dr. Ashish Thakrar”. The Curbsiders Addiction Medicine Podcast.https://thecurbsiders.com/addiction  Published September 15th, 2025.