Rapid transition from methadone to buprenorphine using naltrexone-induced withdrawal: A case report

Abstract

Background:

Patients taking methadone for opioid use disorder may desire transition to buprenorphine for a number of reasons. However, the current recommended approach for this transition generally takes weeks to months as an outpatient, causing considerable discomfort to the patient and a heightened risk of relapse during the transition period.

Case:

We describe the case of a patient on methadone maintenance who was rapidly transitioned to buprenorphine because of her desire to not return to her methadone clinic. In order to rapidly transition the patient from methadone to buprenorphine, naltrexone was administered to precipitate acute opioid withdrawal, which was followed soon after by buprenorphine induction.

Discussion:

Rapid transition from methadone maintenance to buprenorphine can be accomplished in inpatients by precipitating acute withdrawal with naltrexone, providing an effective alternative for patients who cannot tolerate the typical protracted methadone taper required prior to buprenorphine induction as an outpatient.

Introduction

Methadone, buprenorphine, and extended-release naltrexone are evidenced-based treatments currently available for opioid use disorders. Although many patients are successfully treated with methadone, some patients may need to transition from methadone to other medications for a variety of reasons.¹ In some instances, methadone may no longer be appropriate due to adverse effects (e.g., QTc prolongation²) or due to logistical barriers (e.g., insurance coverage, living too far from clinic, or desire to travel for work). Some patients may no longer require the highly structured environment to maintain their recovery and choose to transition to buprenorphine or naltrexone. Still others may wish to transition due to stigma of being enrolled in a methadone program, or due to concerns about having large amounts of methadone in their house.³

The transitioning of patients from methadone to buprenorphine has been described previously.^4–10 Standard outpatient transition procedure can be summarized as follows: in order to successfully transition patients from methadone to buprenorphine, the dosage of methadone should be reduced to 30–40 mg daily and maintained for at least 1 week prior to transition.¹¹ Methadone should then be discontinued at least 24 hours prior to buprenorphine induction due to the risk of precipitated withdrawal. Waiting 36 hours further decreases this risk, as does using a lower dose of buprenorphine, such as 2 mg, for the first induction dose once withdrawal begins.¹² Afterward, 2 mg of buprenorphine is usually administered every 2 hours as needed for ongoing opioid withdrawal symptoms until they have ceased. The patient should then be continued on this daily stabilization dose of buprenorphine. Nonopioid medications should also be administered to treat symptoms of withdrawal throughout induction.

The extended period of time that patients must tolerate being on a low methadone dosage in preparation for the switch to buprenorphine, as well as the need to tolerate opioid withdrawal symptoms for over 24 hours after methadone is discontinued, has made this transition problematic due to increased relapse risk.^1,13–19 Some small British studies indicate that transitioning to buprenorphine from doses of methadone higher than 30 mg is feasible in an inpatient setting using adjunctive lofexidine,^9,20 but this medication has only recently been approved for use in the United States by the Food and Drug Administration.

A novel method of making this transition from methadone to buprenorphine involves the use of oral naltrexone followed by buprenorphine induction. In the only prior study documenting such a transition from methadone to buprenorphine, Urban and Sullivan²¹ demonstrated that patients taking high doses of methadone (70–130 mg) could undergo rapid inpatient detoxification from methadone by the administration of oral naltrexone followed by buprenorphine induction. Patients received their standard methadone dosage until the day prior to hospital admission to an addiction unit. Upon admission, patients were given the option of using clonidine 0.2 mg tablets or transdermal clonidine patches (0.2 mg/24 hours) for symptomatic relief from opioid withdrawal. Patients were then administered 25 mg of oral naltrexone under observation. Within 45 minutes, patients were noted to be in withdrawal that was severe enough to allow for induction on buprenorphine/naloxone at an initial dose of 4–6 mg. Throughout the day, further doses of buprenorphine/naloxone were administered until their withdrawal symptoms had subsided. Patients continued buprenorphine/naloxone at this stabilization dosage. The average length of stay for these patients was 7 days, and all patients expressed gratitude at the efficiency of the transition process. To our knowledge, no further studies have replicated this method.

We report here a case of a woman who sought a rapid transition from methadone to buprenorphine and was successfully transitioned using naltrexone during her medical hospitalization. The patient gave verbal consent for reporting of her case.

Case presentation

Ms. J is a 38-year-old woman with a history of opioid use disorder on methadone maintenance, stimulant (cocaine) use disorder, borderline personality disorder, major depressive disorder, posttraumatic stress disorder (PTSD), chronic pain syndrome, several psychiatric hospitalizations, and several suicide attempts who presented to the emergency department with back and leg pain with concern for epidural abscess. However, magnetic resonance imaging (MRI) of the spine showed no evidence of abscess and cultures (blood and urine) were negative. The patient was ultimately treated for chronic pain syndrome, and while hospitalized, she expressed suicidal ideation conditional upon returning to her methadone clinic. She felt that exposure to other patients at the clinic who were actively using substances was impairing her ability to achieve continued sobriety. The addiction psychiatry service was consulted for safety evaluation and management of her opioid use disorder.

Substance use history was significant for illicit opioids and cocaine. Ms. J began using illicit opioids at age 27. At peak usage, she was using 1–2 g of heroin intravenously daily. She had knowingly used fentanyl in the past. She had a history of one intentional overdose and several unintentional overdoses. She reported treatment with methadone intermittently over the past 11 years, with the longest period of sobriety for 7 years while incarcerated, during which she did not receive methadone. She was most recently on 65 mg methadone daily with a prior highest dose of 200 mg. Her reported that last use of heroin was 3 weeks prior to presentation. She had a history of crack cocaine use but denied the use of marijuana or alcohol. Medical history was significant for pulmonary embolism, endometriosis, obesity, and chronic pain. Family history was significant for opioid use disorder in her daughter. Social history was significant for current homelessness and unemployment, having been discharged from her group home 2 months prior to presentation. Her home medications were clonazepam 2 mg orally 3 times daily as needed for anxiety, clonidine 0.3 mg orally 3 times daily, escitalopram 10 mg orally daily, acetaminophen 300 mg/butalbital 50 mg/caffeine 40 mg orally as needed up to every 4 hours for headache, gabapentin 800 mg orally 3 times daily, and quetiapine 100 mg orally each night with 50–100 mg as needed for anxiety up to every 6 hours.

Upon initial psychiatric evaluation, she described her mood as “not good” and endorsed poor sleep, feelings of worthlessness, poor energy, poor concentration, and suicidal thoughts without active plan or intent. She denied anhedonia and abnormal appetite. She also denied features of mania and psychosis and denied active PTSD symptoms. She reported feeling safe in the hospital, although she stated that she might “kill [herself]” if she were discharged on methadone and back to her methadone clinic. Ms. J expressed concerns that if she were discharged from the hospital and went back to her methadone clinic, she would relapse on substances, as there were many active substance users at the clinic. She also endorsed strong cravings to use illicit opioids. She therefore requested to be transitioned to buprenorphine.

A plan was proposed for an accelerated transition from methadone to buprenorphine using a naltrexone-induced withdrawal followed by buprenorphine induction. Ms. J was amenable with this plan and expressed understanding when informed of the risks and benefits. On the day prior to induction, she received her last dose of methadone 65 mg at 8:00 AM as well 2 doses of oxycodone 10 mg (at 8 AM and 2 PM). On the morning of induction, she reported feeling uncomfortable, due to pain, arthralgia, and anxiety. Baseline Clinical Opiate Withdrawal Scale (COWS²²) score immediately prior to receiving naltrexone was 6 (with points given for report of mild joint pain, nausea/loose stool, slight observable tremor, and report of irritability/anxiety). Ms. J then received naltrexone 25 mg orally. Assessment of withdrawal symptoms was conducted every 15 minutes thereafter (Figure 1). She was provided with as-needed oral medications for opioid withdrawal symptoms (clonidine 0.2 mg every 8 hours, ibuprofen 800 mg every 6 hours, loperamide 2 mg every 8 hours, methocarbamol 750 mg every 8 hours, ondansetron 8 mg every 8 hours, and promethazine 50 mg every 8 hours) in addition to her home medications.

Figure 1.

Clinical Opiate Withdrawal Scale Scores over time. Naltrexone was administered at time = 0. Withdrawal symptoms were assessed using the COWS²² every 15 minutes until rescue with buprenorphine, which was administered at 60, 75, 120, and 360 minutes. An additional 8 mg buprenorphine was administered at 600 minutes.

Over the course of the next 60 minutes, COWS score increased to 17 (with points given for inability to sit still, severe pain, moist eyes, multiple episodes of vomiting and diarrhea, observable tremor, and irritability and anxiety that made participation in clinical interview difficult). Ms. J paced around the room frequently. Buprenorphine 4 mg was then administered sublingually. After 15 minutes, Ms. J’s withdrawal symptoms mildly improved (COWS score of 15), although the patient subjectively reported worsening withdrawal. Due to nausea and vomiting, the patient reported that she accidentally swallowed the buprenorphine tablets. As a result, the decision was made to administer an additional 2 mg of sublingual buprenorphine, given concern for decreased oral bioavailability. Ms. J continued to experience multiple episodes of vomiting and diarrhea and was noted to be yawning repeatedly. She received clonazepam 2 mg, clonidine 0.2 mg, methocarbamol 750 mg, and promethazine 50 mg for symptomatic relief.

One hour after the first buprenorphine rescue dose, Ms. J continued to have symptoms of withdrawal (COWS score of 14), so a second dose of 4 mg sublingual buprenorphine was given. She was monitored and observed hourly for the next 4 hours. She appeared more comfortable and was able to lie in bed, sleeping at times. She reported that her pain was tolerable. She received quetiapine 50 mg for anxiety, acetaminophen 300 mg/butalbital 50 mg/caffeine 40 mg for headache, and another dose of methocarbamol 750 mg for symptomatic relief.

Four hours after the previous buprenorphine dose was administered, Ms. J was observed to be sleeping and was awakened for assessment of withdrawal symptoms. Her affect was irritable, but withdrawal symptoms had returned to baseline (COWS score of 5). A dose of buprenorphine 8 mg was then administered sublingually (Figure 1 and Table 1). A final dose of buprenorphine 8 mg was administered 4 hours later.

Table 1.

Temporal development of withdrawal symptoms.

	Time since naltrexone administration (minutes)
COWS item	0	15	30	45	60a	75	120	360
Pulse
Sweating						X	X
Restlessness			X	X	XXXXX	X	XXX
Pupil size
Bone or joint aches	X	X	XX	XX	XX	X	XX	X
Runny nose or tearing			X	X	X	X	X
GI upset	XX	XX	XX	XX	XXX	XXXXX	XXX	X
Tremor	XX	XX	XX	XX	XX	XX	X
Yawning		X		X		X	XX	X
Anxiety or irritability	X	XX	XX	XX	XXXX	XX	X	XX
Gooseflesh skin						X
Total	6	8	10	11	17a	15	14	5

X = 1 point on COWS.

^aFirst dose of buprenorphine administered.

The following day, Ms. J received buprenorphine 8 mg sublingually 3 times daily. She continued to experience irritability and anxiety, but by the second day after induction she reported feeling “much better” and thanked the team. On psychiatric evaluation, she denied suicidal ideation and was determined to no longer require psychiatric admission. She was referred for an appointment with a local buprenorphine clinic and provided with a 14-day prescription to bridge her until the appointment and discharged from the hospital.

One day after discharge, the patient presented to another local hospital for suicidal ideation in the setting of using heroin with her boyfriend and watching him overdose. Urine toxicology was positive for barbiturates, benzodiazepines, and cocaine. She was medically cleared and admitted to an inpatient psychiatric hospital. Two days later, the patient was sent from this psychiatric hospital to our emergency department with fever of 103 °F and leukocytosis. Urine toxicology was positive for cocaine and fentanyl. She was admitted and treated with intravenous antibiotics, but a workup for endocarditis, bacteremia, and pelvic inflammatory disease was negative, and no definitive etiology of fever and leukocytosis was identified. During this admission, she expressed ambivalence about buprenorphine, but it was ultimately continued. Over the next 8 months, the patient had multiple repeat presentations to the emergency department for medical and psychiatric presentations related to her substance use, including suicidal ideation. Although on multiple occasions during these hospitalizations she reported that buprenorphine was not adequately treating her leg pain, she continued to adhere to treatment, filling buprenorphine prescriptions for 3 months after the initial induction, as verified by a state prescription monitoring program. The presence of buprenorphine in the urine was not assessed during these encounters. However, at a visit to the emergency department 4 months after the initial induction, she reported stopping buprenorphine. Seven months after induction, during a hospitalization for cellulitis, the patient was initiated on methadone. She was scheduled for an intake at a methadone maintenance clinic but never followed up.

Discussion

Treatments for opioid use disorder have evolved rapidly in the last few decades. Previously, emphasis was placed on detoxification. Rapid detoxification assisted with clonidine and ultrarapid detoxification performed under anesthesia were methods developed to ease the detoxification process. However, these procedures are now considered obsolete given their lack of efficacy and potential for medical complications along with the development of efficacious agonist medications (i.e., methadone, buprenorphine, naltrexone) for opioid use disorder.^22,23

With multiple effective medications available, patients may elect to transition from one agent to another for a variety of reasons, including side effects, ongoing cravings for opioids, ease of dosing, cost, and pregnancy.^24–33 The transitioning of patients from methadone to buprenorphine has been reported previously.^4–10 However, the direct transition from methadone to buprenorphine can be problematic. Clinical guidelines recommend that methadone be tapered to 30–40 mg a day for at least 1 week and then transferred to buprenorphine after at least 24 hours since the patient’s last dose of methadone.³ For patients who are on doses of methadone that are substantially higher than 30 mg, the required time to taper can be substantial, since it is recommended that the dosage be decreased by 5–10% every 1–10 weeks.¹ During this time, the patient may experience considerable discomfort and may be at heightened risk for relapse. As such, a more rapid yet safe transition from methadone to buprenorphine could greatly benefit patients seeking this change. Such efforts would also be useful during medical or psychiatric hospitalizations, where the length of stay may be quite short.³⁴

In the case of Ms. J, transition from methadone to buprenorphine was also accomplished in a manner similar to the work of Urban and Sullivan.²¹ However, we sought to expand upon previous work by providing a more detailed account of the transition and induction procedure during a medical hospitalization in a patient with multiple psychiatric comorbidities. We observed a similar time course in which withdrawal severe enough for induction was apparent by 60 minutes. The current recommendation for a successful transition from methadone to buprenorphine generally calls for waiting for COWS score to reach 8–10, whereas others argue for a higher COWS score of 13–15.^1,3,9 Urban and Sullivan²¹ did not report withdrawal severity, as measured by COWS. In our case, at COWS score of 17, this would be categorized as moderate withdrawal.³⁵

Nevertheless, despite receiving multiple adjunctive medications, Ms. J’s withdrawal was severe enough that it interfered with the sublingual administration of buprenorphine due to the agitation, yawning, and vomiting. Urban and Sullivan²¹ report that all participants expressed gratitude for the efficiency of the procedure but do not describe the patients’ experience during acute withdrawal. In our experience, the precipitated withdrawal was quite severe and nearly intolerable, with the patient threatening to leave the hospital at one point. Yet, she, too, was very grateful in the end once she was on buprenorphine.

Our patient’s agitation is consistent with the reported literature, as 96% of individuals who underwent naltrexone-precipitated withdrawal experienced agitation.³⁶ As such, further research is needed to ascertain whether a lower COWS score can lead to improved tolerability and minimize the disruption of the sublingual administration of buprenorphine. Indeed, in a study of pregnant women transitioning from methadone to buprenorphine, a COWS score of 10 was used as a cutoff in order to minimize discomfort and potential complications for mother and fetus.⁵ Urban and Sullivan²¹ do not comment on any comorbid medical or psychiatric diagnoses in their subjects, but our patient’s history of borderline personality disorder, major depressive disorder, posttraumatic stress disorder (PTSD), chronic pain syndrome, and multiple psychiatric hospitalizations and several suicide attempts provides a better perspective on the efficacy of this procedure in a real-world population, where 57%–67% of individuals on opioid agonist treatment have comorbid psychiatric conditions^37,38 and 72%–83% are prescribed psychotropic medication.³⁹

Our experience also confirmed that 25 mg of oral naltrexone was sufficient to precipitate withdrawal. Although there is concern that the short half-life of naltrexone could cause buprenorphine to induce further withdrawal, this was not our experience. The patient reported relief from withdrawal symptoms with each additional buprenorphine dose (Figure 1) and was no longer in acute withdrawal on the day following the induction. More research is needed to determine whether other doses, or other antagonists (i.e., naloxone), would cause less discomfort for the patient. As suggested by Urban and Sullivan,²¹ the inpatient setting is likely the safest setting to conduct this transition. However, it should be noted that in Urban and Sullivan’s work, individuals were admitted to an addiction unit for the sole purpose of rapid detox. In the case of Ms. J, we performed a rapid transition from methadone to buprenorphine during a medical hospitalization with ongoing medical workup. Given the comorbidities from continued opioid use, as evidenced by Ms. J’s repeated hospitalizations for complications from substance use (i.e., workup for endocarditis, treatment of cellulitis), medical hospitalization offers a critical period where this transition can be performed. Finally, further research is needed to determine whether patients on even higher doses of methadone can be safely transitioned to buprenorphine with this method.

However, not every patient on methadone will be suitable for this method. Although opioid withdrawal is not life-threatening, individuals with significant unstable medical comorbidities should be excluded. In a study of naltrexone-induced opioid withdrawal, roughly 1% experienced myocardial infarction, seizure, and respiratory distress.³⁶ Thus, it may not be appropriate to precipitate acute withdrawal in individuals with significant cardiovascular, respiratory, or neurologic comorbidities.

Our replication of this protocol indicates that this is a viable method for rapidly transitioning patients without medical contraindication from methadone to buprenorphine in an inpatient medical setting. Further research efforts should seek to optimize the tolerability of the protocol and determine the patient population for which it is best suited in order to expand its clinical use.