Dan Tuinstra^1* and Charles Draznin²

¹Pine Rest Christian Mental Health Services & Michigan State University College of Human Medicine Psychiatry Residency and Fellowship Programs, USA
²Cherry Health Southside Health Center, USA

We present the first known published case of a 30-year-old female on methadone maintenance treatment for opioid use disorder (OUD) diagnosed with ocular tuberculosis. Her presenting symptom of tuberculosis was vision change. Treatment on rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) was initiated. Rifampin had profound induction effects on the metabolism of methadone. We describe the treatment course, potential risks and benefits, and the patient’s perspective of the experience. We recommend starting with rifabutin rather than rifampin for patients being treated for ocular tuberculosis with concomitant methadone treatment for OUD to minimize risk of adverse clinical outcomes due to a less clinically significant induction of methadone metabolism.

Keywords: Methadone; Rifampin; Rifabutin; Tuberculosis; Ocular Tuberculosis; Opioid Use Disorder

Mycobacterium tuberculosis spreads by aerosolized droplets infecting 10.4 million people and killing 1.8 million people annually worldwide [1]. Ten per cent of individuals infected with tuberculosis (TB) will develop symptoms; sometimes years later [2] affecting various tissues, including ocular tuberculosis in rare occasions (less than one percent of cases in the United States). This infection most commonly develops from hematogenous spread from pulmonary TB but can also arise from direct infection from infected lids or conjunctiva, or as a hypersensitivity reaction after exposure to antigens [3]. Intraocular TB symptoms can include headaches, red eye, floaters, decreased visual acuity, and photophobia [4]. Fine needle aspiration and culture remains the gold-standard for diagnosis [4] but can take up to 10 weeks. Treatment should not be delayed and consists of a four-medication regimen of rifampin, isoniazid, ethambutol, and pyrazinamide in two phases. Phase one consists of all four medications daily, usually with directly observed treatment (DOT), for two months, followed by rifampin and isoniazid for an additional four months or more. Complications of ethambutol can include ocular toxicity [5].

Rifampin treatment requires special considerations for individuals also being treated for opioid use disorder (OUD) with methadone maintenance therapy (MMT). Rifampin, a potent inducer of CYP 3A4 and CYP 2B6 isoenzyme pathways, is well known to reduce the serum concentrations of methadone [6]. The clinical implications of this include distressing withdrawal symptoms which increase the risk of relapse to opioid use with myriad associated risks. These risks are compounded by the increasing prevalence of fentanyl knowingly and unknowingly present in heroin and illicit opioids [7]. Additionally, the compliance rates of TB treatment are poor [8] and may be even more tenuous in people who use IV drugs [9]. The discomfort of withdrawal precipitated by rifampin is likely to lead to premature discontinuation of TB treatment unless the methadone dose is increased [10]. This places the patient at greater risk of increased morbidity, development of treatment resistant tuberculosis, and greater risk of exposing the community to TB. Concomitant treatment of TB while on MMT improves TB treatment adherence [11].

To optimize the treatment of TB and OUD some pharmacokinetic virtual trials have been conducted. The most critical times for dose adjustments of MMT include the initiation and termination of rifampin treatment. Badhan, Gittins, and Al Zabit, [6] reported that with simultaneous initiation of rifampin 600 mg daily and methadone (escalating 20 mg weekly to doses of 60, 90, and 120 mg daily to steady state) there was a significant decrease in the maximum serum concentration (C-max) and area under the curve for all methadone doses. This forced more subjects into the subtherapeutic serum concentration range for the lower dose regimen groups. When the daily methadone dose was increased to 160 mg daily, 96 per cent of patients achieved a C-max within the therapeutic window, and only one per cent of patients had C-max results in the supratherapeutic range.

Concurrent methadone dose reduction with rifampin termination resulted in a large number of supra- and subtherapeutic C-max measures. The authors recommended initiation of methadone dose reduction one week prior to rifampin termination by 10 mg every 2 days to minimize supratherapeutic C-max results. Metabolism of methadone does not appear to rebound to pre-rifampin rates immediately. Rather, the methadone metabolic enzyme pathway CYP 2D6 needed approximately at least 25 days to return to pre-rifampin treatment levels as evidenced by serum plasma concentrations during gradual reduction of methadone following termination of rifampin [6]. The authors identify that these virtual trials are only potential guides to clinical treatment and that the clinician may be best guided by the clinical status of the MMT patient. Indeed, the authors did not appear to give a clinical consideration to the risks of subtherapeutic serum concentrations of MMT including relapse to illicit opioid use. This is a critical benefit vs risk decision that must be made in collaboration with the individual patient.

Clinical studies of patients undergoing TB treatment with rifampin with concomitant MMT date back to publications from 1976 [12]. Of the 30 patients treated with rifampin (600-900 mg daily), 30 per cent experienced opioid withdrawal symptoms and plasma methadone concentrations decreased 33-68 percent. Methadone half-life frequently was reduced with introduction of rifampin. Data also suggested methadone distribution may be affected by rifampin. A case study of methadone maintenance and tuberculosis treatment [10] reported requiring a three-fold increase in the patient’s baseline MMT dose to 150 mg daily; 80 mg initially and 70 mg at five- and one-half hours later, based on pharmacokinetic data at different methadone doses recorded for the individual seven months prior to RIPE treatment initiation.

The treatment of TB with rifampin in patients on MMT is clearly challenging and includes many careful risk considerations. To improve treatment adherence, Elk and colleagues [8] investigated behavioral interventions including contingency based MMT dose increases and reductions and remuneration reinforcement. Additionally, new magnetic macromolecular nanodrug technologies have been investigated for delivery of methadone and rifampin [13] that may have a role in future treatment of this population. Another approach to treating OUD patients with TB includes transitioning from MMT to buprenorphine treatment. Hagelberg et al. [14] reported a buprenorphine 25% AUC reduction. In vitro studies indicate that some of the same metabolic induction challenges exist for buprenorphine, but to a lesser extent, due to small intestine metabolism [15] and may be a treatment option for some patients.

The following case is a 30-year-old female presenting to a community methadone maintenance clinic for treatment of severe opioid use disorder (OUD), primary IV heroin. She was diagnosed in ocular tuberculosis (TB) after approximately six months of methadone treatment. The patient was unclear on source of TB infection but limited the time of infection to within the previous 2 years. Her presenting concern to her primary care clinician was acute vision loss and was later determined to have ocular tuberculosis of the right eye. Treatment of TB was necessary to retain her vision but posed clinical challenges for concurrent treatment of OUD given clinically significant interactions with methadone maintenance treatment. Her case was reviewed in real time during regular visits to the methadone clinic over a two-month period.

The patient was a 30-year-old white female with history of severe opioid use disorder (OUD) with 4 years of abstinence from IV heroin use. She was treated with 125 mg daily of liquid methadone managed by an outpatient methadone clinic. At this dose the patient noted some tiredness approximately 2 hours after her morning dose. She experienced some occasional night sweats. She had side effects of constipation treated with naloxegol, but switched to polyethylene glycol, and a fiber supplement. She had intermitted cannabis use. The patient developed decreased vision in the left eye, prompting evaluation by an ophthalmologist. This was followed by a QuantiFERON TB test which returned positive and led to an infectious disease consultation. She was diagnosed with ocular tuberculosis of the right eye and initiated treatment on difluprednate drops. She was also scheduled for aspiration of fluid from the left eye to assess for the presence of TB which was negative. However, based on symptoms and her ocular exam, it was thought that the patient did most likely have ocular TB. The patient was unable to identify the source of the TB infection, but noted that routine obstetric care included TB testing and was negative within the last 2 years. The patient initiated treatment on rifampin 600 mg daily for one year, isoniazid 300 mg daily for one year, pyrazinamide 1500 mg for 6 months, and ethambutol 1200 mg daily for two months (RIPE) treatment regimen by infectious disease specialists, managed by the county health department via directly observed therapy (DOT) via in-home nursing appointments and video appointments.

Prior to initiating RIPE treatment, the patient consulted with the methadone clinic. It was known that rifampin would likely induce metabolism of the methadone dose and potentially precipitate withdrawal symptoms. RIPE treatment was to be directly observed during business days, but not administered during weekends. This would likely lead to erratic methadone concentrations that could result in potential toxicity on days without rifampin and withdrawal on days with rifampin. The patient agreed to the plan of taking rifampin seven days per week although only five of the seven days could be observed and be recorded as TB treatment doses.

Isoniazid was known to inhibit methadone metabolism, although not to the point of compensating for induction via rifampin. A multidisciplinary consultation with the patient, a review of the literature, and consultation with the county health department and infectious disease physician informed the methadone management plan. The patient declined the option to transition to buprenorphine/naloxone as she was not able to tolerate this medication in the past. Rifampin was known to also induce metabolism of buprenorphine (although with an uncertain severity), but this, along with her prior experience made buprenorphine nonviable. She chose to proceed with methadone management and was primarily motivated by her desire to retain her vision. She felt if she was to discontinue methadone treatment she would likely relapse to illicit opioid use and would be unlikely to continue treatment of tuberculosis and subsequently be at high risk of losing her vision or having TB spread intracranially. Other motivations the patient noted were her opioid abstinence of four years and desire to continue in her positive recovery trajectory, her children, employment, and relationships.

In preparation for an anticipated methadone dose increase to compensate for the induction due to rifampin, baseline labs, EKG, and methadone peak and trough levels were reviewed and within normal limits. Her methadone peak and trough levels were completed nearly one year prior and were in a therapeutic range. The peak: trough ratio was close to the threshold of a 2:1 ratio typically required for split dosing of methadone (twice daily dosing). The patient and treatment team determined that with the initiation of RIPE treatment, the patient would require rapid increases in her 125 mg daily baseline dose. At this clinic, patients taking doses over 60mg typically increase their doses by no more than 3 mg every 5 days. For this patient, however, the plan was to allow larger increases at shorter intervals. An exception from the state methadone regulatory body for split dosing was approved. Random methadone level was 520 ng/ml prior to initiation of RIPE treatment [Figure 1]. A baseline QTc on EKG was 442ms. Due to the rapid increase in dose, she would change from once weekly appointments to daily appointments for methadone administration with once-weekly physician appointments. A “spot” methadone level (not specifically timed, but close to a trough level) was also collected to guide dosing escalation. Inpatient detox treatment was considered, but not an option due to the patient’s psychosocial factors. She opted to continue outpatient management with close monitoring by an informed support person. She was also educated and supplied with multiple intranasal naloxone kits. Releases of information were completed for her primary care physician, retinal specialist, county health department and infectious disease physicians to facilitate coordination of care.

Figure 1: A summary of associated methadone total daily doses and serum methadone concentrations.  The baseline peak and trough levels are prior to rifampin treatment at 125 mg daily methadone dose.  The “baseline” serum concentration data point represents a non-trough “spot” level prior to rifampin treatment.  The “spot” level on Day 10 was performed 2.3 hours later in the day than at “baseline”.  The day 10 level is one day after rifampin treatment stopped and is limited by emergency department administered additional methadone doses of 30 mg on the evening of rifampin day five and 80 mg the evening of rifampin treatment day seven.  These additional doses are not included in the figure.

The patient started rifampin treatment two days after this initial consultation prior to bedtime to avoid being awake during anticipated withdrawal symptoms. She noted some trouble with insomnia that night. By her fourth day of treatment, now at a dose of 131 mg, she was having nausea and sweats. By her fifth day of treatment that she had symptoms of irritability, nausea, vomiting, chills, and diaphoresis, consistent with opioid withdrawal. Ondansetron and clonidine were ineffective. She was unable to sleep and symptoms were severe enough that she presented to the emergency department. The patient was given another 30 mg of methadone in the emergency department as well as intravenous fluids, metoclopramide, and famotidine with some initial benefit, and was discharged home with methadone clinic follow-up the next day. She was seen by the treatment team and was once again presenting with symptoms of methadone withdrawal. The patient’s methadone dose was increased again to 141 mg (81 mg and 60 mg split) with instructions to increase five mg every two days, now split three times daily to allow smaller variations in serum levels in an attempt to increase her comfort. Her symptoms continued to escalate, and by day seven of rifampin treatment, despite increasing methadone doses, she presented to the emergency department again with nausea and vomiting. There she received intravenous fluids, anti-emetics, and a dose of 80 mg of methadone prior to being discharged home.

The patient was unable to tolerate these symptoms and reported using intranasal heroin and five tablets of oxycodone. Her urine drug screens were consistent with her narrative and contained 6-monoacteylmorphine (a heroin metabolite) and opioids, in addition to methadone. The presence of fentanyl was also detected. She reported that she did not intentionally use fentanyl but deduced that the heroin or oxycodone pills must have contained this as a contaminant.

This illicit use to treat her withdrawal symptoms placed her at severe risk for relapse of opioid use disorder and associated severe risks of morbidity and mortality. After consultation with her infectious disease physician, she was transitioned from rifampin to a similar rifamycin medication, rifabutin. Rifabutin is known to be a less potent inducer of the CYP450 3A4 isoenzyme pathway. Due to the discontinuation of the rifampin, the serum concentration of methadone was anticipated to increase. Her daily dose of methadone was decreased by five mg daily, while maintaining split dosing. She initiated rifabutin and reported significant improvement in methadone withdrawal symptoms. She returned to her baseline dose of 125 mg (split 75 mg/50 mg) daily over ten days from discontinuation of rifampin.

This is the first reported case that we know of describing a rare intersection of primary ocular tuberculosis RIPE treatment during concurrent MMT for OUD. This report is important because of the dearth of guidance in clinical MMT management available in the treatment literature for this unique context. The physicians involved in the patient’s treatment collaborated with the patient’s retinal specialist, primary care physician, infectious disease team, and public health department. They engaged the patient in extensive risk vs. benefit discussions before seeking consent for her treatment. She was presented with the option of inpatient detox services for close monitoring, but she declined citing family responsibilities. Medication assisted treatment (MAT) options, risks, and benefits were discussed with the patient including buprenorphine, buprenorphine/naloxone, naltrexone, and methadone maintenance during TB treatment. Buprenorphine treatment was previously intolerable for the patient and she chose to remain on MMT for treatment of OUD despite extensive education on the risks and alternatives to MMT while being treated for TB. Her primary motivations for treatment were retaining her vision, which was jeopardized by ocular TB, and remaining abstinent from illicit opioids because of the anticipated negative impacts in her relationships, and her financial goals which would be jeopardized by illicit opioid use.

Early in the course of rifampin treatment, the patient had opioid withdrawal symptoms that were intolerable. She relapsed to illicit opioid use. After transitioning to rifabutin, a less potent inducer of the CYP 3A4 isoenzyme pathway, she was able to reduce her escalated methadone dose and felt withdrawal symptoms resolve. This may be a better-tolerated first-line treatment component option for TB in some cases instead of rifampin. A third rifamycin, rifapentine, is also a potent inducer of the cytochrome P450 system and may not have any additional benefits relative to rifabutin in its role in methadone metabolism. The half-life of rifapentine is longer (13-14 hours) than that of the 3-4 hours for rifampin. In clinical situations where DOT of a rifamycin medication cannot be guaranteed seven days per week, this could have a potential role in stabilizing methadone serum concentrations during brief lapses in rifapentine treatment compared to rifampin. This could be especially relevant given compensatory increases in methadone doses to toxic levels if a potent inducer such as rifampin is abruptly discontinued from the medication regimen.

This case of concurrent treatment of ocular TB and MMT for OUD demonstrated several clinical strengths. The communication between specialties, disciplines, and regulatory agencies was critical for reducing the risks involved in initiating treatment. The patient in this case was motivated and reliable. Given the two emergency department visits with additional doses of methadone, and use of illicit opioids, pharmacokinetic data was not of any precise utility. The use of split (twice and three-times daily) dosing, frequent appointments, and effective counseling, along with strong engagement with the patient aided the recovery and harm reduction while treating her ocular TB and OUD safely in an outpatient setting. If a similar scenario should arise again, the treatment team would consider recommending starting with rifabutin treatment to the infectious disease team. Future concerns for our index patient include the potential for adverse effects from ethambutol on the patient’s vision [5] and psychosocial instability that could disrupt treatment adherence. The complexity of this treatment scenario highlights the need for vigilance in preventing TB infection in patients on MMT for OUD to avoid potential morbidity and mortality for patients in recovery.

The patient offered her perspective to the treatment team. She recommended future concurrent treatment of TB for patients taking methadone for OUD be initiated with rifabutin rather than rifampin. She identified that the methadone withdrawal symptoms, presumably related to CYP450 3A4 isoenzyme pathways, were intolerable and put her at higher risk of illicit opioid use. The heroin used in this case contained fentanyl, a much more potent synthetic opioid, which increased the likelihood of a potentially fatal overdose. The patient recommended starting RIPE treatment with rifabutin rather than rifampin given her experience of less methadone withdrawal phenomenon attributed to induction of its metabolism from the concomitant TB treatment.

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Corresponding author: Dan Tuinstra, Lecturer, Pine Rest Christian Mental Health Services & Michigan State University College of Human Medicine Psychiatry Residency and Fellowship Programs, USA.

Copyright: © 2022 All copyrights are reserved by Dan Tuinstra, published by Coalesce Research Group. This work is licensed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.