Treatment of concurrent etizolam and tianeptine withdrawal following accidental overdose

Etizolam is a thienodiazepine benzodiazepine with anxiolytic and sedative properties. Etizolam is approved for medicinal use for anxiety disorders in Japan, Italy, and India but is widely available for purchase as a research chemical on the internet.^1,2  Etizolam-associated adverse effects include drowsiness, sedation, and slurred speech.³  Toxicities observed have included CNS depression, ataxia, dysarthria, and respiratory depression.⁴  Withdrawal symptoms include palpitations, poor sleep, agitation, and tremors.²  Etizolam is most commonly ingested as an oral tablet, although powder, sublingual, liquid, blotting paper, and insufflated formulations have been reported.⁵  Therapeutic doses range from 0.25 to 2 mg daily with a maximum of 3 mg daily.^2,3  Etizolam is approximately 6 to 10 times more potent than diazepam for most pharmacologic effects. Clinical studies^1,2,6  suggest that etizolam is about 10 times more potent than diazepam for hypnotic effects. Table 1 describes equivalent benzodiazepine doses.

Tianeptine is an atypical tricyclic antidepressant approved for therapeutic use in several European countries. Although not approved in the United States, tianeptine is available for internet purchase in bulk powders, counterfeit pills mimicking hydrocodone and oxycodone, and stamp bags.⁷  Tianeptine increases serotonin reuptake, has strong agonist activity at mu-opioid receptors, and may increase extracellular dopamine concentrations, resulting in abuse potential.⁸  Usual therapeutic dosing is 25 to 50 mg daily. A recent review of tianeptine dependence and abuse found that the average daily dose of tianeptine in this population was over 1900 mg.⁹  Acute intoxication results in alterations in neurologic status (drowsiness, agitation, confusion), tachycardia, hypertension, and gastrointestinal distress.⁸  Withdrawal symptoms include agitation, anxiety, nausea, vomiting, diarrhea, myalgias, tachycardia, hypertension, tremor, and diaphoresis.^7,8 

This case describes a patient in the United States who experienced concurrent benzodiazepine and opioid withdrawal symptoms following an accidental overdose of internet-obtained etizolam and tianeptine.

A 32-year-old male with a history of insomnia and benzodiazepine use disorder presented to the emergency department after being found at home unconscious with gurgling noises and cyanotic lips. He received naloxone 8 mg and a sternal rub, resulting in return of consciousness. In the emergency department the patient was tremulous and diaphoretic. His mental status was intact although he appeared sedated. Vital signs and pertinent laboratory values are described in Table 2. He received IV diazepam 5 mg and 4 L of lactated ringers resulting in quick normalization of the lactic acid and temperature. He was admitted to a medical-surgical unit.

Patient interview and collateral obtained from family revealed that he had been ingesting several substances he procured from the internet including etizolam and tianeptine. He reported taking liquid etizolam daily for the past 1.5 years. The concentration of the etizolam bottle was labeled as 10 mg/mL. On the day of the overdose he ingested 1.5 mL (15 mg etizolam), noting that usually he takes 2 to 3 mL (20-30 mg) daily. He also reported taking “low doses” (unknown dosage) of tianeptine daily for the past 2 years, but at times takes “megadoses” (50 mg) to achieve opioid effects. On the day of the overdose, he took 50 mg, but stated that it was his first time using a new bag which was marketed to be more potent. He also endorsed occasional social use of phenibut, a glutamic acid derivative with anxiolytic and addictive properties which is not approved for use in the United States but is easily obtainable online.¹⁰  He reportedly did not ingest phenibut on the day of overdose. The patient indicated that the overdose was unintentional although he had felt increasing depression in the weeks leading up to the incident. He was unaware of the addictive potential of these substances despite a history of prior withdrawal symptoms, and he had never experienced a seizure. He treated his symptoms in the past with diazepam and buprenorphine and requested treatment for his substance use disorders on this admission.

During the hospital admission, poison control services were contacted and they recommended IV fluid hydration and serial electrocardiograms for 24 hours to monitor the QTc interval. The patient maintained normal sinus rhythm throughout the hospital stay with no QTc prolongation noted. The day after admission, he began experiencing withdrawal signs and symptoms including dilated pupils, shivering, insomnia, diarrhea, myalgia, anxiety, and irritability. He additionally described tingling and numbness of bilateral lower extremities and auditory and visual hallucinations. These hallucinations included commands to hurt loved ones and seeing “demonic figures” and “weird shapes” in the dark. The internal medicine service initiated oral methadone 5 mg twice daily to treat opioid withdrawal and chlordiazepoxide 25 mg every 6 hours to treat his benzodiazepine withdrawal, the latter of which the patient stated was being tapered too aggressively.

Addiction medicine was consulted. Using a conservative dose equivalence of 1 mg etizolam to 5 mg diazepam as described by Altamura et al,¹¹  we estimated that 20 to 30 mg of etizolam is equivalent to 100 to 150 mg of diazepam daily. We recommended oral diazepam 20 mg 4 times daily with additional diazepam 20 mg every 6 hours as needed for breakthrough symptoms. Gabapentin 300 mg 3 times daily was initiated. Recommended supportive medications included trazodone, clonidine, ibuprofen, loperamide, and ondansetron. Since the patient had already received methadone prior to the addiction medicine consult, we recommended a methadone taper followed by referral to outpatient services to initiate buprenorphine maintenance treatment so as not to complicate the hospital course with possible precipitated withdrawal. He received methadone 5 mg twice daily for 3 days, followed by 5 mg daily for 2 days.

The patient was discharged from the hospital on day 6 on a simplified regimen of diazepam 40 mg twice daily and gabapentin 300 mg 3 times daily. Outpatient follow-up was arranged with an addiction medicine specialist with a warm handoff plan to provide treatment for the benzodiazepine use disorder using a prolonged diazepam taper while concurrently treating the patient's tianeptine use using a medication for opioid use disorder (likely buprenorphine based on patient preference). Information regarding the patient's long-term disposition is limited as he was referred outside of our hospital network. At last known contact, the patient had successfully established care with the outpatient addiction medicine specialist to whom he had been referred.

At therapeutic doses, etizolam may have a reduced potential to induce tolerance and dependence compared with other benzodiazepines.²  However, the increasing prevalence of nonmedical designer benzodiazepine use in several countries over the past decade has resulted in increasing documented instances of etizolam dependence and abuse. In an evaluation of calls about designer benzodiazepines to the US National Poison Data System between 2014 and 2017, etizolam was the most common single agent exposure identified (162 out of 234 exposures, 69.2%). This study also identified an overall increase in exposure to designer benzodiazepines over the 4-year period, increasing from 26 exposures in 2014 to 112 in 2017.¹² 

Furthermore, illicitly manufactured preparations may contain varying and unknown content, often leading to unpredictable consequences.⁶  Garland and colleagues¹³  examined the presence of designer benzodiazepines in over 38 000 healthcare urine samples, where 40 of these specimens contained a designer benzodiazepine, of which 34 were etizolam. Over 82% of samples were copositive with an opioid, and 47.5% with a prescription benzodiazepine. Numerous deaths involving etizolam have been described, often in the setting of mixed ingestions.⁴  In 2019, the World Health Organization²  declared etizolam a public health and social problem. Similarly, the opioid epidemic has been fueled by the availability of nonprescription opioid agonists such as tianeptine. A report¹⁴  of tianeptine exposures in the United States between 2000 to 2017 revealed an increase in use between 2014 to 2017, suggesting that tianeptine also represents an emerging public health risk. Out of 218 calls related to tianeptine exposure, 83 involved coexposures to substances such as phenibut, alcohol, benzodiazepines and opioids.¹⁴ 

Polysubstance overdoses and withdrawal syndromes involving nonprescription substances present a challenging clinical scenario. In our patient, it is likely that the overdose was because of the tianeptine given the recent initiation of a more potent formulation. However it is impossible to know if use of additional substances or contaminants in the preparations might have contributed, as evidenced by presence of barbiturates in the urine. We aimed to treat both withdrawal syndromes concurrently, taking into account patient preference for treatment options. Our initial concern in approaching disposition for this patient was that it might be challenging to find an outpatient provider willing to prescribe benzodiazepines to a patient for whom there was no documented record of benzodiazepine use on the prescription drug monitoring record. Ultimately, proactive discussion with an outpatient addiction medicine specialist allowed for a smooth transition and a plan to treat both substance use disorders, highlighting the importance of a warm handoff in managing substance use disorders.

Clinicians often work with limited information when handling cases involving toxicity and withdrawal from nonprescription substances and may have to rely on case reports to guide their approach. To our knowledge, this is the first case detailing management of concurrent withdrawal from etizolam and tianeptine. Although prior case reports^15,16  have discussed the use of buprenorphine in managing tianeptine withdrawal symptoms, this is the first reported use of methadone to manage such symptoms.

The authors thank Juliet D. Caldwell, MD.