Severe tianeptine withdrawal symptoms managed with medications for opioid use disorder: a case report

Abstract

Introduction

Tianeptine is a tricyclic antidepressant (TCA) without FDA-approval that acts on dopamine and norepinephrine. It has opioid agonist activity and is increasingly being used for recreational purposes to achieve an opioid-like anxiolytic effect. This can lead to clinical addiction with subsequent withdrawal symptoms resembling symptoms of opioid withdrawal. There are limited cases detailing the management of tianeptine withdrawal.

Case Summary

We present the case of a 38-year-old male with chronic tianeptine use admitted to the Intensive Care Unit for treatment of encephalopathy and vital sign changes due to intake of multiple substances and suspected tianeptine withdrawal. He reported 8 to 20 g daily use of tianeptine. He was initially managed with buprenorphine/naloxone and supportive care and reported improvement in withdrawal symptoms within three days of admission. We trialed transitioning to methadone, given possible long-term benefit due to TCA-like properties, but this was discontinued due to difficulty with access on discharge. He was provided with a bridge prescription for buprenorphine/naloxone to cover until his outpatient follow-up visit and was subsequently discharged home.

Conclusion

This case demonstrates management of tianeptine withdrawal in a hospitalized patient presenting with significant daily use not reported previously in the literature.

Keywords:

• Tianeptine
• opioid use disorder
• opioid withdrawal
• medication assisted treatment
• case report

Introduction

Tianeptine is an atypical tricyclic antidepressant that is approved in 25 countries under the brand name Coaxial or Stablon but is not FDA-approved in the United States.¹ However, it can easily be obtained in gas stations, convenience stores, and online.^2,3 Tianeptine has also been encountered in the U.S. by law enforcement in various forms including bulk powder, counterfeit pills, and individual stamp bags that are used to distribute heroin.³

Tianeptine increases the levels of dopamine and noradrenaline in the nucleus accumbens and other parts of the meso-corticolimbic dopamine pathway.^4,5 Importantly, it is an agonist of the μ-opioid and δ-opioid receptors.⁶ Recreational tianeptine induces an opioid-like anxiolytic effect which is reinforced by the activation of the dopamine 1 receptor.^4,6–10 This produces euphoric effects and can lead to clinical addiction with resulting withdrawal symptoms similar to opioid withdrawal.

This case study describes significant daily use of tianeptine with acute opioid withdrawal symptoms alleviated with medications used for opioid withdrawal.

Patient information

A 38-year-old male with a past medical history of anxiety disorder, opioid use disorder, seizure disorder, and cerebral vasoconstriction syndrome secondary to substance use presented to the emergency department (ED) because of symptoms suggestive of acute opioid withdrawal. He was released with a plan for tianeptine taper and methadone treatment in the outpatient setting. The patient used tianeptine once within 24 hours following ED discharge and returned to the same ED following ingestion of hand sanitizer, which he described using to manage withdrawal from tianeptine. He reported consuming tianeptine 8–20 g daily after online and gas station purchases. Additionally, over the three days preceding his presentation, he ingested a bottle of cough sirup (Cough syrup may contain additional agents such as dextromethorphan or codeine, which can be used for their dissociative or opioid-like euphoric effects, respectively, when taken in large quantities than intended.)¹¹ in addition to 20 mg duloxetine daily. His wife reported he was also huffing keyboard cleaner and body spray, drinking mouthwash, and smoking Delta-8 tetrahydrocannabinol (Delta-8 tetrahydrocannabinol is a psychoactive cannabinoid and structural isomer of Delta-9 tetrahydrocannabinol that is unregulated in the United States and used for its euphoric effects).¹²

In the ED, the patient was pale, cyanotic, tachycardic, and hypotensive. Intravenous (IV) fluids and a non-rebreather mask were administered. Elevated lactate raised concern for methemoglobinemia, and methylene blue was administered. The patient was medically admitted to the Intensive Care Unit (ICU) for management of encephalopathy post-ingestion with contribution from tianeptine withdrawal.

Clinical findings

In the ICU, the patient was hemodynamically stable, alert, and capable of participating in conversation. Physical examination was notable for distractibility, acute distress, and diffuse abdominal pain on palpation. The patient was severely anxious and was objectively restless with tapping of hands and feet. He reported fluctuating severity of withdrawal symptoms, incompletely relieved by supportive care and buprenorphine.

Diagnostic assessment

A urine drug screen confirmed the presence of buprenorphine (prescribed to him) and cannabinoids. Lactate was elevated at 1.4 mmol/L, with white blood cell count elevated at 11.98 K/uL. His liver function test and serum electrolytes were within normal limits. Blood alcohol level was undetectable, and urinalysis showed trace bacteria.

The patient was assessed by the psychiatry consult team with concern for acute encephalopathy secondary to substance ingestion and withdrawal, severe tianeptine use disorder, and underlying generalized anxiety disorder with panic attacks. The patient elaborated on his multiple ingestions representing a desperate attempt to control his withdrawal symptoms, adamantly denying intentional self-harm. He disclosed having significant anxious distress with panic attacks since childhood. He initially relied on prescribed benzodiazepines to control his anxiety symptoms. For the past several years, having no access to a benzodiazepine prescriber, he resorted to self-medicating with tianeptine. Initial daily doses ranged from 500 mg to 1 g per day, depending on anxiety severity. With time, he developed tolerance, and withdrawal symptoms occurred six to eight hours following medication ingestion.

To prevent withdrawal, he administered tianeptine three to four times daily, reaching a total daily dose of 15 g. Tianeptine reportedly calmed him, reduced his anxiety, improved focus, and improved concentration. Withdrawal was characterized by anxiety, dysphoria, depression, headaches, diffuse myalgias, restless legs, hot flashes, sweating, chills, abdominal discomfort, nausea, diarrhea, and vomiting. In the absence of tianeptine, physical withdrawal symptoms lasted one to two weeks. Cravings continued during this time and the patient reported he was unable to work. The monthly cost of tianeptine ranged from 500 to 800 United States dollars, causing the patient financial strain. When tianeptine was unavailable, he resorted to drinking large volumes of beverages containing ethanol, supplemented by hand sanitizer, rubbing alcohol, mouthwash, and keyboard/file cleaner. He reported a remote history of opioid use disorder, managed with methadone five years prior. He also reported remote use of marijuana, cocaine, and kratom. The patient reported compulsions of picking at nail beds and shaking of his legs that occurred in the absence of drug use or withdrawal. He was unaware of such behavior until others pointed it out.

Challenges to diagnoses included ingestion of multiple substances complicating assessment of withdrawal and initial altered mental status on presentation.

Therapeutic intervention

Buprenorphine/naloxone sublingual (SL) was ­initiated at 4 mg/1 mg twice daily, with additional as needed buprenorphine/naloxone 2 mg/0.5 mg every 2 h and IV buprenorphine 0.15 every 6 h. Symptoms were monitored with Clinical Opiate Withdrawal Scale assessments.¹³ With improvement in mental status and vital signs, he was transferred into a medical/surgical unit. Upon arrival to the floor, the patient reported feeling “awful” with symptoms of anxiety, fatigue, chills, diaphoresis, and nausea. His anxiety symptoms were managed with hydroxyzine 25 mg every six hours as needed. The patient reported noncompliance with duloxetine, and this medication was held during the acute withdrawal phase. He denied severe depression and suicidal ideation and his wife provided reassuring collateral information.

The addiction medicine consult team recommended outpatient substance use treatment for severe tianeptine use disorder and opioid use disorder. Buprenorphine/naloxone was discontinued since the patient was in favor of methadone maintenance. We also theorized there would be greater benefit with methadone due to its TCA-like properties. Methadone was initiated at 5 mg by mouth daily. For ongoing distress from withdrawal and in the absence of sedation, the patient was provided with an additional 5 mg of methadone. Additional dosing was made available with a total daily maximum daily dose of 15 mg within the first 24 hours of medication initiation. Additional medication provided included clonidine 0.1 mg/24 hour patch as needed for opioid withdrawal and ropinirole 0.5 mg by mouth three times daily as needed for restless leg syndrome.

Withdrawal symptoms improved by day three of admission with initiation of methadone. The patient continued to endorse anxiety, but it was improving with management of withdrawal. Cravings were reduced as well.

Follow-up and outcomes

Since the addiction team was unable to secure an initial outpatient visit and access to methadone on the weekend, to expedite discharge, the patient elected to return to buprenorphine/naloxone at 8 mg/2 mg sublingual films twice a day to manage withdrawal symptoms and cravings. Despite having received methadone, direct resumption of buprenorphine/naloxone was achieved without buprenorphine-precipitated withdrawal. He was provided with a bridge prescription for buprenorphine/naloxone until his outpatient follow-up visit in five days and was subsequently discharged home.

Timeline

Patient presented to the ED initially and was discharged with plan for outpatient tianeptine taper and linkage with a methadone provider. Twenty-hours later, he returned to the ED with worsening withdrawal symptoms and intentional ingestion of multiple substances leading to ICU admission. He was stepped down to a Medical/Surgical Unit after 24 hours and subsequently discharged 48 hours later to outpatient follow-up with a Suboxone provider. Further follow-up could not be determined as the patient pursued follow-up care outside of our healthcare system.

Discussion

Tianeptine is an antidepressant with many psychopharmacological actions in the brain that are not yet well-characterized. Opioid-like properties of this drug seem to be responsible for its worldwide abuse. Lauhan et al.¹⁴ conducted a literature review that included 65 patients with tianeptine dependence or abuse. More than 80% of cases were from outside the United States and 76% were male.¹¹ Tianeptine abuse in France, for example may be explained by the fact that it ranks first among anti-depressants prescribed to patients who engage in “doctor-shopping.”¹⁴

Tianeptine misuse has been documented in the United States over the last decade.¹⁵ Most medical providers in the United States are not aware of this drug since it is not Food and Drug Administration (FDA) approved and does not belong to a group of well-known street drugs. Additionally, since it can be easily and “legally” obtained in gas stations, convenience stores and online, this drug has not attracted the wide attention of law enforcement.

For use as an antidepressant, tianeptine is dosed between 25 and 50 mg/day. Due to a variety of neuropharmacological effects, tianeptine has potential for misuse over a wide dose range. A review of 18 case reports of tianeptine use found average daily use ranging from 1469 mg/day, up to 4125 mg.¹ The Lauhan et al. study documented an average daily dose of 1924 mg and route of intake included oral, intravenous, and insufflation.¹¹ A retrospective review investigating tianeptine-related exposure calls reported to Poison Control Centers in New York State from January 2000 to April 2017, identified some patients using between 5 to 10 g of tianeptine daily.¹²

This case report describes average tianeptine daily use of 15 g. This is 300–600 times the daily dose recommended for depression treatment. To our knowledge, this is the highest reported daily dose. Our patient described using tianeptine for its cognitive-enhancing effects, mood stabilization and relief of anxiety. A quantitative analysis of Reddit posts by tianeptine users revealed that most of them used it for similar reasons, including its anti-depressant and anxiolytic properties. Most users expressed a desire to discontinue it.¹⁶ Reports of adverse events were characterized by initial adherence to clinical dosing recommendations followed by dose escalation, leading to tolerance and emergence of opioid-like withdrawal symptoms between doses. Posts did not consistently or predominantly reflect attempts to “chase a high.” Instead, they reflected attempts to feel capable, healthy, and productive. Our patient shared this sentiment.

Symptoms of overdose and opioid-like withdrawal symptoms from tianeptine are not widely known in US clinical settings even though Center for Disease Control published an analysis of the tianeptine-related withdrawal symptoms.³ Common adverse effects include agitation, nausea, vomiting, tachycardia, hypertension, diarrhea, tremor, and diaphoresis.³ Our patient experienced significant anxiety, depression, restless legs, nausea and emesis. One could speculate that anxiety, excitability, and parasympathetic nervous system (PNS)-mediated symptoms observed during withdrawal might follow N-methyl-D-aspartate receptor activation in the locus coeruleus and in PNS ganglia.⁵

Lacking FDA approval, tianeptine is not in standard toxicology screens in emergency departments across the U.S., complicating establishment of timely and correct diagnoses. We strongly believe it is imperative that medical providers inquire about use of tianeptine in settings that may mimic overdose or withdrawal from opioids.

Our case utilized buprenorphine/naloxone and a brief period of methadone for managing the patient’s withdrawal symptoms, with success. We also favored methadone because, in addition to agonizing µ-opioid receptors, methadone inhibits serotonin and norepinephrine reuptake like a TCA and antagonizes NMDA receptors. He was addicted to a TCA for its opioid-like properties, and we wanted to treat him with methadone, an opioid with TCA-like properties. However, prescriber access issues and difficulty obtaining methadone outpatient led us to pursue treatment with buprenorphine/naloxone on discharge along with a formal outpatient substance use program.

Limitations

This patient presented opportunities for novel approaches to evaluating and treating an opioid-like withdrawal syndrome but there were a few limitations to note. The patient’s use of multiple substances prior to admission and co-morbid anxiety disorder likely complicated the withdrawal syndrome, making it difficult to attribute his presentation completely to tianeptine withdrawal. From a treatment perspective, we chose to initiate higher doses of buprenorphine and methadone for withdrawal and cravings, but we also could have considered a low-dose or even Bernese method of induction. We also could have pursued only symptomatic withdrawal management. Ultimately, we aligned our treatment with the patient’s goals and outpatient follow-up options. Lastly, in terms of assessment of withdrawal, the patient was subjectively noting improvement at the time of discharge, but he was lost to follow-up outpatient and it is unclear if he continued to have a withdrawal syndrome lasting more than a few days.

Conclusion

Amidst the current opioid crisis, rapid and marked increases in calls to poison control centers related to tianeptine, an opioid-like drug, is of pressing public health concern, contributing to the current state of opioid use nationwide.³ The unique mechanism of action and properties contribute to its addictiveness and withdrawal syndrome. We examined a case of a patient presenting with high dose tianeptine use followed by acute withdrawal managed with medications for opioid use disorder (MOUD) in the inpatient hospital setting. This case stands out from previous cases reported in the literature given the high doses of tianeptine being used. There are clear similarities to other case reports in terms of the rationale for use, withdrawal symptoms, and we make a case for FDA-approved treatments of opioid use disorder in managing tianeptine withdrawal symptoms.

Patient perspective

The patient described a history significant for anxiety with attempts to self-manage via multiple substances with potential for abuse. He had strong knowledge of tianeptine’s potential for misuse and took escalating doses to achieve a desired anxiolytic effect. He initially presented in significant anxious distress and sense of hopelessness around how to resolve his withdrawal symptoms. With supportive care, symptomatic withdrawal management, and initiation of MOUD his outlook greatly improved. He expressed desire for his case to be described in the literature in hopes that other patients may benefit from knowledge about tianeptine’s adverse effects and a multidisciplinary approach to managing withdrawal in the future.

Consent form

Patient provided written informed consent (uploaded to the electronic medical record) for his hospital course and relevant objective findings to be published in this case report.

Statement on case report guidelines

This case report was written to adhere to the CARE Case Report Guidelines.¹⁷

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.