Introduction

Across the United States, we are experiencing an epidemic related to opioid use disorder (OUD), which has vastly increased over the past two decades.^1,2 This epidemic was likely initiated by excessive prescribing of opioid analgesics (e.g., hydrocodone, oxycodone, fentanyl), and it has escalated to increased use of illicit substances (e.g., heroin). Now, Americans have discovered novel opioid agonist agents that are easier to acquire legally.^1–3 These products can be used to maintain their addiction, but they may also alleviate opioid withdrawal symptoms. These products have been marketed for various applications, including the self-treatment of anxiety, depression, improved cognition, increased energy, and chronic pain relief.^1,4 Examples include the over the counter (OTC) anti-diarrheal medication, loperamide, the traditional Asian medicinal plant, kratom, and other “research chemicals”, such as acetylfentanyl, ocfentanil, and carfentanil.^1,5–9 Supplements containing tianeptine, alarmingly nicknamed “gas station heroin”, have also become popular amongst individuals seeking relief from pain, depression, and anxiety. Tianeptine is an atypical tricyclic antidepressant (TCA) that is marketed under the brand name Coaxil or Stablon in Europe, Asia, and South America. However, it is not approved by the Food and Drug Administration (FDA) for medical use in the United States.^10,11 This medication is available in multi-ingredient supplement formulations in 47 states throughout the United States, while only Alabama, Michigan, and Minnesota have currently outlawed the sale of products containing tianeptine.^12,13 These supplements, commonly named “ZaZa Red” and “Pegasus”, can be easily purchased at local convenience stores and online resources without a prescription. According to a 2019 report by the Drug Enforcement Administration (DEA), tianeptine is not currently listed as a controlled substance under the Controlled Substances Act.¹¹ The increased use and ease of accessibility at local convenience stores has prompted concern by Mississippi physicians who have encountered patients presenting with opioid withdrawal symptoms, while consuming high daily doses of tianeptine-based products. In the following case series, we will present two patient cases from a local outpatient clinic related to tianeptine use and the presentation of opioid withdrawal symptoms. Informed consent was obtained from both patients, and their health information has been de-identified to maintain confidentiality.

Patient Case #1

A 42-year-old male patient presents to a local outpatient clinic with the chief complaint of worsening anxiety symptoms. Past medical history pertinent to this case includes alcohol use disorder, depression, anxiety, hypothyroidism, and degenerative disc disease. He expressed concerns about the use of a supplement, purchased at a local convenience store over the past six months. No prior use of this supplement was documented in the patient’s medical record prior to this event. He reported feeling “addicted, anxious, and restless” and experiencing “strong cravings”, which were only resolved by taking this supplement. He also brought its container for further review with his physician during the visit, and it was determined that this supplement contained a proprietary blend of ingredients, including tianeptine. The patient initially started taking one to two tablets daily, but gradually escalated to 15 tablets daily. The package labeling recommends taking one tablet by mouth every six hours as needed. Physical examination was unremarkable, and vital signs were within normal limits. Previous encounters indicated well-documented issues of non-adherence to levothyroxine therapy, which may have potentially contributed to the patient’s clinical presentation. Patient was also previously initiated on extended-release bupropion 150mg once daily during a recent visit for treatment of depression and anxiety, but he had reported worsening anxiety, since co-administering with tianeptine. These clinical findings prompted the physician to consult the clinical pharmacist and the local poison control center for additional information. The local poison control center recommended treating the patient similarly to opioid withdrawal, using a gradual taper and monitoring for the treatment need of benzodiazepines for acute cessation or buprenorphine for resistant disease. The physician discussed treatment options with the patient, who eventually chose the self-tapering option. The patient was advised about the symptoms that would necessitate an emergency department visit (e.g., seizures, hallucinations, altered mental status) and about the consequences regarding abrupt discontinuation of tianeptine. The patient was advised to follow-up with the physician in one week if current symptoms worsened or new symptoms developed. The patient attempted self-tapering, but eventually admitted himself to the local inpatient addiction treatment facility for further evaluation and treatment. The patient was treated with individual and group psychotherapy, along with the opioid detoxification protocol, which includes clonidine, ibuprofen, acetaminophen, olanzapine, hydroxyzine, loperamide, and trazodone. The patient eventually discharged himself the facility against medical advice, less than two days into receiving treatment, citing sleep difficulties at the facility. Physical exam was unremarkable, and vital signs were stable at the time of discharge. The patient chose to arrange his own follow-up with his physician later, but no additional follow-up encounters have been documented prior to authoring this case report.

Patient Case #2

A 48-year-old male patient presents to a local outpatient clinic with the chief complaint of “aches all over his body”. Past medical history pertinent to this case includes depression, insomnia, opioid use disorder, and osteoarthritis. The patient reported that his scalp was “on fire” and had experienced “hot and cold sensations on his skin”. He reported taking a supplement, purchased from a local convenience store, over the past two months for the treatment of chronic low back pain. The patient also brought the container for further review with his physician during the visit, and it was determined that this supplement also contained a proprietary blend of ingredients, including tianeptine. As the patient had previously experienced opioid withdrawal symptoms, he recognized these similar signs and symptoms, which prompted him to seek further evaluation at the clinic. The patient reported initially taking one to two tablets daily, but gradually increased to 60 tablets daily. No recommended dosage was available on the package labeling. Physical examination was unremarkable, except for a notably anxious appearance, and vital signs indicated an elevated blood pressure of 174/82 mmHg. The patient scored 10 out of 48 on the Clinical Opiate Withdrawal Scale (COWS) assessment, indicating mild opioid withdrawal symptoms. However, the physician noted a concern for progressively worsening withdrawal symptoms, as the patient had stopped taking this tianeptine-based supplement prior to the appointment. These clinical findings again prompted the physician to consult the clinical pharmacist and social worker for additional information. Upon discussion with the healthcare team, the physician referred this patient to a local inpatient addiction treatment facility for further evaluation and treatment. Upon admission, the patient reported experiencing “rainbow prismatic” visual hallucinations to the attending psychiatrist at the facility. The patient was evaluated and treated for a duration of 30 days, according to the detoxification treatment protocol at the facility, which included buprenorphine-naloxone, gabapentin, ibuprofen, acetaminophen, tizanidine, olanzapine, ondansetron, loperamide, and trazodone. The patient also received individual and group psychotherapy counseling, while undergoing the pharmacologic detoxification treatment protocol. After discharge from the addiction treatment facility, the patient presented for an additional follow-up clinic visit with his primary care physician, where he reported “being clean” from tianeptine for six weeks, including his time with inpatient rehabilitation services. The patient also continued to receive outpatient treatment and follow-up monitoring with psychiatry and counseling services.

Discussion

Tianeptine acts as a full mu-opioid receptor (MOR) and a weak delta-opioid receptor (DOR) agonist that triggers the modulation of the glutamatergic system, which is responsible for antidepressant and anxiolytic effects.^14,15 MORs are broadly exhibited throughout the hippocampus in the brain, which can modulate glutamatergic neurons and synapses through several mechanisms.¹⁴ Tianeptine also increases the availability of dopamine in the nucleus accumbens, which can also modulate glutamate release through activity at presynaptic dopamine receptors on glutamatergic presynaptic terminals.¹⁴ Orally administered tianeptine has a systemic bioavailability of 99%, and it is rapidly absorbed for action in the human body within one hour.¹⁶ The pharmacokinetics of tianeptine differs from many TCAs, as it is not primarily metabolized by cytochrome P-450 enzymes in the liver. Tianeptine, with an elimination half-life of 2.5 hours, is metabolized by beta-oxidation, generating two additional metabolites: MC3 and MC5. While the propanoic acid sidechain metabolite (MC3) is inactive, the pentanoic acid sidechain metabolite (MC5) is active, with an elimination half-life of 7.2 hours. MC5 also exhibits similar behavioral effects to tianeptine through MOR activation. Less than 3% of each tianeptine dose is excreted in its unchanged form through the urine.^15–18

Tianeptine causes less reported adverse effects, when compared to TCAs and selective serotonin reuptake inhibitors (SSRIs). However, the most common adverse effects associated with tianeptine include nausea, constipation, abdominal pain, headaches, and dizziness, which generally decreases in frequency over time.¹⁸ Tianeptine is also less associated with antihistamine effects (e.g., sedation), anticholinergic effects (e.g., urinary retention, dry mouth, constipation), and cardiovascular toxicity (e.g., QTc prolongation).¹⁸ As a full MOR agonist, high doses of tianeptine can also precipitate symptoms of respiratory depression, which can be potentially reversed with naloxone.^1,17,19 Due to its MOR agonist activity, tianeptine can elicit similar opioid-like behavioral effects, including analgesia and reward.^15,20 Since tianeptine can be abused for its euphoric effects, patients may become dependent and tolerant to this substance, requiring higher doses to achieve those desired effects or to alleviate withdrawal symptoms.²⁰ Abuse and dependency are associated with increased dopaminergic activity in the nucleus accumbens, while withdrawal symptoms (e.g., anxiety, agitation) are associated with glutamatergic activation of N-methyl-D-aspartate (NMDA) receptors in the locus coeruleus of the brain.^20–22 Similar to opioid withdrawal, patients who experience tianeptine withdrawal commonly present with neurologic effects (e.g., agitation, anxiety, drowsiness), cardiovascular effects (e.g., tachycardia, hypertension), and gastrointestinal effects (e.g., nausea, vomiting, diarrhea, abdominal cramps).²³

Treatment for tianeptine withdrawal noted in recent medical literature includes a wide array of potential treatment modalities, and it may be dependent upon the clinical presentation and severity of withdrawal symptoms. Marraffa et al. reported five cases of tianeptine withdrawal, where patients were most-commonly treated with benzodiazepines and antiemetics. Severity of symptoms and clinical presentation influenced the location of care, ranging from observation in the emergency department to intensive care unit (ICU) admission or psychiatric inpatient facility.¹ El Zahran et al. described a series of 29 cases of tianeptine withdrawal from the National Poison Data System, where these patients were commonly treated with benzodiazepines, intravenous fluids, and antiemetics.¹⁰ Trowbridge et al. reported one case of tianeptine withdrawal, where the patient was initiated on clonidine for opioid withdrawal, along with mirtazapine and risperidone for insomnia, anxiety, and depression. Resistant withdrawal symptoms and adverse effects from current therapy resulted in the use of buprenorphine-naloxone for maintenance therapy.¹² Rushton et al. described a series of 27 cases of tianeptine withdrawal in Alabama, where patients were most-commonly treated with benzodiazepines, alpha-2 agonists, opioids, antipsychotics, and antimuscarinics. These patients were treated in a variety of healthcare settings, including non-ICU, ICU, or psychiatric inpatient facilities, based on symptom severity and clinical presentation.²³

The increasing incidence of tianeptine intoxication and withdrawal cases has created a serious concern among physicians across the United States, especially in Mississippi. El Zahran et al. reported a statistically significant increase in tianeptine exposure and abuse related-phone calls to poison control centers across the United States from 2014 through 2017, when compared to 2000 through 2013.¹⁰ Rushton et al. reported 48 cases of tianeptine exposure or withdrawal during the study period of 2015 through 2020, with 37 cases occurring within May 2019 and March 2020.²³ The dramatic increase in tianeptine exposure-related cases has prompted public health officials to outlaw the purchase of tianeptine products in Alabama, which has also caught the attention of public health officials in Mississippi. In a recent March 2022 health alert issued by Mississippi State Department of Health, health care providers were advised about the increasing incidence of tianeptine exposure-related calls to the Mississippi Poison Control Center. Since July 2020, a total of 11 cases have been reported, in predominantly male patients ranging in age from 32 to 46 years old. Forty-five percent of patients experienced common neurological adverse effects (e.g., drowsiness, altered mental status, withdrawal symptoms). Thirty-six percent of patients experienced cardiovascular adverse effects (e.g., chest pain, tachycardia), while 18% of patients experienced gastrointestinal adverse effects (e.g., nausea, vomiting, diarrhea). Of the 11 total reported cases, four patients required hospitalization due to tianeptine exposure or withdrawal. Notably, seventy-three percent of patients reported purchasing the tianeptine-based supplements from a local convenience store. This statement from the Mississippi State Department of Health advised physicians to evaluate their patients for a history of tianeptine use, if they presented with symptoms of opioid withdrawal or overdose, contact the Mississippi Poison Control Center at 1-800-222-1222, and report the incident through the FDA’s MedWatch online platform.²⁴

Conclusion

Our findings from these two patient cases, along with other patient cases reported in recent medical literature, suggests that physicians should be concerned about the rising prevalence of abuse, misuse, and withdrawal associated with tianeptine-based supplements in Mississippi. Tianeptine is not approved by the FDA with an indication to treat any medical condition, including depression, anxiety, or chronic pain. However, it is widely available in a variety of multi-ingredient formulations at many local convenience stores throughout Mississippi. Due to the opioid epidemic, patients may seek opioid substitutes like tianeptine, as this substance elicits similar opioid analgesic effects at high doses. Tianeptine also carries a significant risk of misuse and abuse, as it stimulates the body’s reward pathway by increasing dopaminergic activity in the brain. Due to its short half-life, tianeptine can also elicit withdrawal symptoms, much like opioids, which can be problematic for patients from a physical, mental, social, and financial perspective. A wide array of treatment modalities has been used to treat patients with tianeptine withdrawal symptoms. However, limited research is available to describe their efficacy in a clinical trial that would suggest a clear, first-line therapy recommendation. Additional research will be necessary to determine the most effective treatment for tianeptine withdrawal. Following in-suit with the state legislature in Alabama, Michigan, and Minnesota, a call to action from local physicians in Mississippi may be necessary to raise awareness about this public health concern and to promote stricter regulatory oversight over tianeptine-based supplements.