Recognizing serotonin syndrome in the intensive care unit: a case report of serotonin syndrome in a patient taking amitriptyline, buprenorphine, pregabalin, and fentanyl

Introduction

The term serotonin syndrome (SS), an iatrogenic condition stemming from an excess of synaptic serotonin, refers to the constellation of symptoms that manifest within hours to days subsequent to the administration of drugs that elevate serotonin concentrations, either through the synergistic effect of two or more pro-serotonergic drugs or overdose (1). The clinical manifestations of SS encompass altered mental status, which may range from mild agitation and slightly pressured speech to delirium, seizures, and coma, as well as neuromuscular features, including myoclonus, hyperreflexia, muscle rigidity, and severe shivering (1,2). Another component of SS is autonomic instability, which can present with hyperthermia, escalating to temperatures exceeding 41.1 ℃ in severe cases, diaphoresis, tachycardia, hypo-hypertension, diarrhea, and vomiting (1,2). SS has been reported to occur in as many as 14% of patients who overdose with selective serotonin reuptake inhibitors (SSRIs), with a significantly higher incidence expected when an overdose involves multiple serotonergic agents (2). The diagnosis of SS primarily depends on clinical judgment, as laboratory tests and imaging studies do not provide definitive diagnostic confirmation (3). In this report, we describe a case of SS occurring after the administration of fentanyl in a patient with a history of opioid use disorder who had previously been prescribed buprenorphine, amitriptyline and pregabalin. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-40/rc).

Case presentation

A 45-year-old male with a history of opioid use disorder, major depressive disorder, and fibromyalgia was brought to the emergency department (ED) after several falls and with altered mental status. According to the collateral history obtained from the family, the patient had been having multiple falls and getting more confused with deteriorating slurred speech for the last three days before the hospital presentation. On arrival to the ED, the patient was hemodynamically stable; the neurological exam was remarkable for lethargy. Computed tomography (CT) of the head, cervical spine, chest, abdomen, and pelvis without contrast was only remarkable for bibasilar atelectasis. No epileptiform discharges or seizures were observed in electroencephalogram (EEG). Complete blood count (CBC) revealed an elevated white blood cell count (WBC) (14,500/µL), while a comprehensive metabolic panel (CMP) showed no abnormalities. Initial urine, blood, and sputum cultures were collected, with subsequent results indicating negativity in the following days. The patient was started on intravenous ceftriaxone 1 g and oral azithromycin 500 mg in the ED. As his mental status continued to decline, he was intubated and transferred to the intensive care unit (ICU). Fentanyl at a dose of 2 mcg/kg intravenous (IV) and propofol at a dose of 3 mg/kg were administered for intubation. Following intubation, fentanyl and propofol infusions were started for sedation, with doses adjusted to maintain Richmond Agitation-Sedation Scale (RASS) at −4, ranging from 0.7 to 1 mcg/kg/h for fentanyl and 1 to 3 mg/kg/h for propofol. Four hours into admission to the ICU, the patient developed fevers and tachycardia along with diaphoresis, with temperature readings ranging between 38.1 and 39.5 ℃. Initially, the fevers were concerning for infection. The antibiotic regimen was escalated to include ampicillin 2 g IV q6h, ceftriaxone 2 g IV q12h, with IV acyclovir 1,450 q12h due to concerns of meningitis. However, no focus of infection could be identified, and his repeat cultures (blood, sputum, and urine) remained negative throughout his hospitalization. Cerebrospinal fluid (CSF) analysis did not indicate any signs of infection. By the third day of ICU admission, the patient was found to have deep tendon hyperreflexia and inducible muscle clonus during the neurological examination, in addition to persistent hyperthermia (38.1 ℃), tachycardia, flushed skin, agitation and diaphoresis. The patient’s overall condition was congruent with Hunter Serotonin Toxicity Criteria (4). Upon review of the patient’s medications, he was found to be taking buprenorphine/naloxone 16 mg/4 mg daily, amitriptyline 75 mg daily, and pregabalin 200 mg three times a day for several weeks leading up to his admission. As he was on a fentanyl drip, we discontinued this medication as it can promote SS in combination with other agents (5-8). His pregabalin as well as his amitriptyline was discontinued upon concern for SS and his buprenorphine/naloxone dose was reduced. The patient received intravenous fluids, sedation with midazolam, and external cooling in addition to discontinuing suspected medications. Fever began to decrease within 6 hours post cessation of amitriptyline, pregabalin, and fentanyl with resolution of other symptoms and improvement of mentation within 24 hours. The patient was successfully extubated. The patient, his family, and his primary prescribing physician were all involved in a discussion regarding alternatives to his outpatient medication regimen, and the patient was safely discharged. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The accurate diagnosis of SS relies heavily on clinical assessment, which involves identifying potential triggering medications and carefully observing the array of clinical signs and symptoms. Principal differential diagnoses that warrant exclusion include infections, malignant hyperthermia, neuroleptic malignant syndrome (NMS), and other intoxication syndromes such as sympathomimetic toxidrome (1,3). Recognizing SS may pose a challenge in critically ill patients, and determining whether the patients’ symptoms are entirely attributable to complex drug interactions may be uncertain. In the ICU setting, awareness of SS is crucial, as critically ill patients may be at a heightened risk of developing complications associated with SS, including lactic acidosis, rhabdomyolysis, renal failure, and hepatic dysfunction (9). Moreover, drugs related to SS, such as fentanyl, are highly utilized in the ICU, which may deteriorate an undiagnosed SS and increase the risk of fatal complications (10).

Identifying SS relies primarily on clinical judgment, as laboratory tests and imaging studies do not offer definitive diagnostic confirmation. Among the three sets of criteria utilized for diagnosing SS, namely the Sternbach (11), Hunter (4), and Radomski (12) criteria, the Hunter Criteria are regarded as the most accurate, boasting a sensitivity of 84% and a specificity of 97% even though the specificity of which was not tested in ICU patients (10,13). The Hunter Serotonin Toxicity Criteria were formulated using data from patients who overdosed on a single SSRI (n=473) and validated with a larger dataset involving various serotonergic agents (n=2,222) (14). Clonus, including spontaneous, inducible, and ocular clonus, stands out as the pivotal sign in the Hunter Criteria, as this neuromuscular feature has demonstrated a robust association with SS (4). Despite being strongly associated with SS, clonus can be obscured by other manifestations of SS, such as rigidity, and the assessment of clonus is not routinely conducted in the ICU setting. In such scenarios, initiating a prompt response by discontinuing serotonergic agents can serve a dual purpose, aiding diagnosis and treatment.

In the literature, it is evident that monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and SSRIs are among the most concerning serotonergic drugs due to their mechanism of action, which involves increasing serotonin levels (5,15). In this case report, our patient had a history of opioid use disorder, which was confirmed by urine drug screen (UDS), and was on pregabalin, buprenorphine and amitriptyline. SS developed upon administration of fentanyl on top of the existing regimen. Amitriptyline acts by enhancing serotonin and norepinephrine neurotransmission through the blockade of serotonin and norepinephrine reuptake pumps as well as desensitizing both 5-HT1A and beta-adrenergic receptors (6). Fentanyl, akin to other phenylpiperidine opioids such as meperidine, tramadol, and dextromethorphan, appears to act as a weak serotonin reuptake inhibitor while also potentially augmenting serotonin release and is a serotonin agonist with low potency, acting primarily on 5-HT1A and 5-HT2A receptors (7,13). In a retrospective analysis involving 4,583 individuals who received fentanyl along with another serotonergic drug, adverse events were reported in only 23 cases, with just four (0.09%) meeting the criteria for SS (16). Despite the mechanism of which remains incompletely understood, scarce case reports have been published regarding SS induced by IV fentanyl after both single administration or in combination with other serotonergic medications (8,17-20). We found two case reports where SS occurred after intrathecal and transdermal fentanyl administration in patients who had a history of polysubstance abuse (21,22). As previously mentioned, recent case reports indicate a potential risk of fentanyl precipitating SS. However, the exact mechanism underlying this association is still being studied. In their research, Kitamura et al. discovered that analgesic doses of fentanyl can induce SS-like responses, possibly through its activity as a serotonin reuptake inhibitor, independent of its interaction with opioid receptors, as demonstrated in a rat model (23).

The serotonergic properties of gabapentin and pregabalin, antiepileptics that are primarily used for neuropathic pain, are still not fully understood, but they are known to exhibit minimal or no gamma-aminobutyric acid (GABA) ergic activity and mainly interact with voltage-gated calcium channels (24,25). Some authors propose that gabapentinoids-induced myoclonus, a common symptom of SS, may be attributed to their serotonergic properties (26). Several studies have suggested that gabapentinoids may exhibit serotonergic activities; for instance, Rao et al. demonstrated an increase in serotonin concentration in blood following gabapentin administration in healthy volunteers (27). Similarly, it has been shown that pre-administration of serotonin receptor blockers inhibits the antinociceptive effects of gabapentinoids (28). Several case reports were published indicating a temporal association between the development of SS and the use of gabapentinoids, in all of which the patients received another serotonergic drug (29-31).

There are no definitive studies in humans elucidating the effects of opioids on the serotonergic system, with theories derived from animal models (32). However, it is recognized that meperidine, methadone, and tramadol are strongly associated with SS. Additionally, several case reports have been published indicating a link between oxycodone and SS (33,34). Amid the escalating opioid epidemic, buprenorphine has been employed as a medication for opioid use disorder. In their thorough review, Chiew et al. categorized buprenorphine as a “minimal/no-risk” agent for SS due to its lack of direct serotonergic effects (14). Limited case reports of SS in patients using buprenorphine alone or in conjunction with serotonergic medications have been published (32,35). Nonetheless, further investigation is required to understand the relationship between buprenorphine and SS.

Intensivists should be mindful of SS due to its preventable nature and favorable prognosis when the immediate discontinuation of all serotonergic drugs follows timely recognition. Therefore, we believe that our case contributes to the literature in terms of increasing awareness of the possibility of triggering SS with the use of fentanyl, buprenorphine, and pregabalin in patients on serotonergic drugs.

Conclusions

Clinicians need to be able to recognize SS in the ICU, as this can conserve unnecessary workup. This is especially true in those patients who may be on multiple medications that can increase serotonin levels. Involving pharmacists in multidisciplinary rounds may help clarify some of these interactions for intensivists. Closing the loop with all parties involved in the patient’s care upon discharge prevents such events from recurring.

Acknowledgments

The Case Presentation and Conclusions sections of this article have been published on CHEST Annual Meeting 2023.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-40/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-40/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-40/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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