Dextromethorphan-induced serotonin syndrome

Abstract

Introduction. The ability of dextromethorphan to potentiate serotonin levels and lead to serotonin syndrome is well known but few case reports are published. The lack of published cases suggests therapeutic doses of these drugs are not enough to cause serotonin syndrome. We present two cases of serotonin syndrome associated with supra-therapeutic doses of dextromethorphan and therapeutic levels of a selective serotonin reuptake inhibitors (SSRI). Case Series. In case one, serum drug levels from admission revealed a dextromethorphan level of 950 ng/mL (normal<5), escitalopram of 23 ng/mL (normal<200), chlorpheniramine of 430 ng/mL (normal<20) and undetectable levels of aripiprazole and benztropine. In case two, serum drug levels from admission revealed a dextromethorphan level of 2820 ng/mL, sertraline of 12.5 ng/mL (normal<200), and caffeine of 1.4 μg/mL (normal≤ 9 μg/mL). Discussion. To our knowledge, these are the first cases to use serum levels of dextromethorphan and a SSRI to confirm dextromethorphan-induced serotonin syndrome. Conclusion. Our cases suggest supra-therapeutic dextromethorphan doses with a therapeutic amount of a SSRI are required for serotonin syndrome. More work is needed to answer this question more completely.

Keywords:

• Dextromethorphan
• Serotonin syndrome
• Toxicity
• Analytical
• Selective serotonin reuptake inhibitors

Introduction

The pro-serotonergic properties of dextromethorphan are well recognized (1). Due to the ubiquitous use of dextromethorphan-containing cough medications and selective serotonin reuptake inhibitors (SSRI's), serotonin syndrome resulting from this combination of drugs should be common. The paucity of published cases suggests that therapeutic doses of these drugs are not enough to cause serotonin syndrome.

Since the published case reports do not provide information about dose, it is unclear if serotonin syndrome is the result of therapeutic or supra-therapeutic doses of one or both of these medications (26). We report two cases of serotonin syndrome in patients taking an SSRI therapeutically, but exposed to supra-therapeutic doses of dextromethorphan.

Case 1

A 20 year-old man was found confused by his family. Paramedics administered 2 mg of naloxone and 50 mL of 50% dextrose IV for a blood glucose of 59 mg/dL without effect. He was then transported to a local emergency department where he was found to be febrile (temp 102.0 F), confused and tremulous. Due to a history of depression there was a concern about an intentional ingestion. Available medications included aripiprazole, benztropine, escitalopram, and dextromethorphan-containing cough medicines. In the emergency department, a head CT and lumbar puncture were performed; both results were normal. He was given ceftriaxone and then transferred to our medical toxicology service.

Upon arrival at our facility the patient's vital signs were as follows: rectal temperature 38.4 C, pulse 168 beats per minute, respirations 16 breaths per minute, blood pressure 150/80 mmHg, and oxygen saturation was 94% on room air. On exam, the patient was warm, flushed and had generalized diaphoresis, and his pupils were 6 mm and reactive. He was tremulous and lethargic, but easily aroused, with incomprehensible speech. His lower extremities were rigid and hyperreflexic, with seven beat clonus at both ankles. His upper extremities and the remainder of his neurologic examination were normal.

Due to concerns about seizure activity an EEG was performed but revealed no epileptiform activity. A basic drug screen (Dade Behring Emit II; Deerfield, Il) was positive for opiates, marijuana, and phencyclidine (usually a false positive at our facility due to the presence of dextromethorphan); serum acetaminophen, salicylate and ethanol levels were non-detectable. Serum creatine phosphokinase was 327 U/L and a white blood count was 14,500/mm³ while the remainder of the complete blood count, prothrombin time, liver function tests, electrolytes, BUN, creatinine, and thyroid stimulating hormone were all within normal limits. An EKG showed sinus tachycardia with a QRS of 92 milliseconds and a QTc of 462 milliseconds without ischemic changes.

Over the course of 90 minutes, the patient received a total of 6 mg of IV lorazepam, 12 mg of oral cyproheptadine, and intravenous fluids (IVFs). He was then resting without tremor and his heart rate decreased to 124 beats per minute. Generous IVFs and frequent lorazepam doses were used to ensure urine output, control agitation, and prevent clinically significant rhabdomyolysis.

Within 12 hours of his admission, the patient was awake and neurologically normal with a falling creatine kinase. He admitted to ingesting a large amount of dextromethorphan-containing cough medications. He denied any supratherapeutic doses of his prescription medications (escitalopram, benztropine, and aripiprazole.) A comprehensive urine drug test, using gas chromotography-mass spectrometry (GC-MS), confirmed the presence of nicotine, chlorpheniramine, escitalopram and dextromethorphan (no phencyclidine was identified). Serum drug levels sent at the time of admission revealed a dextromethorphan level of 950 ng/mL (therapeutic levels discussed below), citalopram/escitalopram level of 23 ng/mL (therapeutic<200), chlorpheniramine level of 430 ng/mL (therapeutic<20) and undetectable levels of aripiprazole and benztropine.

Case 2

A 6 year old boy, recently started on sertraline, was found lethargic and confused with an empty bottle of dextromethorphan elixir. The estimated amount of ingested dextromethorphan was 40 mg/Kg. The family immediately brought the patient to the emergency department. Upon arrival, his vital signs were: rectal temperature 100.6 F, pulse 118 beats per minute, respirations 24 breaths per minute, and blood pressure 140/69 mmHg. His skin was warm and diaphoretic. Neurologically, he was confused and irritable with rigidity and clonus in his lower extremities only. His pupils were dilated. Otherwise, he had intact cranial nerves and moved all his extremities equally. He was sedated with fentanyl and versed, intubated for airway support, and given IVFs.

A non-contrast head CT, complete blood count, electrolytes, and renal function were normal. A total creatine kinase was 134 U/L. Salicylate, acetaminophen, and ethanol levels were non-detectable. GC-MS confirmed dextromethorphan and caffeine in his urine. Serum drug levels from admission revealed a dextromethorphan level of 2820 ng/mL, sertraline of 12.5 ng/mL (therapeutic<200), and caffeine of 1.4 μg/mL (peak plasma level ≤ 9 μg/mL one hour after 300 mg oral dose). He was extubated and neurologically intact within 15 hours of admission.

Discussion

Serotonin syndrome has been well characterized in the literature since the first description was published by Sternbach in 1991 (7). It is a dose-related response to the use of pro-serotonergic drugs, often in combination (1,7). Drugs that are commonly associated with serotonin syndrome include monoamine oxidase inhibitors, tricyclic antidepressants, SSRIs, trazodone, meperidine, linezolid, cocaine, methamphetamine, lithium, and others (1,78). Signs and symptoms are the result of excessive serotonin in the central nervous system and include the triad of mental status changes, autonomic hyperreactivity, and neuromuscular abnormalities. The diagnosis of serotonin syndrome is clinical, and based on characteristic signs and symptoms. It is a diagnosis of exclusion.

Case 1 and 2 had a dextromethorphan level of 950 and 2820 ng/mL, respectively. In both of our cases, the serum SSRI levels were in the low therapeutic range. In comparison, following a single 20 mg oral dose of dextromethorphan, healthy volunteers reached peak serum levels of 1.8 ng/mL in 2.5 hours (9); when 30mg of dextromethorphan was given orally four times a day for one week, peak plasma concentration averaged 2.4 ng/mL (range: 0.5–5.9 ng/mL) (9). On the other hand, Kim and Yoo reported that dextromethorphan abusers typically achieve serum levels of 5000 ng/mL (10,11).

There are genetic, P-450-mediated, differences in the ability to metabolize dextromethorphan. In fact, dextromethorphan has been used to segregate patients based on their metabolic (CYP2D6) capabilities (12). We do not have information related to our patients' metabolic status. These genetic variables may help explain the differences in clinical experiences reported by those who abuse dextromethorphan for its disassociative effects.

The implication of this drug-drug interaction is important. If therapeutic doses of dextromethorphan and an SSRI are enough to illicit serotonin syndrome, then the combination of these drugs should be avoided. However, our cases suggest supratherapeutic doses of dextromethorphan as a risk factor for the development of serotonin syndrome. This is also concerning when one considers that “high-dose” (up to 960 mg/d) dextromethorphan has been evaluated as an analgesic for certain pain syndromes, especially since this research has involved the concomitant use of “high dose” dextromethorphan and tricyclic antidepressants (13). Our limited information does not allow us to extrapolate to slow 2D6 metabolizers. More information is required to confirm our findings.

To our knowledge, these are the first case reports of serotonin syndrome that include drug levels to confirm the involvement of specific drugs at known concentrations.