Serotonin syndrome triggered by a single dose of suboxone

Abstract

Suboxone (buprenorphine/naloxone) is an oral medication used for the treatment of opiate dependence. Because of its mixed properties at the opiate receptors, buprenorphine has a ceiling on its euphoric effects. We report the first case of serotonin syndrome caused by buprenorphine and review other medications implicated in serotonin syndrome. A 54-year-old man on tricyclic antidepressants took an unprescribed dose of buprenorphine/naloxone. He presented to the emergency department with signs and symptoms of severe serotonin syndrome including clonus, agitation, and altered mental status. His agitation was not controlled with benzodiazepines and was electively intubated. At the recommendation of the toxicology service, cyproheptadine, a serotonin receptor antagonist, was administered with improvement in the patient's symptoms. Emergency physicians should be aware of the potential of buprenorphine/naloxone to trigger serotonin syndrome. In 2002, the Federal Drug Administration approved suboxone (buprenorphine/naloxone) for the treatment of opiate dependence [1]. Buprenorphine/naloxone is an oral medication that contains buprenorphine, an opiate agonist/antagonist, and naloxone, an opiate antagonist. Because of its mixed properties at the κ- and μ-opiate receptors, buprenorphine, in contrast to pure opioid agonists such as heroin, has a ceiling on its euphoric effects. Naloxone has poor oral bioavailability but will block any euphoric effects if a patient attempts to crush and inject the medication intravenously. The naloxone also discourages patients from using heroin or other opiates while taking buprenorphine. The Federal Drug Administration allows certified physicians to prescribe buprenorphine/naloxone from their private offices unlike methadone where a patient must be enrolled in a formal treatment program [2]. A 54-year-old man presented to a community emergency department complaining of jaw spasm and the inability to open his mouth for 1 hour. One and a half hours before arrival, he admitted to taking a friend's buprenorphine/naloxone in an attempt to achieve a euphoric high. The patient's medical history included hypertension, insulin-dependent diabetes, diabetic peripheral neuropathy, seizure disorder, urinary incontinence, insomnia, and chronic lower back pain. His medication list included insulin, doxepin, ramipril, doxazosin, tolterodine, gabapentin, metformin, amitriptyline, fluticasone, repaglinide, ibuprofen, and morphine. His social history included 1/2 pack of cigarettes per day and had a history of intravenous drug use. However, he denied alcohol use. The patient's vital signs on arrival were temperature of 100.4°F rectally, heart rate of 130 beats per minute, respiratory rate of 30 breaths per minute, blood pressure of 210/93 mm Hg, pulse oximetry of 98% on room air, and a bedside glucose of 243 g/d. The patient was extremely anxious but in no acute distress. He was unable to sit still on the bed. He would respond to questions and follow commands but had episodes during which he spoke nonsensically. On physical examination, his head was atraumatic. Pupils were 4 to 2 mm equal, round, and reactive. There was masseter spasm with accompanying trismus. The neck was supple with full painless range of motion. The lungs were clear. Cardiac examination revealed a regular, tachycardic rhythm without murmurs, rubs, or gallops. The abdomen was obese but soft and nontender, without organomegaly. Extremities were without cyanosis or edema. The patient was unable to cooperate with a detailed neurological examination, but there were no obvious cranial nerve deficits. He had 5/5 strength in all extremities; reflexes were 3+ and symmetrical in the upper extremities, with clonus noted in his lower extremities. The patient had spontaneous jerking movements of his upper extremities as well. The patient remained agitated and confused. He was hydrated with 2 L of normal saline. He was given a total of 8 mg of lorazepam (2 mg in 4 separate doses) and 4 mg of midazolam. He was further given diphenhydramine and benzotropin for a possible dystonic reaction. He was given 2 mg of hydromorphone intravenously for possible acute narcotic withdrawal. There was no change in the patient's condition with any of these interventions. Because of the need to obtain a computed tomographic scan and a lumbar puncture, the decision was made, after discussion with the family, to electively intubate the patient. The patient was intubated using etomidate and succinylcholine without difficulty. Furthermore, ceftriaxone 2 g and vancomycin 1 g were given intravenously for possible meningitis. The patient's laboratory work showed complete blood count within normal limits with a normal differential and normal coagulation studies. The patient's chemistry was significant for a blood glucose of 243 mg/dL, calcium of 7.0 mg/dL, and creatine kinase of 1006 U/L, with a normal MB fraction. Troponin-T and liver function tests were all within normal limits. A urine drug screen was positive for methadone and tricyclic antidepressants. The electrocardiogram showed a sinus tachycardia with nonspecific ST segment changes. A chest radiograph and computed tomographic scan of the brain showed no abnormalities. Cerebrospinal fluid gram stain and culture were negative for organisms. The toxicology service was consulted and was concerned about possible serotonin syndrome (SS) from the multiple tricyclic antidepressant medications combined with buprenorphine/naloxone. The patient was started on cyproheptadine 4 mg via nasogastric tube. The patient was transferred to the intensive care unit in critical but stable condition. The patient was continued on cyproheptadine in the intensive care unit with improvement in his mental status. On hospital day 3, the patient self-extubated and was found to be alert, oriented, and cooperative. He complained of chest pain and was ruled out for acute coronary syndrome with 3 negative troponins. On hospital day 4, the patient was discharged home in stable condition and at baseline mental status. At 6 months, the patient complained of no sequela from this episode. We report a case of SS precipitated by an acute ingestion of buprenorphine/naloxone. Serotonin syndrome is a cluster of symptoms that results from an excess amount of serotonin in the central nervous system (CNS). This is usually the result of drug interactions including selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, and certain synthetic opiates. The effects of serotonin range from mild agitation to death. As the number of prescriptions for SSRIs increases, so does the incidence of SS. In 2005, the toxic exposure surveillance system reported 48 279 exposures to SSRIs with 118 deaths [3]. The diagnosis of SS is based on clinical examination because there is no confirmatory laboratory testing available. Although there is no consensus on the diagnostic criteria for SS, a number of criteria have been proposed [4,5]. Mild symptoms include tremor, diaphoresis, and restless. More severe symptoms include altered mental status, autonomic nervous system instability, and hyperreflexia (usually more significant in the lower extremities) [6]. Previous reports have linked several synthetic opiates to SS. Meperidine, methadone, and tramadol are well associated with SS [7-11]. Although opiate analogues do not inhibit serotonin reuptake like synthetic opioids, there have been several case reports of morphine analogues triggering SS [12]. Karunatilake and Buckley [13] report a case of SS involving oxycodone and as does Rosebraugh et al [14]. Gnanadesigan and colleagues [15] reports 3 cases of SS involving oxycodone at a long-term care facility. The patients in these reports developed the classic triad of autonomic instability, neuromuscular changes, and altered mental status. Because morphine analogues do not inhibit serotonin reuptake like opioids, other theories have been proposed to explain SS involving these drugs. There are no definitive studies in humans that explain the effects of opiates on the serotonergic system. All theories involving opiates and SS come from animal models. Hiyami et al [16] showed that buprenorphine itself increased serotonin metabolites in the midbrain of rats. In a 1998 study, placement of morphine pellets into rat brains produced a 50% increase in circulating serotonin levels [17]. After 12 hours, the level of circulating serotonin returned to baseline. In addition, opiates inhibit GABAergic neurons in the dorsal raphe nucleus and, as a result, disinhibit serotonin release in the CNS [18]. Therefore, buprenorphine may increase serotonin in the CNS through disinhibition or a yet undescribed mechanism. We considered the possibility of opiate withdrawal in this patient precipitated by the naloxone component of the buprenorphine/naloxone. The patient's urine drug screen was negative for opiates but was positive for methadone. However, the temporal relationship between the time the patient took the buprenorphine/naloxone and the onset of symptoms suggests that this medication was the cause of the SS. In addition, we treated the patient empirically with hydromorphone without change in the patient's condition. We report the first case of SS associated with the use of buprenorphine/naloxone. Emergency practitioners and physicians prescribing buprenorphine/naloxone should be aware of the possibility of this drug to trigger SS. © 2008 Elsevier Inc. All rights reserved.