Occurrence of Milnacipran-Associated Morbilliform Rash and Serotonin Toxicity

Case Report

A 57-year-old white female presented to the emergency department (ED) with an erythematous, hot, raised maculopapular rash covering her entire body and face. The patient noticed the rash the day prior to presentation. She reported that the rash began on her chest and spread to her entire body within a few hours. The patient denied pruritus during the examination but had noticed minor pruritus before the rash appeared. She also reported diarrhea, nausea, restlessness, dizziness, and increased muscle pain, all of which began the day prior to presentation. Physical examination showed blood pressure 180/100 mm Hg, heart rate 121 beats/min, respirations 20 breaths/min, temperature 38.9 °C, and oxygen saturation 100% on 2 L of oxygen via nasal cannula. Results of a complete blood cell count were within normal limits. Metabolic panel revealed creatinine 0.8 mg/dL, blood urea nitrogen 10 mg/dL, potassium 3.8 mEq/L, chloride 103 mEq/L, sodium 137 mEq/L, and glucose 105 mg/dL. Electrocardiogram confirmed sinus tachycardia, with a heart rate of 121 beats/min. Her baseline vital signs and laboratory values were unknown. Therefore, it is not certain whether tachycardia and elevated blood pressure were abnormal for this patient. She was admitted for further investigation and observation of her rash.

Nine days prior to the ED visit, milnacipran 50 mg twice daily was prescribed for fibromyalgia by the patient's primary care physician. Milnacipran was titrated as follows: 12.5 mg once on day 1, 12.5 mg twice daily on days 2–3, 25 mg twice daily on days 4–7, and 50 mg twice daily thereafter. On day 7 of the milnacipran titration, the patient was instructed to decrease the fluoxetine dose from 40 mg daily to 20 mg daily, as documented in the patient's medical record. She was nonadherent to this recommendation and continued taking fluoxetine 40 mg daily; she did not recall being instructed to decrease the fluoxetine dose. Her history included recurrent breast cancer first diagnosed in 1999, hypertension, fibromyalgia, depression, osteopenia, gastroesophageal reflux disease, insomnia, and endometriosis. Her home medications consisted of milnacipran, fluoxetine, alprazolam, zolpidem, zoledronic acid, anastrozole, doxepin, ranitidine, levocetirizine, doxazosin, tramadol, vitamin D, and ferrous gluconate. Of those medications, milnacipran, fluoxetine, doxepin, and tramadol have serotonergic activity.

The patient's rash was likely related to the start of milnacipran drug therapy and determined to be a morbilliform drug reaction. At presentation, she also appeared to have serotonin toxicity as evidenced by her heart rate, blood pressure, temperature, restlessness, self-reported diarrhea and nausea, and self-reported increase in muscle pain. Milnacipran, fluoxetine, and tramadol were discontinued, and doxepin was continued. Acetaminophen, diphenhydramine, methylprednisolone, and promethazine were administered in the ED to control the patient's symptoms, and intravenous hydralazine 10 mg was given for blood pressure control. The following morning all vital signs were within normal limits and the diarrhea, nausea, dizziness, restlessness, and muscle pain were resolved. The patient was discharged the following morning and she was instructed to follow up with her primary care provider concerning her fibromyalgia treatment. Follow-up was conducted via telephone and the patient reported that the rash resolved after day 2 of hospital discharge, which was the fourth day after discontinuation of milnacipran.

Discussion

Milnacipran was approved based on the efficacy and safety results of 2 randomized, placebo-controlled, multicenter Phase 3 clinical trials consisting of 1260 patients being treated for fibromyalgia. ^2,8 A pooled analysis of these 2 trials revealed that the most common adverse effect was nausea, with a reported incidence of 34.5%, 40.1%, and 20.4% for patients taking 100 mg/day, 200 mg/day, and placebo, respectively. ⁹ Adverse effects reported in 5% or more of patients and at twice the rate reported with placebo included constipation, hot flush, hyperhidrosis, vomiting, palpitations, dry mouth, tachycardia, and hypertension.

While the mechanism by which milnacipran may cause dermatologic reactions is not clear, rash was initially reported in only 3% of patients taking milnacipran. ¹ Postmarketing surveillance revealed at least 1 incidence of Stevens-Johnson syndrome (SJS) and 1 case report of milnacipran-induced generalized exanthema in a patient being treated with milnacipran for bulimia nervosa. ⁵ The rash appeared during the second week of milnacipran therapy and resolved 3 days after discontinuation. Similarly, our patient's rash developed during the second week of therapy and resolved within 4 days after discontinuation of milnacipran. The patient was treated appropriately with diphenhydramine and methylprednisolone. While in rare cases of drug-induced morbilliform rash it would be acceptable not to discontinue the offending agent, milnacipran discontinuation in this case was appropriate to prevent increased severity. No other therapy was warranted, given the relatively mild nature of the rash. The possibility of more severe reactions such as erythema multiforme major and SJS were excluded based on the absence of skin desquamation, lack of mucous membrane involvement, initial involvement of the chest (erythema multiforme major typically begins on the extremities), and the raised nature of the rash (as opposed to the flat rash associated with SJS). ¹⁰

Milnacipran prescribing information addresses the concern of serotonin toxicity when it is used in combination with other serotonergic medications. ¹ Literature review revealed 1 case report documenting serotonin toxicity associated with milnacipran and paroxetine, a selective serotonin reuptake inhibitor. ⁶ Another case report described a patient who developed serotonin syndrome cardiotoxicity, defined by global hypokinesis and an acute decrease in ejection fraction, due to intentional milnacipran overdose. ⁷ Serotonin syndrome is diagnosed based on history and symptoms, and 2 tools exist to aid in making this diagnosis. The most specific and most sensitive tool is Hunter's criteria, which requires that the patient have taken a serotonergic medication and meet 1 of the following criteria: spontaneous clonus, inducible or ocular clonus plus agitation or diaphoresis, inducible or ocular clonus plus hypertonia plus temperature higher than 38 °C, or tremor plus hyperreflexia. ¹¹ The second diagnostic tool is Sternbach's criteria, which requires the patient to have taken a serotonergic medication and have 3 of the following symptoms: restlessness, tremor, confusion, myoclonus, hypomania, shivering, ataxia, diaphoresis, hyperreflexia, or diarrhea. ¹² Other symptoms experienced by the patient that are associated with serotonin toxicity but not included in these diagnostic tools include hypertension, tachycardia, and increased muscle pain. ¹³ Our patient experienced symptoms included in Sternbach's criteria (restlessness and diarrhea) and Hunter's criteria (agitation, temperature >38 °C, and hypertonia as evidenced by increased muscle pain). Because our patient was 1 symptom short of meeting both Sternbach's and Hunter's criteria for serotonin syndrome, she was considered to be experiencing serotonin toxicity, a milder disorder that precedes the onset of serotonin syndrome. ¹⁴ Serotonin toxicity typically presents within a few hours of drug initiation or dosage increase; our patient did not develop toxicity until approximately 1 week after therapy initiation. A potential explanation is that the slow upward titration of milnacipran may have delayed the onset of serotonin toxicity. Because our patient developed serotonin toxicity instead of the more severe serotonin syndrome, her condition was appropriately managed by discontinuation of the offending agent and provision of supportive care with acetaminophen for pain and fever and hydrazine for blood pressure control. Serotonin antagonists such as cyproheptadine were not warranted given the relatively mild presentation of the toxicity. Other potential diagnoses, such as anticholinergic syndrome, malignant hyperthermia, and neuroleptic malignant syndrome, were excluded based on symptoms, history, and results of physical examination. ¹⁴

According to the Naranjo probability scale, milnacipran was determined to be the probable cause of the patient's morbilliform rash and serotonin toxicity, based on the reaction developing after the medication was taken, the existence of previous reports of the reaction, objective evidence of the reaction, and reaction improvement with medication discontinuation. ¹⁵

Few case reports of morbilliform rash or serotonin toxicity associated with milnacipran have been published. It is important to increase awareness of these reactions to ensure that the clinical significance of these reactions is clearly elucidated to ensure patients are monitored and treated appropriately to improve prognosis.