The Administration of Sumatriptan for the Relief of Headache in Serotonin Syndrome

A Kemal Erdemoglu, MD Asst Prof.

Department of Neurology,

Faculty of Medicine,

Kirikkale University,

Kirikkale, Turkey


Serotonin syndrome is a drug induced hyperserotonergic state of the central nervous system (CNS). It is characterized by changes in mental status, agitation, tremor and shivering. It was reported in patients whom used selective serotonin re-uptake inhibitors, monoaminoxidase inhibitors and several different medications concurrently or sequentially (1,2,3,4,5). We report a case of serotonin syndrome which sumatriptan was administered during the highlights of symptoms.


A 32 year old man had a history of co-existing migraine. Phenelzine 15 mg tid was started because of the resistance to all other prophylactic medications. Although the maximum beneficial effect was gained from phenelzine as a prophylactic agent, the advanced side effects and the low tolerance to the medication urged us to change the regimen. It was decided to initiate venlafaxine fourteen days after the last dose of phenelzine. The restrain in hospitalization period by health carriers did not allow the patient to complete the washout period in the hospital. It was ordered to start taking venlafaxine 75 mg bid after two weeks washout period. Patient did not rely on the instructions and started his medication on the sixth day of washout period. Symptoms began approximately in thirty minutes after taking the first dose of venlafaxine 75 mg tablets. Acute onset of nausea and vomiting, profuse sweating, uncontrollably shaking, shivering, lightheadedness, numbness, tingling, shortness of breath and palpitations started. A throbbing, severe headache, covering all of head added to all other symptoms. The severity of headache was rated eight over 10-pain scale.

He was taken to the ER shortly after the onset of symptoms. Blood pressure was 140/60 mm Hg; pulse rate 140 bpm; respiration rate 24 and temperature 37.7 C. He was awake, alert, orientated but markedly agitated and profoundly diaphoretic. Shakiness, tremors, rigors in extremities, incoordination, and hyperventilation was observed. Speech was normal. Cranial nerves were intact. Pupils were dilated with a no sign of anisocoria. None of the meningismus findings was positive. Cardiac examination and EKG were normal other than sinus tachycardia; and chest examination was clear. Tremors through out the extremities, pulses strong, skin diaphoretic

Routine blood biochemistry and blood gases were in normal limits. Hematological studies were normal except a mild degree anemia. (pH: 7.46 PCo2 37 PO2 81 Sat: 95%, WBC: 8.13, RBC 3.92 Hb: 12.0 HCT; 35.9 PLT: 460 NA; 144 K: 4.3 Co2: 30.4 Glucose: 115, BUN: 21, Creatinine 1.1)

Venlafaxine and other medications were stopped immediately. Monitorization and supportive treatment were started. IV hydration and oxygen initiated. Sumatriptan sc. was administered to the patient for the rapid relief of headache with a clue of previous migraine diagnosis but headache did not subside. Other signs and symptoms, mild hypertension and sinus tachycardia persisted. TA: 136/50; pulse rate 108; and respiratory rate 20. In five hours after admission to the ER, patient was not agitated any more; shivering and rigors in legs decreased, sweating stopped but patient was still tired, fatigued. TA: 126/60, pulse 100, respiratory rate 20. In 10 hours after the beginning of symptoms, the intensity of symptoms decreased and vital signs became stable. Patient was not agitated and normotensive, pulse, and respiratory rate was normal. Patient was discharged from the hospital with the resolution of symptoms in twelve hours.


Serotonin has a role in variety of physiologic actions with a wide distribution in the body. Serotonin is found in high concentrations in enterochromaffin cells in GIS (90%), platelets and certain regions of brain as a neurotransmitter. In central nervous system, serotonin is mainly secreted by nuclei that originate in median raphe of brain stem and project to many brain areas (6). Serotonin acts as a neurotransmitter in pain, headache, mood and sleep (7). Serotonin is also assumed to be one of the major transmitter substances in the pathophysiology of migraine (6,8). The important role of serotonin in migraine is supported by the demonstration of change in serotonin metabolism (9).

The modifications of the neurotransmitters through using some of the agents, which act on the neurotransmitters or receptors, are the main proceeding for the management of migraine (8). The field of headache management has changed profoundly in recent years; clinicians have a variety of medications for the treatment of headaches. Sumatriptan and various antidepressants are now available besides classical agents in migraine.

Venlafaxine, one of the new antidepressants, significantly inhibits the re-uptake of serotonin, norepinephrine and lesser extent dopamine. Pharmocodynamically, it resembles the tertiary tricycles antidepressants but lacks the muscarinic-cholinergic, histaminergic or a -1 adrenergic effects. The half-life of the parent drug is approximately five hours and metabolite eleven hours. Venlafaxine is efficacious in the treatment of depression and co-existing migraine (10,11). It is also safe and well tolerated. Sumatriptan is one of the armamentarium of acute migraine treatment in the last decade. It is highly effective and well tolerated in the treatment of acute migraine.

Sumatriptan has the most potent effect on 5HT-1D receptor which is the most common 5-HT receptor subtype in the brain that modulates neurotransmitter release. Sumatriptan has approximately 20 fold less potent at 5-HT1A receptor. 5HT-1D receptor activation inhibits the release of 5-HT, norepinephrine, acetylcholine, and substance P. Sumatriptan is essentially inactive at all other 5-HT receptor subtypes and other receptors such as NA, muscarinic, cholinergic. Double-blind studies have demonstrated that acute treatment with sumatriptan effectively relieves the pain and associated symptoms of migraine.

Serotonin syndrome is a toxic hyperserotonergic state and is characterized by changes in mental status, myoclonus, agitation, hyper-reflexia, restlessness, diaphoresis, shivering, and tremor, muscle rigidity, hyperthermia and autonomic instability. The syndrome typically develops within hours or days of the addition of a new medication or the increment in dosage of the serotomimetic agent which affects serotonin metabolism. The criterias for serotonin syndrome, which was supposed by Sternbach, were shown in Table 1 (2). The definite etiology of serotonin syndrome is unclear. Animal studies suggest that 5-HT-1A receptor stimulation in the brain and spinal cord is the main mechanism of serotonin syndrome (2). 5-HT-2 antagonists could not reserve the serotonin syndrome in rats, but non-selective 5-HT antagonists were effective, presumably through 5-HT-1A receptor blockade (2,12). The appropriate treatment for serotonin syndrome is the immediate discontinuation of both offending drugs and supportive care for observed symptoms. Prompt administration of a non-specific post-synaptic serotonin antagonist such as methysergide or cyproheptadine may be lifesaving (13,14,15,16). B-blockers, which assumed to act as 5-HT-1A antagonists, may also be tried (17,18).

Our case was resulted into serotonin syndrome after the initiation of the first dose of venlafaxine within 6 day after discontinuing of phenelzine. The reinforce in the shortening the number of days for the monitorization by health care providers or carriers and patient's self-desire to start the medication resulted into proceeding of the serotonin syndrome. Clinical picture fulfilled the diagnostic criterias for serotonin syndrome. Patient had been admitted to the emergency room and had been received sumatriptan for the relief of headache during serotonin syndrome. Headache and clinical picture persisted after the administration of sumatriptan.

Serotonin syndrome is supposed to cause by stimulation of 5-HT-1A and 5-HT2 receptors in the brain stem and spinal cord. The serotonin syndrome has been reported in patients using either of these popular 5HT1 agonists, sumatriptan or DHE, despite the fact that they are frequently combined with serotomimetic antidepressants serving as a migraine prophylactic agent (19). Although sumatriptan is a potent migraine abortive agent and acts on dominantly 5-HT-1D and less potent 5-HT-1A, it poorly penetrates the blood brain barrier. Therefore, it may not be expected to intensify or decrease the duration of symptoms by the appliance of sumatriptan as in our case. However, sumatriptan should not be used in serotonin syndrome because it has a potential threat to intensify the symptoms and not effective in alleviating headache in serotonin syndrome. Physician should be alert for the potential for undesirable and even potentially life-threatening interactions between medications. Heightened awareness by the clinicians of the serotonin syndrome, monitoring and supportive treatment may prevent the development of  severe or complicated cases.



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Table 1

Criteria for Serotonin Syndrome

The symptoms must coincide with the introduction or dosage increment of a known serotomimetic agent.

At least three of the following signs and symptoms must be present.

  1. Mental status changes such as confusion or hypomania
  2. Agitation
  3. Myoclonus
  4. Hyper reflexia
  5. Diaphoresis
  6. Shivering
  7. Tremor
  8. Diarrhea
  9. Poor coordination
  10. Fever

Other aetiologies must be ruled out, such as infection, metabolic disturbance, and substance abuse or withdrawal.

Neuroleptic malignant syndrome should be excluded from the differential diagnosis (a neuroleptic agent should not have been initiated or increased in dose prior to the onset of signs and symptoms).



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