Myocardial Ischemia Related to Ergot Alkaloids: A Case Report and Literature Review

Ergotamine tartrate and methysergide are widely used headache treatments with important vasoconstrictive properties. We report a 31-year-old man with cluster headaches who developed severe, prolonged myocardial ischemia following combination therapy with ergotamine tartrate and methysergide. We reviewed the cardiovascular complications of each agent alone and in combination. Given the pharmacologic similarity of these agents, we propose that they may have additive or synergistic cardiac toxicity, at least in vulnerable individuals. We recommend caution when these agents are used together.     

Transformed migraine is a cause of chronic daily headaches

Chronic daily headaches (CDH) consist of episodes of head pain occurring daily; more than 15 days each month; often associated with a history of migraine, with or without aura; or with a history of tension-type headaches occurring alone or both occurring together. Chronic daily headaches are frequently associated with rebound headaches after ergotamine, barbiturate, caffeine, and analgesic abuse. We previously reported that migraineurs with typical intermittent headaches exhibited excessive cerebral cortical vasodilation after oral acetazolamide which usually precipitated and reproduced their typical headaches. In the present study, cerebral vasodilator responses were tested by measuring changes in local cerebral blood flow (ΔLCBF) utilizing xenon-contrasted CT scanning, before and after oral administration of 14.3 mg/kg of acetazolamide, in 11 patients with CDH. The results were compared with 12 age-matched typical migraineurs, with and without aura, who had a history of migraine attacks occurring at intervals of 1 month or longer. Global and subcortical gray and white matter ΔLCBFs were quantitated and compared between both groups. After acetazolamide, ΔLCBF increased in cortical gray matter by 11.8% among patients with CDH and by 16.7% among migraineurs, with no significant differences between groups. Typical migraine attacks were provoked by acetazolamide in 9 patients (82%) with CDH and in 11 (92%) migraineurs with intermittent headaches. These observations are taken as evidence that at least 82% of patients with CDH have transformed migraine as judged by the provocation by acetazolamide of typical migraine attacks associated with excessive ΔLCBF increases. Serotonin agonists should be considered in the treatment of CDH to avoid ergotamine, caffeine, barbiturate, and analgesic abuse.     

Menstrual Migraine and Intermittent Ergonovine Therapy

The treatment of patients suffering with menstrual migraine is sometimes a difficult and frustrating problem for the physician. As many menstrual migraine headaches are refractory to abortive therapy, prophylactic therapy is often needed. Ergonovine maleate, an ergot derivative with vasoconstrictive properties, has been used with some success in migraine headache patients. Forty patients who were treated with intermittent prophylactic ergonovine were studied over six months. The patients ranged in age from 22 to 40 years, and all suffered with menstrual migraine headaches which were refractory to abortive therapy. Each patient took ergonovine maleate 0.2 mg three to four times daily during menses and recorded headache occurrence and severity. After three months, 24 patients (60%) reported significantly less severe attacks, six patients (15%) reported less frequent headaches and 14 patients (35%) reported no improvement. After six months there was a decrease in effectiveness with 20 patients (50%) reporting significantly less severe headaches and two patients (5%) reporting less frequent headaches. This limited study suggests that ergonovine maleate may be of value in the treatment of difficult menstrual migraine patients.     

Tolfenamic Acid and Ergotamine Abuse

SYNOPSIS
Thirteen migraine patients using ergotamine tartrate on a daily basis for their headaches were found to have developed the so called "ergotamine headache," a dull constant headache always reappearing if the patient did not take their daily doses. They were treated with tolfenamic acid, an inhibitor of prostaglandin synthesis and action, combined with chlordiazepoxide during the acute withdrawal phase after discontinuing their daily habit of taking ergotamine. As a whole, the results of the discontinuation of the use of ergotamine were encouraging in the group of these patients showing a serious medical problem. None of the patients relapsed into ergotamine abuse, and during the subsequent 3–6 months nine of the patients also treated their migraine attacks solely with tolfenamic acid.     

Ergotamine Dependency- a Review

SYNOPSIS
Ergotamine tartrate has been recognized as the drug of first choice for the treatment of acute attacks of migraine. This paper draws attention to a common but poorly delineated state of addiction that can develop when ergotamine tartrate usage exceeds two or three days per week. This syndrome is characterized by a self-sustaining, rhythmic headache/medication cycle, with daily or almost daily migraine headaches and the irresistible and predictable use of ergotamine tartrate as the only means of alleviating the headache attacks. This report further delineates the clinical features, criteria for recognition, and treatment alternatives for this syndrome. In order to avoid this condition, usage should be restricted to 2 days per week.     

Effects of 5-hydroxytryptamine and ergotamine on human superficial temporal artery

Isometric tension was recorded in ring preparations of human superficial temporal arteries contracted by noradrenaline (NA), 5-hydroxytryptamine (5-HT), and ergotamine. In contrast to NA and 5-HT, ergotamine induced long-lasting contractions refractive to additional stimulations and resistant to repeated wash-out. When tested against 5-HT, ergotamine acted as a non-competitive antagonist. When repeating the 5-HT stimulations (4.7 × 10-5 M) the contractile response decreased indicating tachyphylaxis to this agent. As ergotamine revealed both a vasoconstrictive and a 5- HT-blocking activity, the beneficial effect in migraine may be by an interference during both the vasoconstrictory and vasodilatory phases.     

Aborting a Migraine Attack: Naproxen Sodium v Ergotamine plus Caffeine

SYNOPSIS
The tolerability and efficacy of naproxen sodium and of ergotamine tartrate plus caffeine (ergotamine) were compared in the treatment of acute migraine attacks and associated symptoms. In this multicenter, double-blind, parallel study of up to six headaches over a 3-month period, patients took naproxen sodium 825 mg, ergotamine 2 mg, or placebo at the time of the first symptom of an attack; 30 minutes later, if necessary, patients repeated naproxen sodium 275 mg, ergotamine 1 mg or placebo, as appropriate. Rescue medication was allowed 30 minutes following the second dose if needed. Active drugs provided notably better relief of head pain than did placebo; 1 hour following the first dose the difference between naproxen sodium and placebo was statistically significant. Naproxen sodium was as efficacious as ergotamine in the relief of migraine attacks and associated symptoms. Relief of vomiting, nausea, photophobia, and motor symptoms favored naproxen sodium over ergotamine; these differences were statistically significant for nausea and motor symptoms. Ergotamine-treated patients reported more complaints and had more severe and longer-lasting complaints than patients on the other two regimens. Overall tolerance ratings by both investigators and patients indicated that naproxen sodium and placebo were tolerated significantly better than ergotamine.     

Hypothesis: Serotonin-1C Receptor Activation in Migraine: An Alternative Point of View With Therapeutic Implication

Brewerton's observation that meta-chlorophenylpiperazine, the major metabolite of trazodone, with high affinity and intrinsic activity for the serotonin-1C receptor precipitates migraine headaches in subjects with a personal and/or family history of migraine, prompted Fozard and Gray to postulate that activation of serotonin-1C receptors plays a significant role in the initiation of the attack. Little note was taken, however, of the significant delay between administration of meta-chlorophenylpiperazine and the onset of the headaches. This delay prompts another hypothesis, that the vasoconstrictive action of this substance, as it wears off leads to rebound vasodilation, precipitating migraine. Under this hypothesis, specific serotonin-1C receptor activation is not a necessary condition for the genesis of the migraine attack. As a practical corollary, the vasoconstrictive effect of meta-chlorophenylpiperazine may have therapeutic potential.     

Brachial artery stenosis secondary to ergotism and responsive to nifedipine

Ergotism is an uncommon drug reaction that may lead to severe ischemic vasoconstriction, which is usually unilateral and more commonly involves the lower extremities. Successful therapeutic measures have included invasive vascular surgery and the use of various available intravenous and oral vasodilators. Reported here is the case of a 56-year-old woman with Marfan's syndrome and chronic migraine headaches who presented with upper extremity pulselessness that responded promptly to oral nifedipine (Procardia). This relatively inexpensive agent with potent peripheral arterial vasodilative properties appears to be the agent of choice in severe ergotamine poisoning.     

Transformation of Episodic Migraine Into Daily Headache: Analysis of Factors

SYNOPSIS
Seventy-six percent of patients with daily headaches were found to have a history of episodic migraine in the past, more than half of them hormone dependent headache such as menstrual migraine. Various factors possibly influencing the transformation of episodic migraine into daily headaches were analyzed in a series of 61 patients who presented with daily headaches. Abnormal personality profile, especially neuroticism including depression, excessive stress, excessive use of medications such as caffeine containing analgesics, narcotic analgesics and ergotamine, and development of hypertension were found to be significant in the transformation of episodic migraine into daily headache.
The problem of daily headache is discussed. It is suggested that the majority of daily headaches are a continuum of episodic migraine, influenced and perpetuated by various factors such as neuroticism, excessive medication, stress, and development of hypertension. It is pointed out that diagnosis of tension headache under those circumstances is not justified.     

Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: five-year follow-up

Thirty-eight patients with "chronic daily" headache and ergotamine and/or analgesics abuse according to the criteria proposed by the international Headache Society were re-investigated 5 years after inpatient drug withdrawal. At the end of the observation period, 19 patients (50.0%) had their headaches on only 8 days per month or less, 18 patients (47.4%) were free of symptoms or had only mild headaches. A close correlation was found between the frequency of headache and the duration of drug abuse, as well as between the intensity of headache and the number of tablets taken per month. Frequency and intensity of headache had changed within the first 2 years after withdrawal, but remained stable afterwards. Fifteen patients (39.5%) reported on recurrent drug abuse. Patients with migraine showed a tendency towards a better prognosis compared to patients with tension-type headache or with combined migraine and tension-type headache. The results of this study highlight the long-term efficacy of inpatient drug withdrawal in patients with headache and ergotamine and/or analgesics abuse.     

Migraine headache. Its diagnosis and treatment

Many theories exist on the pathogenesis of migraine. However, the clinical picture of migraine is agreed on universally as a familial disorder characterized by recurrent attacks of headache that are variable in intensity, frequency, and duration. The attacks are usually unilateral and often associated with anorexia, nausea, and vomiting. Migraine therapy is complex and difficult, focusing on abortive and prophylactic regimens. General therapeutic measures, including diet and establishing schedules for meals and sleeping, may benefit many migraineurs. A variety of medications, including ergotamine, propranolol, the calcium channel blockers, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been beneficial in the prophylactic treatment of migraine. Ergotamine is the drug of choice in the abortive treatment, although other agents, such as the NSAIDs, have been used successfully. Inpatient therapy in a specialized unit for headache patients may be indicated for the recidivist patient, the patient habituated to analgesics or ergotamine, or the patient with the mixed headache syndrome, i.e., migraine occurring with coexistent muscle contraction headaches.     

Treatment choices and patterns in migraine patients with and without a cardiovascular risk profile

Treatment patterns in migraine patients with cardiovascular risk factors are largely unknown. A retrospective observational study was conducted to characterize the baseline cardiovascular risk profile of new users of specific abortive migraine drugs, and to investigate treatment choices and patterns in patients with and without a known cardiovascular risk profile. New users of a triptan, ergotamine or Migrafin^® ( n  = 36 839) from 1 January 1990 to 31 December 2006 were included. Approximately 90% of all new users did not have a clinically recognized cardiovascular risk profile. The percentage of new users with a cardiovascular risk profile did not differ between new users of a triptan, ergotamine or Migrafin^® and also did not change during the study period of 17 years. Differences in treatment choices and patterns between migraine patients with and without a known cardiovascular risk profile reveal a certain reticence in prescribing vasoconstrictive antimigraine drugs to patients at cardiovascular risk.     

Ergotamine abuse. Do patients benefit from withdrawal?

A follow-up study of 40 patients (migraine 39, cluster headache 1) previously treated for ergotamine abuse was conducted. Their statements regarding ergotamine intake were checked using butalbital (contained in the suppositories abused by 90% of the patients) as a tracer, and later by contact with the family doctor. Eleven patients abused ergotamine again during a median observation time of 21 months. Nineteen patients had more than a 50% reduction in headache days after withdrawal and half of the patients were relieved of other symptoms of ergotamine toxicity. Even with a failure rate of approximately 25% it is concluded that efforts to withdraw after abuse of ergotamine are worthwhile.     

Comparison of pharmacodynamic effects and plasma levels of oral and rectal ergotamine

Plasma levels and the vasoconstrictive effect of 1 mg ergotamine tartrate given as tablets or suppositories were compared. In a crossover study, eight male volunteers received tablets or suppositories containing ergotamine in a drug combination (Anervan) and, as a control, suppositories without ergotamine. Blood sampling and measurement of toe-arm systolic gradients with a strain-gauge technique were done for up to 6 h and again after 24 h and 48 h. Only 29 of 160 blood samples contained detectable (greater than 0.1 ng/ml) amounts of ergotamine, and kinetic comparison could not be performed. Only ergotamine-containing suppositories caused a significant (p less than 0.008) decrease in toe-arm systolic gradient which was significantly different (p less than 0.003) from the effects of ergotamine tablets and control suppositories. Rectal ergotamine is thus more biologically active, for the factor used, than oral ergotamine. We suggest that a rectal dose of 1 mg ergotamine tartrate should be tried as the initial dose in the treatment of migraine attacks.     

Psychophysiological Studies of Headache: Is There Similarity Between Migraine and Muscle Contraction Headaches?

SYNOPSIS
Typically migraine and muscle contraction headaches are thought to be different disorders. Recently some investigators have argued that these headache categories are quantitatively, but not qualitatively distinct. Studies of vasomotor and electromyographic (EMG) reflexes and treatments for these headaches were reviewed to elucidate similarities and differences. Similarities include for both types of headaches high levels of tension in the muscles of the head and neck, a vasoconstrictive component, a responsiveness to treatment by relaxation or reduction of frontalis muscle tension. Differences between migraine and muscle contraction headaches relate to the status of the temporal artery between and during headaches and the standard medical treatments used for each. Systematic research is needed to establish if fundamental differences exist between these two major categories of headache.     

History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925. In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine i.v. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation. Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs. From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the relatively rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials. A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review of 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.     

Ergotamine-induced headache can be sustained by sumatriptan daily intake

We describe the case report of a migraine sufferer who developed ergotamine-induced headache and subsequently replaced ergotamine with daily sumatriptan (100 mg p.o.). The features of the headache were unchanged except for the presence of superimposed migraine-like headaches that occurred every 24 h.     

The influence of ergotamine abuse on psychological and cognitive functioning

Migraine patients abusing ergotamine often have chronic daily headaches associated with tiredness, sleep and memory disturbances, and reduced general well-being. We quantified psychological and cognitive functioning in 12 migraine patients with and 12 without ergotamine abuse (> or = 5 days/week for > or = 6 months) and 12 healthy controls. Psychological functioning assessed by Symptom Checklist-90 (SCL-90) and Profile Of Mood State (POMS), was impaired in ergotamine abusers compared to healthy controls. Cognitive functioning divided into four domains: attention (critical flicker frequency analysis and mental control subscale of the Wechsler Memory Scale (WMS), speed of information processing (reaction time tasks and lexical decision tasks), memory (four subscales of the WMS) and cognitive flexibility (trailmaking test and WMS digits backwards), was impaired in ergotamine abusers in speed of information processing and cognitive flexibility. These differences disappeared after correction for total SCL-90 scores. In conclusion, ergotamine abuse is associated with high psychological distress but not with structural impaired cognitive functioning.