Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: systematic review of observational studies.

BACKGROUND: Apart from the underlying cardiovascular (CV) risk associated with migraine, both triptans and ergotamines can induce vasoconstriction and potentially increase the risk of serious ischemic events. Because of the low frequency of such events in eligible patients, randomized controlled trials are not exhaustive to assess the drug-related CV risk. Observational studies are, therefore, an essential source of information to clarify this matter of concern. AIM: The aim of this study was to systematically review the available published observational studies investigating the risk of serious CV events in triptan or ergotamine users, as compared to unexposed migraineur controls. METHODS: We systematically searched MEDLINE and EMBASE electronic databases for cohort or case-control studies up to December 1, 2013. Studies retrieved from CDSR, DARE and HTA databases of the Cochrane Library were used for snowballing. Studies investigating the risk of any CV outcome in patients with a migraine diagnosis and exposed to triptans or ergotamines were considered for inclusion. Selection of studies, data extraction, and risk of bias assessment were conducted independently by two reviewers. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were computed using a random-effects model for studies and outcomes judged eligible for quantitative data synthesis. RESULTS: From a total of 3370 citations retrieved, after duplicate removal and screening, only four studies met the inclusion criteria (three nested case-control analyses and one retrospective cohort study). These studies investigated the risk of different CV outcomes associated with either the recency or the intensity of exposure to the studied drugs. As for the intensity of use, the pooled OR of serious ischemic events was 2.28 (95% CI 1.18-4.41; I (2 )= 0%) for ergotamine use (two studies), whereas for triptans (three studies) it was 0.86 (95% CI 0.52-1.43; I (2 )= 24.5%). Recent use of ergotamines was not significantly associated with any CV outcome (only one available study). Two studies investigated the risk of stroke related to recent triptan use: the first study reported an OR of 0.90 (0.64-1.26), and the second one suggested an increased risk of 2.51 (1.10-5.71). In this case, because of the high degree of heterogeneity, results were not pooled. CONCLUSIONS: To date, few comparative observational studies have investigated the CV safety of migraine-specific drugs in clinical practice. Evidence gathered here suggests that intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues, although no firm conclusions can be drawn. In particular, evidence on stroke risk is conflicting. However, if an increase of the absolute stroke risk in recently exposed patients does actually exist, it must be small. Overall, residual uncontrolled confounding factors reduce the confidence in the risk estimates collected from the included studies. Further investigations are needed to better define the risk for rare but serious CV events related to triptan and ergotamine use for treatment of migraine.

Medication overuse headache in Europe and Latin America: general demographic and clinical characteristics, referral pathways and national distribution of painkillers in a descriptive, multinational, multicenter study.

BACKGROUND: Medication overuse headache (MOH) is a very disabling and costly disorder due to indirect costs, medication and healthcare utilization. The aim of the study was to describe general demographic and clinical characteristics of MOH, along with the national referral pathways and national painkillers distribution in several European and Latin American (LA) Countries. METHODS: This descriptive cross-sectional observational study included 669 patients with MOH referred to headache-centers in Europe and LA as a part of the COMOESTAS project. Information about acute medication and healthcare utilization were collected by extensive questionnaires, supplemented with structured patient interviews. RESULTS: Triptans were overused by 31 % European patients and by 6 % in LA (p < 0.001), whereas ergotamines were overused by 4 % in Europe and 72 % in LA (p < 0.001). Simple analgesics were overused by 54 % in Europe and by 33 % in LA (p < 0.001), while combination-analgesics were more equally overused (24 % in Europe and 29 % in LA). More European patients (57 %) compared with LA patients (27 %) visited general practitioners (p < 0.001), and 83 % of European patients compared to 38 % in LA consulted headache specialists (p < 0.001). A total of 20 % in Europe and 30 % in LA visited emergency rooms (p = 0.007). CONCLUSION: There are marked variations between LA and Europe in healthcare pathways and in acute medication overuse regarding patients with MOH. This should be considered when planning prevention campaigns against MOH.

Ruminal motility, reticuloruminal fill, and eating patterns in steers exposed to ergovaline.

Fescue toxicosis is problematic for growing steers, causing lower DMI and productivity when fed endophyte-infected (E+) tall fescue. A complete understanding of underlying mechanisms of how fescue toxicosis affects growing steers is lacking. Therefore, the overall objective of this multiexperiment study was to determine whether ruminally dosed ergovaline (ERV) affects rumen motility, rumen contents, and eating patterns. In Exp. 1, an 8-h period to assess ruminal motility began 4 h after feeding by monitoring pressure changes using a wireless system for 21 d. Eight ruminally cannulated steers (283 kg BW) were pair fed with alfalfa cubes (1.5 × NEm) and assigned to endophyte free (E-; 0 µg ERV/kg BW/d) or E+ treatment (20 µg ERV/kg BW/d). Overall, E+ steers had more frequent rumen contractions (Seed P = 0.05 and day of feeding P = 0.02). On days 7 to 9, both treatments showed lower frequencies and E- steers had greater amplitude of contractions (P < 0.001) that corresponded with decreased DMI. In Exp. 2, steers remained in pairs assigned in Exp. 1 (322 kg BW), but reversed seed treatments while increasing ERV levels (titrated 0, 5, 10, 15, and 20 µg ERV/kg BW/d over 57 d). There were no differences between E- and E+ for frequency (P = 0.137) or amplitude of contractions (P = 0.951), but increasing ERV dosage, decreased frequency (P = 0.018) and amplitude (P = 0.005), coinciding with lower DMI. In Exp. 3, 8 steers (589 kg) were pair fed and ruminally dosed 15 µg ERV/kg BW/d, and rumen motility data were collected for 21 d. E- steers showed higher amplitude and lower frequency of contractions than E+ steers with seed (P < 0.001), day (P < 0.001), and seed × day (P < 0.04) effects, but rumen fill was not different between E- and E+ (P > 0.29). Serum prolactin concentrations were lower in E+ steers in Exp. 1 to 3. Eating patterns of pair-fed E- and E+ steers were relatively slower in E+ than E- (Exp. 4) by measuring every 2 h across 24 h. Number of meals were higher in E+ than E- steers, but meal duration and meal size were not different between treatments. Rumen content (DM%) tended to be higher in E+ than in E- when steers were fed once a day (P = 0.07), but there was no difference for rumen content (DM%) when E- and E+ steers were fed 12 times a day (P = 0.13). These results suggest the changes in rumen fill associated with fescue toxicosis may be driven more by changes in feeding behavior and eating pattern rather than by changes in motility.

[Medication overuse headache]. / Abuzusnaia golovnaia bol'.

Rebound headache (RH) is a chronic daily headache which occurs when analgesics, triptans, ergotamines are taken frequently (more than 15 days/month for more than 3 months) to relieve headaches. The prevalence of RH is 1 to 4% in the general population. RH commonly occurs in patients with migraine and tension-type headache. The deficit of central sensitization and psychological factors play an important role in initiating and maintaining of RH. Treatment of noofen for 2 months is effective in 75% of patients with RH.

Pleuropulmonary lesions, ergotamines and asbestos exposure.

OBJECTIVES: This study investigated the possibility of pleuropulmonary lesions, which can occur as rare but serious side effects of different ergot drugs, occurring more commonly in persons earlier exposed to asbestos. METHODS: All reports of pleuropulmonary side effects of the ergot drugs used in Sweden in the Swedish side effect registry from 1985 to 2003 were studied. In addition, the literature was reviewed. RESULTS: In the registry, 47 men and 3 women were found. Of the men, 24 were exposed to asbestos, and 2 denied such exposure; 2 of the 3 women were exposed. In the literature, 111 patients were found--32 had confirmed exposure and 15 denied it. For most of the patients, it was not possible to determine exposure. CONCLUSIONS: Enough evidence exists to postulate that earlier asbestos exposure in combination with the intake of ergot drugs can cause pleuropulmonary lesions.

[Ergotism. A case report and review of the literature]. / Ergotismo. Presentación de un caso y revisión de la bibliografía.

INTRODUCTION: Ergotism is characterised by an intensive generalised vasoconstriction of small and large blood vessels. The symptoms derive from the regional ischemia caused by the vasospasm produced by ergotamine. Nowadays, ergotism is almost exclusively due to the excessive ingestion of ergotamine tartrate used in the treatment of migraine. The main treatment consists in withdrawing the medication. CASE REPORT: Our study involves a 53-year-old male with a history of migraine since his youth, who was treated with ergotaminic preparations up until the day before admission to hospital. He was admitted because of a 7-day history of symptoms including bilateral and symmetrical anaesthesia of the fingers and a general feeling of weakness, associated with intense pain and cyanosis of the right thenar eminence. On admission, it was not possible to measure his AT in the upper limbs and his peripheral pulses dropped in a generalised manner. Aetiologies involving vasculitis were ruled out. An angiography study showed segmented stenosis of arteries in the upper and lower limbs. Ergotaminic agents were withdrawn and nifedipine was indicated. The symptoms disappeared, the physical examination was normal and results of a control angiography study were also normal. CONCLUSIONS: Ergotamine intoxication can be detected by a thorough interview and physical examination; it should be suspected when faced with symptoms that are compatible with vasospasms and a history of ingestion of the drug, in the absence of any prothrombotic, liver, kidney or vasculitic pathology. This condition is treated by withdrawing the drug and administration of vasodilators if the symptoms are intense. In this paper, we review the history, pathophysiology, initial symptoms and signs, diagnosis and treatment of ergotamine poisoning.

Symptomatic relief of migraine: multicenter comparison of Cafergot P-B, Cafergot, and placebo.

A multicenter, randomized, double-blind trial was conducted to compare the efficacy of Cafergot P-B with that of its components, Cafergot, pentobarbital, and Bellafoline, and with placebo for the treatment of migraine. Patients with vascular headaches of the migraine type who regularly experienced nervous tension and some form of gastrointestinal distress with their headaches were randomized to one of five treatment groups. They were given treatment packets containing their assigned drug for use during two separate migraine attacks. Patients made pretreatment evaluations of the following symptoms: head pain, nervous tension, nausea, vomiting, anorexia, abdominal cramps, and photophobia. They made posttreatment evaluations of these symptoms 0.5, 1.0, 1.5, 2.0, and 3.0 hours after ingesting their assigned drug. Improvement scores were calculated from the differences between the pretreatment and the posttreatment ratings. Patients also made a final global assessment of their drug's efficacy. All patients who took at least one dose of the study medication and completed a baseline evaluation and at least one postdose evaluation of severity of pain were included in the analysis (n = 254). The comparisons of particular interest were those between Cafergot P-B and Cafergot and between Cafergot P-B and placebo. Cafergot P-B was significantly more effective than Cafergot in relieving head pain at hours 2 and 3, nervous tension, nausea, vomiting, anorexia, and photophobia. Cafergot P-B was significantly more effective than placebo in relieving head pain, nervous tension, nausea (second headache only), vomiting, and photphobia. The incidence of reported adverse effects was no greater with Cafergot P-B than with Cafergot; however, patients given Cafergot P-B reported less vomiting than did patients given Cafergot. The results of this study show that addition of pentobarbital and Bellafoline to Cafergot provides greater relief of pain, vomiting, nervous tension, photophobia, and other symptoms associated with migraine, while reducing the severity of the nausea that may accompany a migraine headache or Cafergot therapy.

Ocular ergotamine tartrate toxicity during treatment of Vacor-induced orthostatic hypotension.

A 20-year-old woman developed severe orthostatic hypotension after attempting suicide by ingesting the rodenticide, Vacor. Oral ergotamine tartrate, 6 mg a day, was useful in treating the orthostatic hypotension. However, a bilateral toxic retinal vasculopathy, consisting of a severe generalized vasoconstriction and mild macular edema, occurred within three weeks. Additional findings were an extinguished electroretinogram and a reduced dark-adaptation retinal sensitivity; because we performed these two tests after instituting ergotamine therapy we do not know whether to attribute their abnormal results to Vacor toxicity, ergotamine toxicity, or a combination of the two.

Respiratory dysfunction in Parkinson's disease.

The parkinsonian syndromes include idiopathic Parkinson's disease, parkinsonian syndromes secondary to several known causative agents, and parkinsonian syndromes associated with more widespread CNS lesions and extensive neurologic deficits. They constitute movement disorders with a similar constellation of symptoms: rigidity, tremor, bradykinesia, gait impairment, and postural instability. All of the parkinsonian syndromes are associated with excess morbidity and mortality from respiratory causes, and all can produce the pattern of pulmonary function impairment consistent with neuromuscular disease. In addition, the parkinsonian syndromes can produce upper airway obstruction and abnormalities of ventilatory control, both of which can be life-threatening in those with MSA. The medications used to treat these disorders can also produce respiratory disease. A syndrome of L-dopa-induced respiratory dysfunction has been described, which may be a heterogeneic disorder of choreiform movements of the respiratory muscles, rigidity-akinesis of the respiratory muscles, or abnormal central control of ventilation, all related to the drug. In addition, the ergot-derived dopamine agonists can cause pleural and pulmonary fibrosis.

Ergotamine tartrate dependency: features and possible mechanisms.

Based on our clinical experience and the data reviewed and presented in this report, we propose that a state of physical dependency to ergotamine tartrate exists. This dependency state is characterized by the irresistible and dependable use of ergotamine tartrate and is contingent upon a self-sustaining, rhythmic headache/medication cycle that reflects the dependency. The headache and accompaniments (withdrawal headache?) represent the primary withdrawal symptoms. The presence of this state appears to render patients refractory to other forms of preventative therapy, which can be effective only when ergotamine is discontinued and the cycle broken. If the condition is left untreated, it is likely though by no means certain that the more traditional aspects of ergotism will evolve, although variable susceptibility and tolerance to ergotamine tartrate have been demonstrated. The mechanism of this disorder remains uncertain but might be related to the influence of ergotamine tartrate on the limbic-hypothalamic-pituitary-adrenal axis and other aminergic centers (locus ceruleus), areas considered by some as the central loci for the pathogenesis and associated symptoms of migraine.

Effect of Bellergal Retard on climacteric complaints: a double-blind, placebo-controlled study.

The effect of Bellergal Retard (BR) on climacteric complaints was evaluated versus a placebo in an 8-wk double-blind study, followed by a 4-wk open study in which only BR was used as medication. There was a marked decrease in complaints in both the BR and the placebo groups. Statistically significant differences were observed between the groups after 2 and 4 wk of treatment, indicating superior results with BR. After 8 wk of study however, these differences were no longer apparent. It was concluded that studies on medication for climacteric complaints should not only be placebo-controlled, but also be of at least 8 to 12 wk duration for proper evaluation.

Severe vascular spasm due to erythromycin-ergotamine interaction.

We report a case of ergotism due to the interaction of erythromycin with a small dose of ergotamine tartrate (2 mg). Besides severe peripheral vasospasm with dysaesthesiae there was transient renal ischaemia. Recovery occurred after several weeks without sodium nitroprusside therapy. Cases previously reported in the literature are reviewed.

Acute myocardial infarction induced by ergotamine tartrate: possible role of coronary arterial spasm.

A 45-year-old woman with almost normal coronary arteries suffered from acute inferior myocardial infarction after taking 2 tablets (2.0 mg) of ergotamine tartrate for headache. She had had attacks of variant angina and spasm of the right coronary artery had been demonstrated during the attack. After the recovery from myocardial infarction the intravenous injection of ergonovine maleate 0.05 mg induced spasm of the right coronary artery again. We conclude that acute myocardial infarction in this patient was probably caused by coronary arterial spasm induced by ergotamine tartrate.

Tongue necrosis in temporal arteritis.

Temporal arteritis, or cranial arteritis, is a granulomatous arteritis with the common presenting manifestations of headache and visual loss. The disease is generally limited to elderly individuals; its pathogenesis is unknown, but may be of an immunological nature. Although otolaryngologic manifestations of the disease are common, few reports have been published. Visual loss is one of the most serious complications. Tongue necrosis has been reported in only 23 cases. We report a case of tongue necrosis and partial visual field loss in a patient with temporal arteritis. These complications were probably released by ergotamine tartrate administered because of migrainoid headache. This particular complication has been described only once previously.

The effects of endophyte-infected tall fescue consumption on diet utilization and thermal regulation in cattle.

Two experiments were conducted to determine the effects of endophyte fungus (Acremonium coenophialum) ingestion in tall fescue diets and environmental temperature on heat dissipation and diet utilization by cattle. In Exp. 1, 12 Angus heifers (average weight 244 kg) were allotted by weight to either an endophyte-free (E-) or endophyte-infected (E+; 381 ppb of ergovaline) diet. Environmental temperature varied between 22 and 32 degrees C. Voluntary DM and water intakes were similar (P > .10) among treatments. Rectal temperatures and concentrations of prolactin in plasma were lower (P < .05) after ingestion of the E+ diet. Plasma triiodothyronine, thyroxine, and cortisol concentrations were not affected by diet. In Exp. 2, 24 Holstein steers (average weight 114 kg) were allotted by weight to either E- or E+ (285 ppb of ergovaline) and one of two environmental temperatures (22 or 32 degrees C). At 32 degrees C, feed intake was reduced by 22%, and water consumption was increased by 62% compared with steers housed at 22 degrees C. Consumption of E+ reduced feed intake by 10% but did not influence water consumption. Plasma concentration of prolactin was decreased (P < .05) within 48 h after consumption of E+. Rectal temperatures increased in response to both environmental temperature (P < .05) and E+ consumption (P = .06). Digestibilities of DM and OM for E+ were 9% lower (P < .05) than for E-.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of endophyte-infected tall fescue consumption and use of a dopamine antagonist on intake, digestibility, body temperature, and blood constituents in sheep.

Two experiments were conducted with lambs that consumed endophyte-infected (Acremonium coenophialum) tall fescue diets under elevated temperature and humidity and supplemented with the dopamine antagonist metoclopramide (M). In Exp. 1, 12 ruminally cannulated wethers (average weight 49 kg) were allotted by weight to either an endophyte-free diet (E-) or endophyte-infected diet (E+; 1,170 ppb of ergovaline), or E+ supplemented with M (15 mg/kg of lamb BW; E+M). Ad libitum DM intake and digestibility were lower (P < .05) for E+ than for E- diet. Supplementation of E+ with M increased (P < .05) DM intake by 27.6% but did not change DM digestibility. Body temperature increased (P < .05) when lambs consumed E+ and was further increased when M was supplemented. For Exp. 2, 19 wether lambs (average weight 24 kg) were allotted to treatments to evaluate the effects of endophyte consumption (0 vs 2,430 ppb of ergovaline) and supplementation with M (0 vs 20 mg/kg BW). An interaction (P < .05) of main effects was measured for DM intake. Lambs that consumed E+M consumed more DM than did lambs fed only E+, but lambs offered the E- diet and supplemented with M did not increase DM consumption. Diet DM digestibility was not different among treatments. Skin vaporization decreased (P < .05) due to E+ consumption and M supplementation. The concentration of prolactin in plasma was decreased (P < .05) by consumption of E+ (8 vs 136 ng/mL) and did not increase due to M supplementation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ergotism--a rare cause of acute ischemia of the extremities]. / Ergotismus-seltene Ursache der akuten Extremitätenischämie.

Clinical ergotism as seen today results almost exclusively from the excessive intake of ergotamine tartrate in the treatment of migraine headache. Vasospasm of peripheral arteries is the leading clinical picture. Beside formation of collaterals and secondary thrombosis, vasospasm is one of the specific findings in angiography. Early diagnosis and withdrawal of the medication makes complete restitution possible. In all other cases intraarterial or intravenous infusion of sodium nitroprusside or nitroglycerin has turned out to be the most effective therapy. Balloon dilatation or operative intervention are an alternative therapy in those cases, where amputation of the limb seems to be necessary.

Ergotism with therapeutic doses of ergotamine tartrate.

Two cases of acute ergotism are described in patients taking therapeutic oral doses of ergotamine tartrate and concomitant triacetyloleandomycin. Both showed satisfactory response to infusion of sodium nitroprusside with normal perfusion being obtained in the affected limbs. The treatment of ergotism with sodium nitroprusside is reviewed and the apparent interaction of ergotamine and triacetyloleandomycin is discussed.

[Severe ischemic accidents from ergotism. A report on 3 cases. Value of a new antidote : sodium nitropruside (author's transl)]. / Accidents ischémiques graves par ergotisme. A propos de 3 cas. Intérêt d'un nouvel antidote : le nitroprussiate de sodium.

The autors describe 3 recent cases of severe ischemic accidents from ergotism affecting different regions. Two of the cases resulted from taking Gynergene (ergotamine tartrate) for a short period, while the other case followed continuous administration of Desernil (Methysergide) for 3 years. The third case was treated at a late stage by continuous peridural anesthesia and various vasodilators without success and led to very severe mutilations in two young women. The third case was treated by continuous infusions of sodium nitropruside (SNP) under hemodynamic control, and recovery was rapid and complete. The value of SNP as an antidote for severe ergotism is discussed, together with its mode of administration, and precautions necessary when prescribing this extremely powerful vasodilator treatment for this indication.