Tolfenamic acid, metoclopramide, caffeine and their combinations in the treatment of migraine attacks

Tolfenamic acid is a fenamate which inhibits prostaglandin (PG) biosynthesis and may act as a PG antagonist as well. Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks, but controlled clinical studies on fixed combinations with analgesics are rare. The effects of orally given tolfenamic acid (200 mg), caffeine (100 mg), metoclopramide (10 mg), tolfenamic acid + caffeine (200 mg + 100 mg), tolfenamic acid + metoclopramide (200 mg + 10 mg) and placebo were studied in 49 migraine patients (3 men, 46 women) in a double-blind randomized cross-over study comprising 482 migraine attacks. The patients were allowed to take either one or two capsules of each preparation for an attack. Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered. Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack. Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences.     

Tolfenamic Acid Rapid Release Versus Sumatriptan in the Acute Treatment of Migraine: Comparable Effect in a Double-Blind, Randomized, Controlled, Parallel-Group Study

The efficacy and safety of tolfenamic acid and oral sumatriptan in the acute treatment of migraine was studied at five neurological centers in Finland. One hundred forty-one patients experiencing 289 migraine attacks, fulfilling the diagnostic criteria for migraine with or without aura as defined by the International Headache Society, were randomized.
For first attacks, 77% of patients receiving tolfenamic acid experienced a reduction of the initial severe or moderate headache to mild or no headache after 2 hours, as compared to 79% in the sumatriptan group and 29% in the placebo group. No significant difference was found between active treatments ( P =0.85, 95% Cl [−22%, 18%]), however, both active treatments were significantly better than placebo; P =0.001, 95% Cl (26%, 69%) for tolfenamic acid and P =0.001, 95% Cl (28%, 71%) for sumatriptan. For second attacks, results were similar with 70% of patients receiving tolfenamic acid experiencing relief, as compared to 64% in the sumatriptan group and 39% in the placebo group.
No significant differences were observed in accompanying symptoms.
Both drugs were well tolerated with the frequency of adverse events; 30% for tolfenamic acid and 41% for sumatriptan, a nonsignificant difference.
In this study, tolfenamic acid and oral sumatriptan are comparably effective in the acute treatment of migraine. When comparably effective, factors like individual effect, tolerance, and cost of treatment should be considered when prescribing migraine medication.     

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.     

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.     

The biography of Mary E. O'Sullivan: an early American headache specialist

The aim of this study was to review the life of Mary E. O'Sullivan and to summarize her important contributions to the study of migraine. Mary E. O'Sullivan underwent extensive training to become a neurologist at a time when only 5% of women in America were physicians. She published five papers on migraine. In a 1936 Journal of the American Medical Association article, she described a patient with ergotamine overuse headache and recommended that daily doses of oral ergotamine should be avoided. Three years later she described migraine as a 'complex' syndrome with multiple causes and multiple cures. Mary E. O'Sullivan, an ambitious female headache specialist of the 1930s, was an early advocate of the use of ergotamine to treat migraine, yet she was one of the first to report ergotamine overuse headache. Although her life was short, her research, knowledge and ambition at a time when women had limited opportunities in medicine have left a mark.     

Cellular adaptation in migraineurs with chronic daily headache

Ergotamine and analgesic misuse are now recognized as causes of chronic daily headache and the condition responds well to drug withdrawal with reduced headache frequency. In this study, we have investigated whether medication misuse is associated with an alteration in membrane transduction which is sensitive to drug withdrawal. This was carried out by assay of the thrombin-stimulated generation of inositol phosphates in platelets from 12 migraine patients with chronic daily headache and analgesic misuse, 7 migraine patients with chronic daily headache and ergotamine misuse and 7 control subjects. After drug withdrawal, a significant decrease in headache frequency was seen at one month in both patient groups. Withdrawal of analgesics produced a significant decrease in thrombin-stimulated inositol phosphate production at one month; this was further decreased a month later with a reduction in B_max of 60% and no significant change in K_D. A similar pattern was obtained in ergot misuse patients, with the K_D value decreasing by 56% one month after drug withdrawal. These results provide evidence of an adaptation in transduction with misuse of analgesics and ergotamine which correlates with headache frequency.     

Reduced serotonin vascular sensitivity in ergotamine abusers

The action of ergotamine on the 5-hydroxytryptamine (5-HT) venous sensitivity was studied in ergotamine abuser and non-abuser migraine patients. Ergotamine abusers showed reduced 5-HT hand vein contraction during abuse, compared to seven days after ergotamine withdrawal. In non-ergotamine users, the 5-HT venoconstriction was not significantly modified 12 h after a single intramuscular ergotamine (0.25 mg) administration. Even the administration of ergotamine locally into the vein did not change the venospasm of 5-HT given acutely in the same vein. Therefore, it seems that the 5-HT antagonism does not contribute to the therapeutic effect of ergotamine during the migraine attack. Moreover, the reduced 5-HT responsiveness during ergotamine abuse may possibly be compatible with the chronic headache present in some abusers, the withdrawal headache attacks and the abuse itself.     

Tolfenamic acid decreases migraine recurrence when used with sumatriptan

Although sumatriptan is an effective drug for the treatment of acute migraine attacks, recurrence has been cited as an important limitation for its use. Tolfenamic acid is also effective in the acute treatment of migraine attacks. We studied the recurrence rate of migraine attacks with the use of sumatriptan plus tolfenamic acid among patients who presented frequent recurrence with sumatriptan. Fifty migraineurs were retrospectively studied, all having treated at least 10 attacks with 100 mg P.O.; sumatriptan was effective in at least eight of them. The patients also presented recurrence in less than 24 h in at least five of the treated attacks. We then used sumatriptan 100 mg plus tolfenamic acid 200 mg P.O. during the first 60 min of the attack; 240 attacks were treated and there was recurrence in 57 (23.8%). With sumatriptan alone, 5 out of 8 attacks (62.5%) presented recurrence. We therefore conclude that the combination sumatritpan plus tolfenamic acid is effective in reducing the recurrence rate from 5 of 8 (62.5%) to 1.19 of 5 (23.8%). Further prospective studies with a double-blind design and a higher number of treated attacks are necessary to confirm these initial observations.     

Ergotamine-induced anorectal strictures: report of five cases.

Dis Colon Rectum . 2002 Feb;45(2):271-2
Purpose: Ergotamine tartrate suppositories are used for treatment of migraine headache attacks. Chronic abuse may lead to severe anorectal complications such as ulceration, stricture, and rectovaginal fistula. These complications are rare, and only sporadic reports may be found. Nevertheless, awareness of this entity on the part of prescribing physicians and treating colorectal surgeons is essential for a successful outcome, because withdrawal of this medication is an inherent part of treatment.
Patients: Five female patients were referred for treatment of symptomatic strictures of the anal canal and lower rectum. All of these patients admitted prolonged, nearly daily use of three to seven ergotamine tartrate suppositories.
Results: Three patients with severe stenosis of the anal verge and anal canal were treated by Y-V anoplasty, and two patients with circular stricture of the lower third of the rectum had balloon dilatations. In all patients the use of ergotamine suppositories was stopped, and alternative medication was instituted. Long-term follow-up (3-12 years) showed complete resolution of symptoms.
Conclusion: In view of the availability of new effective drugs for treatment of migraine headache (serotonin agonists) and considering the potentially severe complications of chronic use of ergotamine, the use of this medication should be abandoned.
Comment: Ergotamine users beware of the sting in the tail! DSM.     

Transcranial Doppler ultrasonographic features during drug withdrawal from drug-induced headache. A transcranial Doppler follow-up study

BACKGROUND: A vascular component in ergotamine-induced headache has been proposed. No study has been carried out to evaluate cerebral hemodynamic changes by means of transcranial Doppler during withdrawal from migraine medication; in particular, ergotamine-containing drugs. METHOD: We examined 21 patients suffering from drug-induced headache during their in-hospital withdrawal from ergotamine (n=8) and compared them with patients during withdrawal from analgesics (n=13) and with healthy controls (n=14). Cerebral blood flow velocities were measured with transcranial Doppler, and pulsatility indices were calculated. Blood pressure, heart rate, and end-tidal carbon dioxide were documented. A subjective analog headache rating scaling was used for day-to-day evaluation of headache severity. RESULTS: Mean cerebral blood flow velocities dropped significantly after discontinuation of ergotamine-containing drugs but not after stopping common analgesics. Pulsatility indices remained unchanged. Cerebral blood flow velocities were higher in drug-ingesting patients compared to the control group and showed significant changes in patients with headache using ergotamine and in those using analgesics. Carbon dioxide, heart rate, and blood pressure remained unchanged. The headache rating scale did not show a constant trend. COMMENTS: Our results indicate that ergotamine and, to a lesser extent, common analgesics including caffeine might influence cerebral blood flow velocities and pulsatility indices causing transient and reversible disturbance of cerebral autoregulation.     

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.     

Alteration of Central Excitation Circuits in Chronic Headache and Analgesic Misuse

Central excitatory circuits could be involved in the pathophysiology of pain; particularly, the genesis of chronic pain. The "second pain" is the sensation that follows the initial pain after an appropriate nociceptive stimulus. The second pain is amplified by repeating the stimulus after brief intervals (temporal summation). This phenomenon is the psychophysicaI correlate of the excitatory pain circuits. The temporal summation of the second pain was evaluated in four groups of subjects: one group affected by migraine without aura, one by episodic tension headache, one by chronic daily headache, and a group of healthy subjects. A percutaneous electrical shock was used as the nociceptive stimulus. The intensity of the second pain was significantly greater in the group of patients with chronic headache in comparison with the other groups. The patients with chronic headache were subdivided into three groups on the basis of their clinical history: a group with transformed migraine; a group with chronic headache ab initio a form related to the first one; (both groups suffered from chronic daily headache with a frequent superimposition of episodes of migraine attacks) and the third group consisted of patients with chronic tension headache. The temporal summation of the second pain was altered in the first two groups. The patients with chronic migraine abused ergotamine given as a symptomatic drug. Those who were able to discontinue this drug were retested and reported a decrease of the second pain in comparison to the previous measurements. The results of the present study indicate that central excitatory circuits could be involved in the mechanism leading to the development of chronic daily headache.     

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.     

Ergotamine and dihydroergotamine: a review

The ergot alkaloids were the first specific antimigraine therapy available. However, with the advent of the triptans, their use in the treatment of migraine has declined and their role has become less clear. This review discusses the pharmacology, efficacy, and safety of the ergots. In randomized clinical trials, oral ergotamine was found to be superior to placebo, but inferior to 100 mg of oral sumatriptan. In contrast, rectal ergotamine was found to have higher efficacy (73% headache relief) than rectal sumatriptan (63% headache relief). Intranasal dihydroergotamine was found to be superior to placebo, but less effective than subcutaneous and intranasal sumatriptan. Ergotamine is still widely used in some countries for the treatment of severe migraine attacks. It is generally regarded as a safe and useful drug if prescribed for infrequent use, in the correct dose, and in the absence of contraindications; however, safer and more effective options do exist in the triptans. In patients with status migrainous and patients with frequent headache recurrence, ergotamine is still probably useful.     

Tolfenamic acid and caffeine: A useful combination in migraine

Tolfenamic acid is a potent inhibitor of prostaglandin biosynthesis, which has been proved effective in the treatment of acute migraine attacks. The usefulness of caffeine, metoclopramide and pyridoxine as adjuncts to tolfenamic acid was tested in acute migraine attacks in ten patients. A combination of tolfenamic acid (200 mg) with either caffeine (100 mg), metoclopramide (10 mg) or pyridoxine (300 mg) was given twice to each patient in random order. Thus 60 attacks were treated. The tolfenamic acid-caffeine combination proved the most effective as judged by duration and intensity of attacks, working ability, vigilance, and overall evaluation of the drugs by the patients. Metoclopramide was somewhat better than pyridoxine as an additive.     

Enhancing the Effectiveness of Abortive Therapy: A Controlled Evaluation of Self-Management Training

Research suggests that approximately one half of recurrent headache sufferers fail to adhere properly to drug treatment regimens with as many as two thirds of patients failing to make optimal use of abortive medications such as ergotamine. In spite of these findings there are no controlled studies that have attempted to evaluate methods for improving adherence to drug regimens for the treatment of chronic headache disorders. In an initial effort to address this adherence problem thirty-four recurrent migraine sufferers were randomized to abortive therapy with ergotamine tartrate plus caffeine (standard abortive therapy) or to standard abortive therapy accompanied by a brief educational intervention designed to facilitate the migraine sufferer's effective use of ergotamine. Patients who received the adjunctive educational intervention attempted to abort a greater percentage of their migraine attacks (70% vs 40%) and showed larger reduction in headache activity (e.g., 40% vs 26% reduction in month two of treatment). However, patients in both treatment groups used similar amounts of abortive medication when attempting to abort a migraine attack and showed similar reductions in analgesic medication use with abortive therapy. There results suggest that brief educational interventions designed to address the problem of patient adherence may yield significant improvements in standard therapies. We argue that such educational interventions deserve more attention in the headache treatment literature than they have received to date.     

Medical therapy for menstrual migraine

A menstrual migraine occurs in approximately 7-10 % of women suffering from migraine. The migraine occurs from 2 days before until 3 days after the end of the menstrual period. The choice of treatment depends on the duration of the attack, which ranges from 3 to 7 days. An attack of up to 3 days duration should be treated with acetylsalicylic acid, ergotamine tartrate or naproxen, each in combination with an antiemetic (domperidone, metoclopramide). If there is no response, sumatriptan can be administered orally (25-100 mg) or subcutaneously (6 mg). In the attacks continue for more than 3 days, short-term prophylaxis with naproxen or the application of an estrogen-containing patch is indicated. Neither ovulation inhibitors nor traditional migraine prophylaxis has an influence on menstrual migraine. Patients should keep a headache diary. Short-term prophylaxis with ergotamine tartrate or tamoxifen is obsolete.     

Effect of withdrawal of misused medication on sleep disturbances in migraine sufferers with chronic daily headache

OBJECTIVES: To evaluate the sleep pattern of migraineurs with chronic daily headache and to determine whether and to what degree it is improved by withdrawal of medication, and to reconfirm relief of headache by withdrawal of medications in migraineurs with chronic daily headache due to medication misuse. BACKGROUND: Misuse of ergotamine and analgesics by migraineurs is one of the causes of chronic daily headache. The latter is alleviated or abolished in these patients by abrupt withdrawal of the misused medication. In common with patients with chronic daily headache, migraineurs frequently complain of insomnia, usually verifiable by polysomnography. METHODS: Twenty-six women with migraine, aged 18 to 49 years, with chronic daily headache due to medication misuse, voluntarily discontinued ergotamine and analgesics, and were followed at monthly intervals for 3 months. In 25 subjects, polysomnography was performed before withdrawal of medication and 3 months after withdrawal. All subjects filled out a standard sleep questionnaire on those two occasions and a daily self-assessment questionnaire focused on headaches. RESULTS: After 3 months, a significant decrease in mean headache frequency (P<.001) and intensity (P<.001) was demonstrated. Polysomnography performed 3 months after medication withdrawal showed significant improvement in total sleep time (P<.05), sleep efficiency (P<.05), and number of arousals (P<.001). The score of the sleep questionnaire was also significantly improved (P<.01). CONCLUSIONS: In migraineurs with chronic daily headache due to medication misuse, withdrawal of the misused medications alleviates the associated sleep disturbance along with diminution in frequency and intensity of chronic daily headache.