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.     

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.     

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.     

Drug abuse in chronic headache: a clinico-epidemiologic study

Among the patients referred to the Headache Centre in Parma between 1979 and 1984, 95 (5%) were found to be drug abusers, having taken analgesics every day for at least a year. They had had chronic headache for at least 12 months: migraine with interparoxysmal headache in 83.1% and chronic tension headache in 16.9%. Almost all patients were combination-analgesics abusers, and only about a quarter of them were taking ergotamine. The largest single factor favouring the transformation of episodic headache into a chronic one was the drug abuse. The patients studied during 1984 were subjected to detoxification with 6 months' follow-up study. Our investigation suggests that all instant-relief drugs can sustain and possibly initiate a chronic headache.     

Comparison Between Venoconstrictor Effects of Sumatriptan and Ergotamine in Migraine Patients

SYNOPSIS
The vasoconstrictor activity of sumatriptan and ergotamine were compared by injecting these drugs in the hand vein of migraine subjects. We used the "venotest method", which permits the evaluation of the venoconstrictor effect of small doses of drugs, acting locally in the hand vein.
Sumatriptan injected at increasing doses in the hand vein provoked contraction only at high doses (500 μg): venoconstriction lasted 5–15 minutes and was similar in intensity and duration to that induced by 0.5-1 μg of 5-hydroxytryptamine (5-HT). Likewise, ergotamine induced contraction only at a dose of 50 μg: this venoconstrictor effect was long lasting (at least I hour). Ergotamine-induced hand vein contraction, almost completely inhibited by ketanserin, seems mediated at least in part by 5-HT ₂ receptors, like the one induced by 5-HT and sumatriptan, already observed in a previous study.
Clinical doses of ergotamine (0.25 mg intramuscular) and of sumatriptan (6 mg subcutaneous) do not provoke hand vein contraction for at least I hour: this could be due to a low activity of these drugs on the 5-HT ₂ vein receptors or a technique that is unsuitable to detect the vasoconstrictor effect of drugs given by the systemic route.
The long lasting venoconstrictor effect of ergotamine may be due to a slow dissociation from receptor sites. The short vasoconstriction induced by sumatriptan could account for the recurrence of headache in many sumatriptan-treated migraine subjects.     

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.     

Headache Caused by a Sphenoid Mucocele but Presenting as an Ergotamine-Induced Headache

In a 65-year-old woman, symptomatic headache caused by a mucocele of the sphenoid sinus led to ergotamine abuse and subsequent ergotamine-induced headache. Since there were no neurological symptoms initially and the patient previously suffered from migraine, the mucocele was not recognized. Only after unsuccessful drug withdrawal therapy and an MRI, was the correct diagnosis made. Surgical removal of the mucocele led to complete relief of headache within 3 weeks. We conclude that ergotamine-induced headache can develop on the basis of symptomatic headache. In spite of the effectiveness of ergotamine tartrate, an MRI should be performed if focal neurological symptoms occur.     

Subcutaneous Sumatriptan in the Treatment of Headache During Withdrawal From Drug-Induced Headache

In a pilot study (5 patients) we investigated the effects of subcutaneous sumatriptan, a 5-HT1-like receptor agonist, on headache experienced during the withdrawal period of drug-induced headache. The pilot study indicated that the substance was effective mostly in patients who originally suffered from migraine. In a patient with tension headache the substance was less effective. In a second double-blind study on six migraine patients with severe drug-induced headache, the drug was highly effective in ameliorating headache and autonomic disturbances. Blood flow velocities measured in extracranial parts of internal and external carotid arteries by duplex-sonography and in middle cerebral and basilar arteries by transcranial Doppler showed no changes after administration of sumatriptan or placebo. This result suggests sumatriptan does not act primarily via constriction of the large cerebral arteries.     

Ergotamine abuse: Results of ergotamine discontinuation, with special reference to the plasma concentrations

Twenty-three patients suffering from continuous headache linked with habitual daily use of ergotamine tartrate were studied. Their headaches were classified clinically, and possible side effects of ergotamine medication, plasma levels of ergotamine, and occurrence of withdrawal symptoms after discontinuation of drug abuse were recorded. Seventeen of the patients were clinically diagnosed as suffering from "ergotamine headache", and seven of them complained of coldness in the extremities. Plasma ergotamine levels were measured by using a radioimmunoassay. In almost half of the patients the 1 h plasma levels after the daily dose were below the detection limit of the procedure (0.12 ng/ml). The duration and severity of the withdrawal symptoms did not correlate with the doses and plasma levels of ergotamine. In only 4 of the 21 patients who were followed up for 3 to 6 months did headache symptoms not improve after ergotamine withdrawal. The results indicate that even small (0.5–1.0 mg/day) doses of ergotamine tartrate taken regularly may cause continuous headache symptoms and withdrawal symptoms after discontinuation.     

ERGOTAMINE AND METHYSERGIDE AS SEROTONIN PARTIAL AGONISTS IN MIGRAINE

SYNOPSIS
Potentiation of venospastic action of 5-HT by methysergide and ergotamine was demonstrated in man by using venomotor receptors as substrate in a venoconstriction test. 5-HT facilitation was observed only when anti-migraineous drugs were tested in concentrations similar to those expected after therapeutic administration. When ergotamine and methysergide were used in higher concentrations, the expected antagonism to 5-HT was clearly demonstrated. It is concluded that methysergide and ergotamine therapy is not antiserotonergic. These drugs act as partial agonists of 5-HT. Methysergide and ergotamine facilitation of 5-HT activity may occur at peripheral vasomotor receptors, or centrally in the brain. This latter probably is consistent with the postulated central nature of pain in essential headache.     

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.     

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.     

NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release

The aim of the present study was to investigate changes in the plasma calcitonin gene-related peptide (CGRP) concentration and platelet serotonin (5-hydroxytriptamine, 5-HT) content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Fifteen female migraineurs (without aura) and eight controls participated in the study. Sublingual nitroglycerin (0.5 mg) was administered. Blood was collected from the antecubital vein four times: 60 min before and after the nitroglycerin application, and 60 and 120 min after the beginning of the migraine attack (mean 344 and 404 min; 12 subjects). In those subjects who had no migraine attack (11 subjects) a similar time schedule was used. Plasma CGRP concentration increased significantly (P<0.01) during the migraine attack and returned to baseline after the cessation of the migraine. In addition, both change and peak, showed significant positive correlations with migraine headache intensity (P<0.001). However, plasma CGRP concentrations failed to change during immediate headache and in the subjects with no migraine attack. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in subjects who experienced a migraine attack. Platelet serotonin content decreased significantly (P<0.01) after nitroglycerin in subjects with no migraine attack but no consistent change was observed in patients with migraine attack. In conclusion, the fact that plasma CGRP concentration correlates with the timing and severity of a migraine headache suggests a direct relationship between CGRP and migraine. In contrast, serotonin release from platelets does not provoke migraine, it may even counteract the headache and the concomitant CGRP release in this model.     

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.     

Long-term ergotamine abuse: effect on adrenergically induced mydriasis.

The mydriatic action of sympathomimetic eyedrops after a therapeutic dose of ergotamine was measured in migraine patients with and without histories of long-term ergotamine abuse. Mydriasis induced by the postsynaptic alpha 1-agonist phenylephrine was similar in both groups of patients tested, whereas pupillary dilation caused by the release of noradrenaline tyramine was markedly greater in patients with histories of ergotamine abuse. The enhanced response to tyramine disappeared after drug withdrawal. These findings indicate that continuous ergotamine medication causes a reversible alterations in iris sympathetic transmission. This manifestation may reflect a central inhibition of pupillary sympathetic activity.     

Derangement of Serotonin System in Migrainous Patients With Analgesic Abuse Headache: Clues From Platelets

Accumulating evidence indicates that serotonin (5-HT) may be involved in the process of analgesic-induced headache transformation. In order to clarify this hypothesis, we investigated the 5-HT system in migraine patients with analgesic abuse headache by using platelets as a neuronal model. Our results revealed a significant decrease in platelet 5-HT content in these patients compared to migraine patients and nonheadache controls (179.24 ± 10.18, 451.22 ± 14.35, and 480.22 ± 13.98 ng/10⁹ platelets, respectively; P <0.001). This biochemical result was well correlated with a significant decrease ( P 2/cells, respectively). As this canaliculi system plays a significant role in the platelet secretory response, such dilatation may imply an excessive release of substances from this system. Based on this platelet model, we suggest that excessive use of analgesics alters the central 5-HT system by depleting 5-HT from its storage sites and results in the hyposerotonergic state. This analgesic-induced 5-HT alteration may be a possible mechanism of headache transformation observed in this condition.     

Specificity and Sensitivity of Temporalis ES2 Measurements in the Diagnosis of Chronic Primary Headaches

We have evaluated the specificity and sensitivity of temporalis ES2 measurements for the diagnosis of primary headaches. Ninety-four outpatients diagnosed according to IHS criteria were prospectively included: 25 had chronic tension-type headache (code 2.2.), 15 episodic tension-type headache (code 2.1.), 20 migraine without aura (code 1.1.) and 34 chronic daily headaches with daily analgesics/ergotamine abuse (code 8.2.). In chronic tension-type, the sensitivity of the ES2 test was 84% at the 0.1 and the 0.5 Hz, but only 56% at the 2Hz stimulation rates. Its specificity was 100% at 0.1Hz, 90% at 0.5Hz and 95% at 2Hz compared to migraine; positive predictive values were at similar levels. Sensitivity of ES2 at 0.1 Hz was 67% in episodic tension-type headache, but its positive predictive value versus migraine was excellent. Comparing chronic tension-type headache and analgesic abusers, the specificity and positive predictive value of the ES2 test for diagnosing chronic tension-type headache were less satisfactory (60%) while the negative predictive values, however, remained good (83% at 0.1Hz).
The results confirm that the temporalis ES2 test has a higher diagnostic sensitivity in chronic and episodic tension-type headache, but that it has a high negative predictive value for both types of tension-type headache compared to other primary headaches. For diagnostic purposes, the 0.1Hz stimulation rate seems optimal. The 2Hz stimulation rate is the least sensitive, although it may induce total disappearance of ES2 in up to 40% of patients. ES2 is of limited usefulness for separating chronic tension-type headache and chronic drug-abuse headache, possibly because the latter group comprises both tension-type headache and migraine patients.     

Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?

Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand ¹²³I-3-iodo-6-methoxybenzamide (¹²³I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of ¹²³I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities.     

Drug abuse in migraine patients

Records of all patients discharged with a diagnosis of migraine from 2 Danish neurological departments were examined to determine the incidence of drug abuse. These departments had fixed uptake areas with a population of approximately 500,000 during the 5 year study period (1-1-1976--31-12-1980). Patients were selected for detailed analysis if (1) they used morphinomimetic drugs once a month or more, (2) took 7 or more tablets of weak analgesics a day or (3) consumed more than 60 mg ergotamine a month. A total of 92 patients fulfilled these criteria, 27 only because of ergotamine overuse. Injections of morphinomimetic drugs were given once a week or more frequently to 32 patients. These patients also usually had an escalating consumption and were usually regarded as abusers by their doctors. During admission morphinomimetics were discontinued. None deteriorated, 1/3 remained unchanged whereas 2/3 improved. Thus 32 patients can be regarded as abusers of morphinomimetics which represents an annual incidence of 13 per million inhabitants. We caution against the use of morphinomimetics in migraine.