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Abstract

Glyceryl trinitrate (GTN) is known to induce single extra attacks of cluster headache (CH) during active cluster periods, most probably via actions of nitric oxide (NO). Induction of whole periods of CH by organic nitrates has, however, attracted little attention in the literature. We report on eight patients with episodic CH and coexistent effort-induced angina pectoris. Cases 1-6 had been free of their headaches for many years but got recurrence of CH within a few weeks after the administration of long-acting organic nitrates (isosorbide-dinitrate, isosorbide-5-mononitrate or slow-release GTN) aimed at treating their chest pains. These nitrate-induced headache periods were more severe and had a longer duration than the previous spontaneous ones. Furthermore, one of the subjects and two additional cases experienced a marked reduction of their anginal attacks during successive CH periods. Exercise time to effort-induced angina was increased in all three patients and one of them revealed a markedly elevated threshold for eliciting ischaemic cardiac symptoms by standardized physical exercise on a cycle ergometer. We hypothesize whether extra CH periods elicited by sustained nitrate therapy and remission of angina pectoris during active clusters are caused by central mechanisms involving inhibition of sympathetic tone and effects on both cranial vessels and cardiac functions.

Keywords

Angina pectoris cluster headache glyceryl trinitrate nitrates nitric oxide

Introduction

It is well known that patients with cluster headache (CH) are extremely sensitive to histamine (1) and glyceryl trinitrate (GTN) (2) during active headache periods. These agents may induce additional headaches after a relatively constant latency period, which generally amounts to 30–50 min following drug administration. Attacks are followed by a refractory period with a duration of a few hours when no further paroxysmal pain can be elicited. Towards the end of the cluster periods this hypersensitivity diminishes and between periods no attack can be provoked (2).

The mechanisms behind the actions of nitrates in CH, as well as the varying thresholds for evoking cluster pain, and the cyclical appearance of spontaneous CH attacks still remain obscure. However, there is increasing evidence that nitric oxide (NO) has a key role in the pathogenesis of the disease (3–8). GTN is a pro-drug for NO, which is a small endogenous messenger molecule intimately involved in physiological processes such as vasodilatation, neurotransmission and inflammation. NO-mediated vasodilatation and activation of hypothalamic and trigeminovascular systems (9, 10) have all been demonstrated in CH in recent years, and it has been proposed that this disease should be regarded as a neurovascular form of primary headache (9).

In order to add some further clinical information on the possible role of NO in episodic CH we report on six patients who had been free of their disease for many years. All of them got a recurrence of a new severe cluster period within a few weeks following treatment of effort-induced angina pectoris with isosorbide-dinitrate (ISDN) or isosorbide-5-mononitrate (5-ISMN) or slow-release GTN, nitrate drugs that are metabolized to NO (11). Interestingly, one patient and two additional CH sufferers, seen in previous years, displayed a spontaneous marked reduction of their angina pectoris during active cluster periods.

Patients and methods

The case material consisted of eight patients (one female, seven males), aged 45–74 years (mean 60.8), examined at the Out-patient Department of Neurology. All patients had had typical symptoms of episodic CH according to the criteria of the International Headache Society (IHS) (12) but were free of headaches (cases 1–5) for many years. All patients suffered from effort-induced angina pectoris since the ages of 44–73 years. In four patients effort-induced angina pectoris had been present for the past year only. The others had a history of ischaemic heart symptoms for an average of 9.5 years. Four patients (cases 2, 3, 7 and 8) had previously suffered from a myocardial infarction.

Cases 1–6 were referred from internal medicine or cardiology departments because of reappearance of CH attacks. They had recently been prescribed long-acting organic nitrates in the form of ISDN or 5-ISMN or GTN in a slow-release formulation, in conventional doses, against ischaemic heart symptoms. The duration of nitrate treatment averaged 6.4 weeks (range 1.5–12).

Results

Patient characteristics are shown in Table 1. Age at onset of CH averaged 38.6 years, varying from 18 to 52 years. Five patients had a long history of episodic CH while two (cases 3 and 5) had suffered from one headache period only, prior to the present newly developed cluster symptoms. Case 4 was diagnosed as suffering from CH periodicity undetermined (IHS 3.1.1), his very first headache period possibly being induced by an organic nitrate (vide infra).

Table 1

History of episodic cluster headache (CH) in eight patients

Patient	Sex (M/F)	Age (years)	Age at CH onset (year)	No. of previous CH periods	Duration of CH periods (weeks)	Years since last CH period
1	M	74	18	2 per year	3–4	7
2∗	M	57	41	2	2	11
3	F	56	51	1 only	2	5
4	M	45	45	None	–	See text
5	M	61	51	1 only	?	10
6	M	71	25	1 per year	See text	1/2
7∗	M	59	52	2 per year	8	1/2
8∗	M	62	26	1 per year	5–6	2

∗See case report.

In cases 1–5 previous CH periods had displayed a rather short duration ranging from 2 to 4 weeks. Case 6 had had typical CH periods once a year lasting 1–2 months since the age of 25. However, during the last 7 years the cluster periods were mild, infrequent and lasted for about 1 week only. Four out of the first five cases had been completely free of CH symptoms for 5–11 years (mean 8.3) prior to the present admission.

CH periods induced by organic nitrates (cases 1–6)

Clinical data are shown in Table 2. Soon after nitrate administration (0.5–12 weeks, mean 6.4) a new CH period appeared. The CH attacks had a greater intensity but were otherwise mainly identical to those experienced during previous years. Two patients noticed that oral intake of ISDN repeatedly induced an extra CH attack within 30–60 min after administration. Although nitrates were discontinued, the new CH periods lasted for 3–16 weeks (mean 8.0), i.e. they had a considerably longer duration than the past spontaneous ones.

Table 2

Nitrate therapy∗ against effort-induced angina pectoris in eight patients with coexisting cluster headache (CH)

Patient	History of angina pectoris		Nitrate treatment		Induced CH period, duration (weeks)
Patient	Age at onset	Duration (years)	Dose (mg/day)	Duration (weeks)†	Induced CH period, duration (weeks)
1	73	1	ISDN 5 mg × 3	1.5	6
2	56	1	5-ISMN 60 mg × 1	12	16‡
3	48	8	5-ISMN 30 mg × 1	1.5	16
4	44	1	ISDN 5 mg × 3	9	4
5	60	1	5-ISMN 30 mg × 1	8	3
6	65	6	GTN 2.6 mg × 2	3	3
7	52	7	‡	‡	‡
8	46	16	‡	‡	‡

∗Organic nitrates prescribed: isosorbide-dinitrate (ISDN, Sorbangil^R), or isosorbide-5-mononitrate (5-ISMN, Imdur^R) in cases 1–5, or slow-release glyceryl trinitrate (GTN, Nitroglyn^R) in case 6.

†Time between start of treatment and appearance of CH.

‡See case report; CH periods associated with remission of attacks of angina pectoris.

Remission of angina pectoris during active CH periods

In three patients (cases 2, 7 and 8) there was a marked spontaneous reduction of angina pectoris during cluster periods.

Case 2

This male patient aged 57 had previously suffered from CH periods, in 1981 and 1986, with a duration of 2 weeks each. In April 1996 he sustained a myocardial infarction. In October 1996 he was prescribed 5-ISMN (Imdur^R) by his cardiologist 30 mg once daily increasing to 60 mg once daily and GTN 0.25 mg for the relief of acute chest pain. He was also treated with simvastatin (Zocor^R) 10 mg in the evening, felodipine (Plendil^R) 2.5 mg once daily, metoprolol (Seloken^R) 100 mg once daily and ASA (Trombyl^R) 75 mg once daily, but he still suffered from frequent attacks of angina pectoris; they appeared once or twice daily.

In February 1997 severe attacks of CH reappeared, being identical to those experienced in the 1980s. He was admitted to us and had several visits to the Out-patient Department. He kept a careful diary of his headache attacks and eventual chest symptoms. Felodipine was replaced by verapamil (Isoptin^R) 80 mg t.i.d. CH attacks occurred once or twice every day; they were partially relieved by oxygen inhalation, whereas a prophylactic treatment with pizotifen (Sandomigrin^R) 0.5 mg up to four tablets a day had no definite effect. Interestingly, he noticed a marked change in the frequency of his angina pectoris; the attacks of chest pain clearly diminished both in number and severity, and they disappeared after slightly more than a week. The CH period lasted for 16 weeks but there were no attacks of angina pectoris at all during the last 12 weeks of the period. He emphasized that he had regular daily routines and that he maintained constant physical activity during the whole CH period.

Case 7

This was a 59-year-old man whose clinical CH history has been reported earlier (13). During three successive cluster periods in 1967, 1968, and 1970, each of them lasting for 6–7 weeks, there was a marked reduction of his coexistent angina pectoris. During CH periods he very seldom required GTN, this being in clear contrast to his state during asymptomatic intervals between cluster periods when he had to take GTN up to four times a day. The ratio of number of anginal attacks per week during two active CH periods and the succeeding headache-free remission periods was fairly constant (1 : 7–8). The patient had very constant daily routines and regular low-grade physical activities. In a standardized physical exercise test on a cycle ergometer during an active cluster period the threshold for eliciting of angina pectoris was found to be manifestly elevated; the work performed, expressed as kpm, corresponded to an increase of > 80% compared with four control tests made in the asymptomatic intervals between headache periods. He used analgesics, containing acetylsalicylic acid, against headaches. During one of the three clusters (in 1968) he was also treated with pizotifen (BC 105, i.e. Sandomigrin^R) 3 mg daily. This compound did not appear to have affected his angina pectoris, as for control purposes it was given in the same dose for 4 weeks in a headache-free period without any effect on the cardiac symptoms.

Case 8

This was a man of 62 years with episodic CH since the age of 26. Clusters of headache appeared once a year, each of them lasting for 5–6 weeks. In 1967 (at the age of 46) he suffered a myocardial infarction and angina pectoris occurred thereafter almost every day. He was prescribed GTN 0.5 mg sublingually by his general practitioner but got side-effects in the form of rather severe short-lasting headaches; during CH periods he therefore did not use GTN at all. In 1982 he had another myocardial infarction. In July 1982 he sustained a slight left hemiparesis secondary to a minor cortical brain infarction. During the winter of 1984–85 (November–March) rather severe attacks of chest pain occurred daily or at least several times a week. In March 1985 a new CH period appeared. He was treated with pizotifen (Sandomigrin^R) 0.5 mg a day increasing to four tablets a day. CH attacks appeared regularly once to twice a day for a period of 7 weeks and during that time there was no angina pectoris at all. The cluster period ended in May, and he then had an immediate recurrence of angina pectoris, the chest pains appearing up to three to four times a day. He regularly took some light exercise and used to walk around a small lake, four to five times a week. The walking distance was about 2 km each time. He then noticed that he had to stop once or twice during the walks because of chest pain. During similar walks in the preceding CH period (in April–May) he had, on the other hand, occasional slight dyspnoea only but no chest pains.

Discussion

Our patients had been free of their severe CH for many years but developed headache periods within a few weeks after the administration of long-acting organic nitrates, such as ISDN, 5-ISMN, or slow-released GTN aimed at treating their effort-induced angina pectoris. Interestingly, one of the remitted patients and two additional sufferers seen in previous years became free of angina pectoris for several weeks during successive active CH periods. Anginal attacks recurred on a daily basis immediately after the end of the headache periods.

As far as we are aware there are only two previous case reports on de novo whole periods of CH having been triggered by organic nitrates. Jacobson (14) reported on a 64-year-old man with known coronary heart disease. He had previously suffered from an acute myocardial infarction and had had a period of frequent severe headaches 8 years before the present hospital admission. Following sublingual intake of GTN ‘six tablets’ because of severe chest pains, he contracted 10 cluster headaches over the next 5 days, these attacks notably being accompanied by marked sinus bradycardia. After discharge on day 7 he had ‘a few’ headaches but remained free of these episodes thereafter. Bernat (15) reported on a 59-year-old man who was admitted with a 3-month history of extremely intense right-sided headaches that occurred daily in the early morning. Attacks were brief and accompanied by marked conjunctival injection and profuse tearing of the eye. At first a diagnosis of chronic paroxysmal hemicrania was suspected but the clinical picture was eventually more in favour of CH. On a subsequent ambulant follow-up the patient was found to be free of his headaches and it was then suggested that ‘heart medicines’ had provoked the pains. He had been on ISDN 10 mg q.i.d. because of angina pectoris but, following discharge from the hospital, he had recently by himself discontinued nitrate therapy. He agreed to restart ISDN treatment, whereupon the headaches recurred ‘worse than ever’ and he therefore stopped the drug after ‘two uncomfortable days’.

Are the organic nitrates responsible for the ‘superinduction’ of the CH periods in our present patients? Patients had been free of symptoms of CH for many years when they received oral nitrate treatment against their angina pectoris. In our opinion the very short latency from administration of nitrates to recurrence of the present CH periods definitely favours such a causal relationship. It is of course difficult to make a correct prognosis in our patients but it seems reasonable to presume that they would have been free of spontaneously occurring headaches also in future years. A recurrence of CH following a prolonged remission of a cluster period is, however, seldom recorded. Thus, in only three (1.6%) of 189 patients of Manzoni et al. (16) did the remission period last for more than 10 years. The induced CH periods in our patients displayed a more than four-fold increased duration compared with the previous spontaneous ones, which also seems to be supportive of a connection between long-lasting organic nitrates and a ‘superinduction’ of CH periods. A somewhat similar ‘rebound’ phenomenon may be seen in patients who have been free of their headaches for one or more days following an extremely severe and/or long-lasting attack in an active cluster. This kind of hyper-responsiveness in our elderly CH patients is otherwise not commonly recorded in sufferers who have been free of spontaneous headaches for many years.

The coexistence of CH and angina pectoris has attracted little interest in the literature. In a case report Horton (17) briefly mentioned that vasoconstricting agents employed to relieve the headaches made the angina worse, and vasodilating agents for the angina provoked attacks of ‘histaminic cephalgia’. Kudrow (18) and Saper (19) found no significant difference in the prevalence of coronary heart disease in CH compared with control groups. In a large series of patients (n = 189) referred to Parma and Pavia Headache Centres in Italy (16) angina pectoris had occurred in four patients only and myocardial infarction in two. Patients with CH and coexistent angina pectoris may, however, be difficult to handle and there is need for more studies on eventual interactions between the two diseases and their treatment. Our CH sufferers had previously had few and/or infrequent short-lasting clusters of headache. This illustrates some additional difficulties when considering type of treatment of angina pectoris in patients with episodic CH, apparently in clinical remission.

Organic nitrates (ISDN, 5-ISMN, GTN) are widely used in the treatment of angina pectoris and congestive heart failure. They are all metabolized to NO and are evidently potent agents to provoke attacks of CH in susceptible individuals. It can be discussed whether or not they should be regarded as being contraindicated in active CH. If there is a definite need of prescribing nitrates against ischaemic heart disease in CH patients, a low dosage is to be recommended in order to avoid induction of headaches but also nitrate tolerance.

It is well known that a single dose of GTN does not provoke an attack of CH when administered in the asymptomatic interval between two cluster periods (2). The half-life of intravenous GTN in man is about 2.3–2.8 min (20). Short-lasting vascular effects of such a single dose of GTN are evidently not capable of inducing the critical pathogenic mechanisms in CH patients during their quiescent state. This refractoriness might be due to an insensitivity of some local neurovascular receptors involved in the attacks (21, 22).

ISDN is rapidly metabolized to form two metabolites of which 5-ISMN is the major metabolite with a half-life of 4–5 h. 5-ISMN (Imdur^R) is administered by a controlled-release formulation (Durules^R) that has been developed to reduce the number of daily doses required. Repeated dosing of nitrates with a substantial half-life seems to provide a greater risk in CH and may according to our observations even induce an extra CH period.

Nitrates are known to induce headache both in healthy subjects and in migraineurs. These adverse effects may be prominent but they often disappear during more lengthy treatment. Such a tolerance to nitrates is well known (23) and has recently even been studied in an attempt to prevent attacks of CH (24). Nine patients with chronic CH received 5-ISMN 30 mg orally t.i.d. for a period of 4 weeks in a double-blind, randomized, placebo-controlled crossover design. There were no significant differences in headache attack frequency or number of treated attacks during 5-ISMN therapy compared with placebo, and it was concluded that induction of tolerance to nitrates cannot be used to treat CH.

In some of our cases angina pectoris improved markedly during CH periods. This was apparently not explained by changes in physical activity or smoking habits in our patients, nor by medication against the headache attacks. There are no reports on eventual anti-angina effects of pizotifen according to the pharmaceutical company. Such a lack of effects against chest pains by pizotifen was also shown in case 7 in our series of patients.

Seasonal or psychological factors had no appreciable influence on the results of the exercise tests, at least in one of the patients. The increased physical work tolerance and prolonged exercise time to development of effort-induced angina during CH periods support the hypothesis that there is a change in vegetative tone between headache periods and asymptomatic intervals (remission phases) which seems to affect the reactivity of both the cranial vessels and cardiac functions. It may be of some significance that two patients of Graham (25, 26) suffering from claudicatio intermittens reported a definite improvement of their leg pains during attacks of CH. Graham suggested that spontaneous headaches are associated with some general effects on the arterial circulation and transitory changes in the vasomotor tone. Interestingly, Strittmatter et al. (27) determined plasma norepinephrine and epinephrine in 12 patients four times a day in the cluster period and found evidence of ‘a decreased activity of the sympathetic nervous system and a consequent alteration of circadian rhythmicity during the cluster period’.

Increased nitrite levels have been found during CH attacks both in serum and in peripheral blood mononuclear cells (28). D’Amico et al. (6, 8) showed that plasma nitrites are increased in episodic CH both during active headache periods and in the remission phase, and they suggested a basal hyperfunctioning of the L-arginine–NO pathway in this primary headache. In our opinion this might possibly also contribute to the rather unexpected remission of ischaemic heart symptoms during active CH.

NO might cause headache via direct effects on perivascular sensory nerve terminals (3, 4) and a release of calcitonin gene-related peptide (CGRP) (29). Such a release has been demonstrated in blood samples from the extracerebral circulation both in spontaneous (10) and in GTN-induced (30, 31) CH attacks. An increased CGRP-like immunoreactivity has been found in plasma of CH patients during active headache periods (30, 31) compared with patients in clinical remission. Abnormal activity of regional perivascular nociceptive fibres containing CGRP may thus be important when trying to explain the triggering action of GTN in CH (30). Since there seems to be an inverse relationship between CH and angina pectoris in some of our patients, it is of interest that CGRP is released locally in myocardial ischaemia. This may thus serve as an endogenous cardio-protective mechanism (32).

Central sympatho-inhibitory effects of nitrites (33, 34) and activation of structures within the brain stem and the hypothalamus, as shown in animal models (35–37), may contribute to those neurovascular mechanisms that are responsible for spontaneous and provoked CH attacks and active headache periods. Further, the secretion of melatonin is decreased during active CH periods compared both with clinical remission (38, 39) and with healthy controls (39, 40). Low serum melatonin levels may, among others, be explained by altered β-adrenergic receptor functions in the pineal gland related to changes in the sympathetic tone (38).

To summarize, in a series of CH patients with coexistent effort-induced angina pectoris we found induction of extra headache periods by sustained nitrate therapy and a remission of angina pectoris during active clusters. We suggest that such an ex-posure of long-acting organic nitrates may induce additional CH periods via central mechanisms. Remission of angina pectoris during active clusters might be associated with increased release of CGRP, inhibition of sympathetic tone and subsequent effects on both cranial vessels and cardiac functions.

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Periods of Cluster Headache Induced by Nitrate Therapy and Spontaneous Remission of Angina Pectoris During Active Clusters

Abstract

Keywords

Introduction

Patients and methods

Results

CH periods induced by organic nitrates (cases 1–6)

Remission of angina pectoris during active CH periods

Case 2

Case 7

Case 8

Discussion

References