Treatment of acute cluster headache with 20 mg sumatriptan nasal spray – an open pilot study

We investigated the efficacy and tolerability of 20 mg sumatriptan nasal spray in the acute treatment of cluster headache attacks in an open-label study. 10 patients met the criteria of the International Headache Society (IHS) for episodic or chronic cluster headache and were enrolled in our study. The primary efficacy measure was “pain free” 30 minutes after treatment. Secondary endpoints included “headache response” (defined as headache improvement from “very severe”, “severe” or “moderate” pain to “mild” or “no” pain) 15, 30, 45 and 60 minutes after treatment. We also assessed the participant's overall treatment satisfaction at the end of the study. Sumatriptan nasal spray was applied in 154 “moderate” to “very severe” cluster headache attacks. 30 minutes after nasal spray application, 50 % of attacks were completely aborted and 58 % of attacks responded to treatment. The overall efficacy of sumatriptan nasal spray was considered “excellent” in two, “good” in four, “reasonable” in two and “poor” in two patients. Eight patients indicated their intention to treat further attacks with intranasal sumatriptan. Seven patients were interviewed after a follow-up period of six months. Four patients continued to treat all cluster headache attacks with the intranasal sumatriptan formula, two patients had switched to subcutaneous sumatriptan and one patient was in remission since the end of the study. We conclude that 20 mg sumatriptan nasal spray might be an alternative therapy for the treatment of cluster headache attacks, but double-blind studies are needed to further evaluate its efficacy. Received: 26 March 2001, Received in revised form: 13 June 2001, Accepted: 18 June 2001     

Sumatriptan overuse in episodic cluster headache: lack of adverse events, rebound syndromes, drug dependence and tachyphylaxis

This observational study was designed to examine the pattern of sumatriptan use in patients with cluster headache using more than the recommended daily dose of subcutaneously injected (s.c.) sumatriptan. Thirteen patients suffering from episodic cluster headache were asked to record the characteristics of their attacks and drug intake for 1 year. All reported a high daily frequency of attacks (more than 3 per day) and the related overuse of s.c. sumatriptan. The results show that the overall incidence of adverse events among patients receiving sumatriptan injections for the treatment of cluster headache is low. The extended administration of this drug in episodic cluster headache did not result in tolerance problems or tachyphylaxis. Only 4 patients experienced minor adverse events and recovered more slowly than the others. They suffered from migraine without aura and cluster headache, and showed a family history of migraine. Even though they must be viewed with caution, due to the observational nature of the study and the low number of patients included, these results suggest that the profile of sumatriptan may differ in cluster headache compared with migraine.     

The efficacy of subcutaneous sumatriptan in the treatment of recurrence of migraine headache.

OBJECTIVES: To investigate the efficacy of a second subcutaneous dose of 6 mg sumatriptan in the treatment of recurrence of headache after successful treatment of a migraine attack with an initial 6 mg dose. METHODS: In a prospective, randomised, placebo controlled, double blind, parallel group study, 803 patients were treated for one to three migraine attacks with severe or moderate headache with a subcutaneous injection of 6 mg sumatriptan. Any subsequent recurrence of migraine headache was treated with a randomised second injection of sumatriptan or placebo. Recurrence was defined as a headache of moderate or severe intensity occurring 1-24 hours after the initial dose in a patient whose headache had been relieved by sumatriptan (reduction of headache severity from severe or moderate to mild or none after one hour). RESULTS: Headache recurrence was reported by 10%-15% of patients. At each attack, 6 mg sumatriptan given subcutaneously was significantly (P < 0.0005) more effective than placebo at relieving recurrent headache after one hour (84%-93% v 31%-50% of patients); 76%-83% of patients reported headache relief one hour after the initial dose of sumatriptan. Sumatriptan was generally well tolerated. CONCLUSIONS: Up to 15% of patients with migraine experience significant recurrence of headache after successful treatment with subcutaneous sumatriptan, and this recurrence is effectively treated by a further dose of subcutaneous sumatriptan.     

Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study

Current practical evidence-based acute treatments of cluster headache are limited to subcutaneous and intranasal formulations of sumatriptan, and oxygen. Two small randomized, double-blind trials suggested efficacy of somatostatin in cluster headache. We sought to determine whether octreotide, a somatostatin analog, is effective in the abortive treatment of acute cluster headache. Patients with episodic and chronic cluster headache, as defined by the International Headache Society, were recruited to a double-blind placebo-controlled crossover study. Patients were instructed to treat two attacks of at least moderate pain severity, with at least a 24-hour break, using subcutaneous octreotide microg or matching placebo. The primary end point was the headache response defined as very severe, severe, or moderate pain becomes mild or nil, at 30 minutes. The primary end point was examined using a multilevel analysis approach. A total of 57 patients were recruited of whom 46 provided efficacy data on attacks treated with octreotide and 45 with placebo. The headache response rate with subcutaneous octreotide was 52%, whereas that with placebo was 36%. Modeling the treatment outcome as a binomial where response was determined by treatment, using the patient as the level 2 variable, and considering period effect, sex, and cluster headache type as other variables of interest, we found that the effect of subcutaneous octreotide 100 microg was significantly superior to placebo (p < 0.01). Subcutaneous octreotide 100 microg is effective in the acute treatment of cluster headache when compared with placebo. Nonvasconstrictor treatment of acute cluster headache is possible.     

Cluster headache and other trigeminal autonomic cephalalgias: diagnosis and treatment]

Cluster headaches are characterized by strictly unilateral paroxysmal attacks of severe pain with associated autonomic sign and symptom. Prevalence is 5 times higher in men than in women in our cases. About 10-15% of patients have chronic symptoms without remissions, but we estimated less frequent in Japanese (6.6% in our series). Pain almost invariably recurs on the same side, but in some patients (16.4%) the affected site switches. Cluster headache may be inherited in about 5% of our cases. Attacks frequently occur at night (60.7%). The patients (64.8%) are restless or agitated during an attack. Recent PET studies elucidated that acute attacks causes activation of the posterior hypothalamic grey matter. The excitement of the area might be responsible for peculiar clinical characteristics of agitation. Some patients (66.0%) have also have symptoms (especially a visual aura) usually attributed to migraine. Treatment of cluster headache includes both acute therapy aimed at aborting individual attacks and prophylactic therapy aimed at preventing recurrent attacks during the cluster period. There are many choices using for both therapies. Based on our clinical experience, we recommended the combination of nasal sumatriptan for acute attacks and verapamil 240 mg/day for prophylaxis.     

European Academy of Neurology guidelines on the treatment of cluster headache

Background and Purpose

Cluster headache is a relatively rare, disabling primary headache disorder with a major impact on patients' quality of life. This work presents evidence-based recommendations for the treatment of cluster headache derived from a systematic review of the literature and consensus among a panel of experts.

Methods

The databases PubMed (Medline), Science Citation Index, and Cochrane Library were screened for studies on the efficacy of interventions (last access July 2022). The findings in these studies were evaluated according to the recommendations of the European Academy of Neurology, and the level of evidence was established using GRADE (Grading of Recommendations Assessment, Development, and Evaluation).

Recommendations

For the acute treatment of cluster headache attacks, there is a strong recommendation for oxygen (100%) with a flow of at least 12 L/min over 15 min and 6 mg subcutaneous sumatriptan. Prophylaxis of cluster headache attacks with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy and tolerability) is recommended. Corticosteroids are efficacious in cluster headache. To reach an effect, the use of at least 100 mg prednisone (or equivalent corticosteroid) given orally or at up to 500 mg iv per day over 5 days is recommended. Lithium, topiramate, and galcanezumab (only for episodic cluster headache) are recommended as alternative treatments. Noninvasive vagus nerve stimulation is efficacious in episodic but not chronic cluster headache. Greater occipital nerve block is recommended, but electrical stimulation of the greater occipital nerve is not recommended due to the side effect profile.     

EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias

Cluster headache and the other trigeminal‐autonomic cephalalgias [paroxysmal hemicrania, short‐lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome] are rare but very disabling conditions with a major impact on the patient's quality of life. The objective of this study was to give evidence‐based recommendations for the treatment of these headache disorders based on a literature search and consensus amongst a panel of experts. All available medical reference systems were screened for any kind of studies on cluster headache, paroxysmal hemicrania and SUNCT syndrome. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies resulting in level A, B or C recommendations and good practice points. For the acute treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7 l/min over 15 min and 6 mg subcutaneous sumatriptan are drugs of first choice. Prophylaxis of cluster headache should be performed with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy or tolerability). Although no class I or II trials are available, steroids are clearly effective in cluster headache. Therefore, the use of at least 100 mg methylprednisone (or equivalent corticosteroid) given orally or at up to 500 mg i.v. per day over 5 days (then tapering down) is recommended. Methysergide, lithium and topiramate are recommended as alternative treatments. Surgical procedures, although in part promising, require further scientific evaluation. For paroxysmal hemicranias, indomethacin at a daily dose of up to 225 mg is the drug of choice. For treatment of SUNCT syndrome, large series suggest that lamotrigine is the most effective preventive agent, with topiramate and gabapentin also being useful. Intravenous lidocaine may also be helpful as an acute therapy when patients are extremely distressed and disabled by frequent attacks.     

Sumatriptan and ergotamine overuse and drug-induced headache: a clinicoepidemiologic study.

Drug-induced headache, particularly ergotamine-induced headache, is a common problem in migraine treatment. Some case reports suggest that even the new serotonergic antimigraine drugs such as sumatriptan can lead to overuse and subsequent drug-induced headache. We performed a controlled study to identify the rate of sumatriptan overuse and sumatriptan-induced headache and compared it to the rate of ergotamine overuse and ergotamine-induced headache. Two thousand sixty-five consecutive heachache patients, all experienced in intake of sumatriptan (n = 631) or ergotamine (n = 620), were enrolled over a three-year study period. The rates of overuse and drug-induced headache and the clinical features of the subgroups were compared. Risk factors for sumatriptan overuse were identified. The rates of ergotamine and sumatriptan overuse were 14.2% and 3.5%, respectively (p < 0.001). Drug-induced headache could be found more frequently in cases of ergotamine overuse than in cases of sumatriptan overuse (68% versus 32%; p < 0.01). Development of sumatriptan overuse was most common in patients with previous drug-induced headache (68%), combined headache as the primary headache type (45%), and subcutaneous application of sumatriptan (45%). We conclude that sumatriptan intake can lead to overuse and subsequent drug-induced headache. The risk for overuse and drug-induced headache is significantly lower than in patients with ergotamine intake. This might be caused in part by the relatively short period of sumatriptan availability on the market. The new generation of serotonin-1B/D-receptor agonists in the treatment of headache should have a potential for overuse similar to that of traditional headache drugs.     

A systematic review of the use of triptans in acute migraine

OBJECTIVE: A systematic review of the literature was undertaken, to consolidate evidence concerning the efficacy and safety of triptans currently available in Canada (sumatriptan, rizatriptan, naratriptan, zolmitriptan), and to provide guidelines for selection of a triptan. METHODS: Data from published, randomized, placebo-controlled trials were pooled and a combined number needed to treat (NNT) and number needed to harm (NNH) was generated for each triptan. Direct comparative trials of triptans were also examined. RESULTS: The lowest NNT for headache response/pain-free at one/two hours is observed with subcutaneous sumatriptan. Among the oral formulations, the lowest NNT is observed with rizatriptan and the highest NNT with naratriptan. The lowest NNH is observed with subcutaneous sumatriptan. CONCLUSIONS: Triptans are relatively safe and effective medications for acute migraine attacks. However, differences among them are relatively small. Considerations in selecting a triptan include individual patient response/tolerance, characteristics of the attacks, relief of associated symptoms, consistency of response, headache recurrence, delivery systems and patient preference.     

Eletriptan vs sumatriptan: a double-blind,placebo-controlled,multiple migraine attack study

OBJECTIVE: To compare the efficacy of oral eletriptan, 40 mg and 80 mg, and oral sumatriptan, 50 mg and 100 mg, in the acute treatment of migraine. METHODS: Patients with a history of migraine (n = 1,008) were randomly assigned to receive placebo, 40 mg of eletriptan, 80 mg of eletriptan, 50 mg of sumatriptan, or 100 mg of sumatriptan to treat up to three attacks. Early headache response (at 1 hour) was the primary endpoint, in addition to the standard endpoint, 2-hour headache response. RESULTS: Headache response rates were 12% at 1 hour and 31% at 2 hours for placebo; 24% at 1 hour and 50% at 2 hours for sumatriptan 50 mg; 27% at 1 hour and 53% at 2 hours for sumatriptan 100 mg; 30% at 1 hour and 64% at 2 hours for eletriptan 40 mg; and 37% at 1 hour and 67% at 2 hours for eletriptan 80 mg. More patients receiving eletriptan 80 mg achieved a 1-hour headache response than did patients receiving sumatriptan 50 mg (p < 0.05). All doses of eletriptan were superior to sumatriptan at 2 hours for headache response and complete pain relief (p < 0.05). Significantly more patients on eletriptan 80 mg achieved headache response in all attacks than did patients receiving either sumatriptan dose. Eletriptan 40 mg was superior to both sumatriptan doses in functional improvement (p < 0.005). The superior efficacy of both eletriptan doses was associated with higher rates of patient acceptability than sumatriptan 50 mg (p < 0.05). Eletriptan and sumatriptan were well tolerated. CONCLUSION: Oral eletriptan (40 mg and 80 mg) is effective, safe, and tolerable in the acute treatment of migraine and yields a consistent response.     

Coronary vasospasm and myocardial infarction induced by oral sumatriptan

Coronary vasospasm is well documented as a side effect of injectable subcutaneous forms of sumatriptan; only one such case has been reported so far with oral ingestion of sumatriptan in a patient with underlying coronary artery disease. This report describes a case of coronary vasospasm induced by oral sumatriptan even in normal coronary arteries. Physicians and patients should be aware of a small and unpredictable risk of the serious cardiac side effects of this drug.     

Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study

BACKGROUND: Cluster headache is a form of primary headache in which attacks are rapid in onset with very severe pain. The mainstays of acute therapy are inhaled oxygen and sumatriptan succinate injection. OBJECTIVE: To evaluate zolmitriptan nasal spray in the acute treatment of cluster headache. METHODS: Ninety-two patients, aged 40 +/- 10 years (mean +/- SD) (80 men and 12 women), with International Headache Society-defined cluster headache were randomized into a placebo-controlled, double-blind crossover study. Patients treated 3 headache attacks using placebo for 1 attack, 5 mg of zolmitriptan nasal spray (ZNS5) for 1 attack, and 10 mg of zolmitriptan nasal spray for 1 attack. The primary end point was headache relief at 30 minutes, defined as reduction from moderate, severe, or very severe pain to no or mild pain. The study was approved by the appropriate ethics committees. RESULTS: Sixty-nine patients were available for an intention-to-treat analysis. The 30-minute headache relief rates were placebo, 21%; ZNS5, 40%; and ZNS10, 62%. Modeling the response as a binary outcome, the Wald test was significant for the overall regression (chi(2)(1) = 29.4; P<.001), with both ZNS5 and ZNS10 giving significant effects against placebo. Headache relief rates for patients with episodic cluster headache were 30% for placebo, 47% for ZNS5, and 80% for ZNS10, while corresponding rates for patients with chronic cluster headache were 14%, 28%, and 36%, respectively. Zolmitriptan was also well tolerated. CONCLUSION: Five-milligram and 10-mg doses of zolmitriptan intranasal spray are effective within 30 minutes and well tolerated in the treatment of acute cluster headache. Trial Registration controlled-trials.com Identifier ISCRTN27362692.     

Zolmitriptan versus sumatriptan for the acute oral treatment of migraine: a randomized, double-blind, international study

This randomized, double-blind, parallel-group study compared the efficacy and tolerability of zolmitriptan (2.5 or 5 mg) and sumatriptan (50 mg) in the acute oral treatment of up to six moderate-to-severe migraine attacks. The intention to treat (ITT) population comprised of 1522 patients: 500 treated with zolmitriptan 2.5 mg (2671 attacks), 514 with zolmitriptan 5 mg (2744 attacks) and 508 with sumatriptan 50 mg (2693 attacks). Overall, the 2-h headache response rates in these groups were 62.9, 65.7 and 66.6%, respectively. There were no statistically significant differences between sumatriptan 50 mg and zolmitriptan 2.5 mg (P = 0.12) or 5 mg (P = 0.80). Approximately 40% of patients in each group reported a 2-h headache response in > or = 80% of attacks. There were no statistically significant differences between the groups in the rates of headache response at 1 h (zolmitriptan 2.5 mg 36.9%, zolmitriptan 5 mg 39.5% and sumatriptan 50 mg 38.0%) or 4 h (70.3, 72.9 and 72.2%, respectively) or in the rates of meaningful migraine relief at 1, 2 or 4 h or sustained (24-h) pain relief. All treatments were well tolerated. In conclusion, zolmitriptan (2.5 or 5 mg) proved similarly efficacious compared with sumatriptan (50 mg), both in terms of response rates and consistency across attacks.     

Cluster headache: present and future therapy

Cluster headache is characterized by severe, unilateral headache attacks of orbital, supraorbital or temporal pain lasting 15–180 min accompanied by ipsilateral lacrimation, rhinorrhea and other cranial autonomic manifestations. Cluster headache attacks need fast-acting abortive agents because the pain peaks very quickly; sumatriptan injection is the gold standard acute treatment. First-line preventative drugs include verapamil and carbolithium. Other drugs demonstrated effective in open trials include topiramate, valproic acid, gabapentin and others. Steroids are very effective; local injection in the occipital area is also effective but its prolonged use needs caution. Monoclonal antibodies against calcitonin gene-related peptide are under investigation as prophylactic agents in both episodic and chronic cluster headache. A number of neurostimulation procedures including occipital nerve stimulation, vagus nerve stimulation, sphenopalatine ganglion stimulation and the more invasive hypothalamic stimulation are employed in chronic intractable cluster headache.     

Headaches with (ipsilateral) autonomic symptoms

Abstract. Primary short-lasting headaches broadly divide themselves into those associated with autonomic symptoms, so called trigemino-autonomic cephalgias (TACs), and those with little autonomic syndromes. The trigeminoautonomic cephalgias include cluster headache and paroxysmal hemicranias, in which head pain and cranial autonomic symptoms are prominent. The most striking feature of cluster headache is the circadian and circannual periodicity of the attacks. Inheritance may play a role in some families. The attacks are of extreme intensity, of short duration, occur unilaterally, and are accompanied by symptoms of autonomic dysfunction. Medical treatment includes both acute therapy aimed at aborting individual attacks and prophylactic therapy aimed at preventing recurrent attacks during the cluster period. Some types of trigemino-autonomic headaches, such as paroxysmal hemicrania and hemicrania continua have, unlike cluster headaches, a very robust response to indomethacin, leading to a consideration of indomethacin-sensitive headaches.     

Subcutaneous sumatriptan in the acute treatment of cluster headache: a dose comparison study

This multicentre, double-blind, randomised, crossover study compared the efficacy, safety and tolerability of subcutaneous sumatriptan (6 mg and 12 mg) with placebo in 134 in-patients with cluster headache. Headache improvement to mild or no pain at 5, 10 and 15 min after treatment was recorded. At 10 min, headache relief was reported by 25% placebo), 49% (6 mg) and 63% (12 mg) of patients and at 15 min the results were 35% (placebo), 75% (6 mg) and 80% (12 mg) (p < 0.001 for all comparisons with placebo). The 12 mg dose was not significantly better than the 6 mg dose and was associated with more adverse events. The 6 mg dose is therefore recommended for the acute treatment of cluster headache.     

Sumatriptan has no clinically relevant effect in the treatment of episodic tension-type headache

In a randomized, multi-centre, double-blind, placebo-controlled, parallel group study, the efficacy of 100 mg oral sumatriptan was compared with that of placebo in the treatment of episodic tension-type headache. The patients were recruited from the general population in the vicinity of the study centres, by randomly mailed invitations. One or more attacks were treated with sumatriptan by 54 patients and with placebo by 57 patients. A seven-point verbal rating scale was used for hourly assessments of headache relief, 1–4 h after treatment According to the predefined primary end-point of the study, which was moderate or complete relief of headache 2 and 4 h after treatment of the first attack, there was no significant difference between sumatriptan and placebo treatment Sumatriptan did perform statistically significantly better than placebo at some time points, but the effect was not considered clinically relevant We conclude that sumatriptan should not be used in treatment of tension-type headache. The marked difference in effect of sumatriptan in treatment of migraine and tension-type headache argues against the idea that migraine and tension-type headache are part of a continuum of headache disorders.     

Diagnosis and treatment of cluster headache

Cluster headache is an uncommon yet distinctive neurovascular syndrome occurring in either episodic or chronic patterns. The most unique feature of cluster headache is the unmistakable circadian and circannual periodicity. The attacks are stereotypical, that is, of extreme intensity, of short duration, occurring unilaterally, and associated with robust signs and symptoms of autonomic dysfunction. Unlike migraine, during an attack the patient with cluster headache often paces about. Attacks frequently occur at night, awakening the patient from sleep. Although the pathophysiology of cluster headache remains to be fully elucidated, several seminal observations have recently been made. The medical treatment of cluster headache includes acute, transitional, and maintenance prophylaxis. Agents used for acute therapy include inhalation of oxygen and triptans, such as sumatriptan, and dihydroergotamine. Transitional prophylaxis refers to the short-term use of fast-acting agents. This typically involves either corticosteroids or ergotamine derivatives. The mainstay of prophylactic therapy is verapamil. Lithium, divalproex sodium, or topiramate may also be useful. As the sophistication of functional neuroimaging increases, so too will our ability to better understand the anatomic and metabolic perturbations that underlie cluster headache.     

Patient preference for eletriptan 80 mg versus subcutaneous sumatriptan 6 mg: results of a crossover study in patients who have recently used subcutaneous sumatriptan.

This current randomized, open-label, crossover study evaluated preference for oral eletriptan 80 mg compared with subcutaneous sumatriptan 6 mg (suma-sc) amongst patients (n = 311) meeting IHS criteria for migraine who had recently used suma-sc, and found it well tolerated. Three attacks were treated on each study medication. Assessment of subjective preference was evaluated, after which patients freely chose which study medication they wished to use to treat each of three additional migraine attacks. A slight majority (50.6%) preferred or greatly preferred eletriptan, whilst 43% preferred suma-sc. When permitted to choose between eletriptan and suma-sc for subsequent treatment, 78% of patients who had preferred eletriptan took eletriptan during the extension phase for all three of their attacks, whilst only 37% of patients who preferred suma-sc took suma-sc for all of their extension-phase attacks (P < 0.05). Secondary efficacy measures showed comparable efficacy for each study medication, except for faster headache response and pain-free rates favor of suma-sc, and a significantly lower recurrence rate on eletriptan (25% vs. 40%; P < 0.05). The results of this study suggest that eletriptan is a strong alternative option for patients who have been prescribed suma-sc.     

The safety and tolerability of sumatriptan: an overview.

Safety information was pooled from 4,859 patients, mainly treated in controlled clinical trials with a dispersible tablet of sumatriptan or by a subcutaneous injection, and from 1,164 patients who received placebo by these routes. Safety monitoring involved collection of all adverse events, regardless of their relationship to treatment, and included routine laboratory screening tests and some special investigations. Individuals experienced several groups of symptoms that might be considered to be features of migraine itself or of the post-migraine period or due to treatment. The commonest complaints were an unpleasant taste or pain on injection. After oral sumatriptan (100-300 mg), some events (nausea, malaise) were characteristic of migraine and others (fatigue, sedation, weakness) were characteristic of the recovery period. With subcutaneous sumatriptan (4-8 mg) similar events were observed, but certain distinctive symptoms variously described as heaviness, pressure sensation, tingling, feelings of heat or warmth, were more common and affected various parts of the body. Their early onset and transient nature suggests some pharmacological mechanism, as yet not identified. Despite the mixed picture of symptoms recorded after treatment, they were not serious, they were transient and they were accepted by patients. Close patient monitoring allowed detailed evaluation of any possible cardiovascular side-effects as seen with other anti-migraine agents, particularly ergotamine. The evidence is reassuring but, since experience in patients with symptomatic ischaemic heart disease is limited, it is recommended that they should initially be treated with sumatriptan under medical supervision for their first two or three attacks.(ABSTRACT TRUNCATED AT 250 WORDS)