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12. Prophylactic Drugs
Keywords
Cluster headacheCluster headache prophylaxisProphylactic drugsProphylactic treatments12.1 Introduction
Prophylactic treatment is the mainstay in the management for both episodic and chronic cluster headache (CH). The typical CH patient may suffer one to eight attacks a day requiring abortive therapy with risk of medication overuse and drug toxicity.
The primary goal of prophylactic treatment is to shorten cluster episodes, reduce the number of attacks during the bouts, and maintain the patient attack-free for all the expected duration of the cluster period. An appropriate prophylactic medication can reduce triptans use, save medical resources, and improve quality of life of CH patients.
Prophylactic therapy often becomes effective quite rapidly, but unfortunately total attack suppression is not always achievable, and patients need to wait the natural ending of the bouts. Patients with active CH require close follow-up both to monitor the efficacy and the toxicity of maintenance treatments. Moreover, patients with chronic CH (CCH) often need periodic tailoring of medications, and some of them may become refractory to prophylactic treatments [1].
Medications should be selected on the basis of CH course (episodic or chronic), attack frequency and duration, pain intensity, contraindications, and patients comorbidities.
Prophylaxis should begin at the first signals of the start of a new cluster bout with caution to find the lowest effective dose, maintained during the cluster period and then discontinued by slowly tapering the doses after full remission.
Treatments for CCH may need to be continued long-term without reduce maintenance medications and sometimes patients may require prophylaxis indefinitely.
Combinations of prophylactic medications are often required, particularly for CCH patients, although the high potential for toxicity.
Only few randomized clinical trials (RCTs) investigated efficacy of preventive drugs in CH, and drugs employed as prophylactic treatments for the disease have been introduced on empirical bases rather than full knowledge of pathophysiological mechanisms [3].
Another issue is for how long prophylaxis should be maintained after the patient has no more attacks. It is helpful to know the average length of a patient’s cluster period to estimate if attacks were stopped due to treatment or to the natural history of the disease. Once cluster attacks stopped, it is recommended to continue prophylaxis for a period of time that is at least the half of the duration of previous cluster periods, but also tapering in shorter periods can be done [4]. In the case of prolonged cluster that lasts ≥3 months, prophylaxis may need to be maintained for at least the same period.
Therapy | Dose | Monitoring | Comment | Common AEs | Advice (EFNS) | |
|---|---|---|---|---|---|---|
First-line medications | Verapamil | 240–960 mg | Baseline and periodic EKGs | Starting dose is 80 mg or 120 mg three times daily and increase the dosage by 80 or 120 mg every week up to a dose of 480 mg a day CCH patients may need higher doses | Constipation, gastrointestinal discomfort, dizziness, distal edema, hypotension, fatigue, bradycardia, cardiac conduction impairment (AV blockade), gingival hyperplasia, dull headache | A |
Second line medications | Lithium carbonate | 600–1800 mg | Lithium levels, CBC, thyroid function, renal function | Starting dose is 300 mg twice a day Increase to 300 mg three times a day after 1 week if no response, and increase further if necessary Usual therapeutic range 0.4–0.8 mEq/L | Tremor, insomnia, nausea, diarrhea, slurred speech, blurred vision, polyuria, polydipsia, arrhythmias, thyroid dysfunction | B |
Methysergide | 4–12 mg | Laboratory controls, chest X-ray, EKG, abdominal MRI | Starting dose is 1 mg/day and then increase of 1 mg every 3–5 days up to maximum of 12 mg/day Usage interrupted for at least 1 month in every 6 months Not recommended to be used concomitantly with sumatriptan (synergistic vasoconstrictive effects) | Nausea, dizziness, abdominal pain, and peripheral edema, retroperitoneal, pulmonary, pleural, and cardiac fibrosis | B | |
Topiramate | 50–200 mg | Serum bicarbonate | Starting dose is 25 mg that should be slowly increased by 25 mg to reach at least 100 mg/day Drink at least 2 L of water per day (to prevent nephrolithiasis) | Paresthesias, cognitive symptoms, fatigue, insomnia, nausea, alteration in taste, loss of appetite, weight loss, anxiety, dizziness, taste alteration, glaucoma, nephrolithiasis | B | |
Third-line medications | Valproic acid | 500–2000 mg | CBC, liver function | Contraindicated in females in their childbearing years because of the risk of fatal birth defects | Weight gain, fatigue, tremor, hair loss, nausea | C |
Melatonin | 10 mg | None | Preferably in the late evening before going to sleep | Fatigue, sedation | C | |
Baclofen | 15–30 mg | None | Starting at low dosage, increased slowly, and slowly decreased when stopping | Drowsiness, dizziness, ataxia, muscle weakness | C | |
Pizotifen | 1.5–3 mg | None | Preferably in the late evening before going to sleep | Sedation, dry mouth, drowsiness, increased appetite, weight gain | Not rated | |
Capsaicin | 0.025% cream | None | Applied twice daily | Burning, itching, dryness, pain, redness, swelling, or soreness at the application site | Not rated | |
Civamide | 100 mL of 0.025% | None | In each nostril daily | Burning, lacrimation, pharyngitis, rhinorrhea | Not rated | |
Gabapentin | 800–3600 mg | CBC | – | Somnolence, fatigue, dizziness, weight gain, peripheral edema, ataxia | Not rated | |
Clonidine | 5–7.5 mg | None | Transdermal patch | Tiredness, hypotension | Not rated | |
Botulinum toxin A | 155–195 U | None | – | Weakness of injected muscles, pain at injection sites | Not rated | |
Transitional therapies | Corticosteroids | Prednisone and prednisolone: 60–100 mg Methylprednisolone: i.v. 500 mg Dexamethasone: 4 mg | Laboratory controls | Prednisone: starting dose for 5–7 days and then tapered every 2–3 days by 10 mg down to zero Methylprednisolone: sometimes followed by oral steroids Dexamethasone: starting dose for 2 weeks followed by 4 mg/day for the subsequent weeks Possible CH relapse during dose reduction | Blood glucose imbalance, hypertension, sleep disturbance, aseptic bone necroses | A |
Ergotamine and DHE | 2–4 mg | Liver function | IV, IM, SC, or IN Repeated two or three times a day for a week if tolerated and may be continued Once or twice a day for another week—longer if necessary and tolerated Not recommended to be used concomitantly with sumatriptan (synergistic vasoconstrictive effects) | Nausea, diarrhea, muscle cramps, cold numb hands and feet, chest tightness, unpleasant taste (IN) | B | |
Occipital nerve block | Methylprednisolone (slow release): 40–80 mg (or equivalent) | None | Is usually done in combination with lidocaine Repeated injections can be used | Abscess, hair loss, procedural risks of injection | Not rated |
12.2 First-Line Medications
12.2.1 Verapamil
Verapamil, a calcium channel blocker, is considered the first choice for the prophylaxis of both episodic and chronic CH [2–9]. The prophylactic efficacy has been established by clinical evidence and by two RCTs [8, 9]. In a double-blind placebo-controlled trial of verapamil 360 mg daily, 80% of patients receiving verapamil had a ≥50% reduction in headache frequency with half of responders improving in the 1st week and the rest responding in the 2nd week of therapy [8]. A double-blind, crossover study compared verapamil (360 mg daily) for 8 weeks to lithium (900 mg daily) for CCH prophylaxis. Both substances provided similar reductions in analgesic consumption and headache index, but verapamil showed more rapid action and better tolerability [9].
Although there is no evidence for an optimal dosage, for CH prophylaxis a daily dosage of 240–960 mg of verapamil is typically used [5, 6, 10, 11]. Most patients will improve at 240–480 mg/day [12], but in some cases, a daily dose of >720 mg can be necessary [6, 7, 13], up to 1200 mg/day in rare refractory cases [4]. Only experienced physicians should give higher dosages.
Given the short half-life of verapamil (3–7 h), the daily dose is divided into three administration, and regular release tablets are preferred to slow release preparations because they are more reliable in maintaining drug blood levels.
A baseline electrocardiogram (EKG) is mandatory before initiating verapamil therapy and should be repeated with each dosage increase to monitor atrioventricular conduction. The dosages required for CH prophylaxis are considerably higher than those used for cardiovascular indications (240–480 mg/day) [11]. Consequently, PR interval prolongation, bradycardia, hypotension, syncope, dizziness, crural edema, constipation, and impotence are more likely to occur [14, 15]. Nearly 20% of patients receiving verapamil develop EKG abnormalities, the great majority of these consisting of prolonged PR intervals. Moreover, 5% of patients develop complete heart block with junctional rhythms, in particular those taking higher doses (720 mg or more) [16, 17]. Blockade of atrioventricular conduction can be caused not only by verapamil but also by some of its metabolites such as norverapamil [18]. Because of this, slow titration up to the target dose has been recommended to reduce the AEs.
Long-term verapamil administration can reduce its clearance and increase the plasmatic availability through the CYP3A enzymes auto inhibition [19]. Verapamil metabolism could be affected also by xenobiotics. Patients should be warned to avoid grapefruit and related fruit as limes and pomelos, which contain furanocoumarins that cause irreversible inactivation of CYP3A4 resulting in increased verapamil levels [20, 21]. An excess of coffee and/or tea consumption may enhance both the excretion of verapamil and its first-pass metabolism by CYP1A2 [22].
There are no evidence-based guidelines suggesting the optimal way of dosing verapamil, and the recommendations are based on effectiveness and tolerability. Slow dosage escalation is questionable considering the severity of CH attacks and the additional risks of prolonged use of bridging medications, but on the other hand, faster dosage escalation (80–160 mg every 2 or 3 days) increases the risk of cardiac AEs. An acceptable compromise would be to start verapamil at 80 mg or 120 mg three times daily and then increase the dosage by 80 mg every week up to a dose of 480 mg a day. However, verapamil is generally well tolerated and can be co-administered with sumatriptan, ergotamine, corticosteroids, and other preventive substances with less concern about drug interactions and then with other prophylactic treatment (e.g., lithium carbonate). Lithium and verapamil should be co-administered with great caution in elderly: profound bradycardia developed was reported on two elderly manic patients taking the combination and was followed by a fatal myocardial infarction in one case [23].
The full efficacy of verapamil can be expected within 1–3 weeks in episodic CH at doses of 240–360 mg/day, while CCH patients may need higher doses and up to 4–5 weeks to manifest a response. In the first 2 weeks of verapamil administration, some clinicians also administer corticosteroids as transitional therapy (see after).
12.3 Second-Line Medications
12.3.1 Lithium
Lithium (lithium carbonate), a mood stabilizer medication, has been studied in CH prophylaxis in more than 20 open trials [24]. It was noted that patients suffering from psychiatric disorders improved their cluster headaches while on lithium therapy [25]. Lithium is considered a second-line treatment for maintenance prophylaxis of CH because of its narrow therapeutic window, the need for periodical blood test monitoring during therapy, frequent adverse events (AEs), and several drug interactions.
As mentioned above, a RCT compared lithium (900 mg daily) to verapamil (360 mg daily) for 8 weeks in patients with CCH; the efficacy was similar, but lithium acted more slowly and had more AEs [9]. A recent placebo-controlled trial comparing lithium to placebo in patients with episodic CH found no difference in the primary outcome (cessation of attacks within 1 week) [26]. Even if this study did not reproduce the beneficial effect found in CCH, the dose used (800 mg) was too low and the treatment period (1 week) too short for an adequate efficacy assessment.
Common dosage to obtain benefit is 900 mg (600–1200 mg) per day usually corresponding to 0.4–0.8 mEq/L lithium serum levels [27]. Higher daily dosages can be required in non-responders; it is important to consider that above 1.2 mEq/L lithium serum levels, the risk to develop AEs is high [28]. The drug should be started considering both age and severity of CH, usually a single dose of 300 mg bedtime, then increased after 3–4 days. Lithium plasma level should be measured after 10 days. The dose can be increased to 300 mg three times a day and increased even more in steps of 150–300 mg/day if necessary. Some patients may require 1200 mg/day. In general, if the subject improves or headaches stop at a given dosage, there is no need to further increase the dose. The dosage increase should be stopped if AEs appear.
Baseline thyroid, renal, and liver function tests, as well as electrolytes, should be done prior to start lithium and regularly monitored thereafter. Long-term use can induce hypothyroidism, polymorphonuclear leukocytosis, and renal dysfunction leading to polyuria due to diabetes insipidus [29]. The probability of drug-induced AEs is increased by dehydration; thus patients have to be warned of the importance of an appropriate water intake.
Special caution is again needed when lithium is administered in the elderly particularly because lithium effects and drug interactions on renal function, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce lithium renal clearance [22, 30], and angiotensin-converting enzyme (ACE) inhibitors can increase the steady-state serum lithium levels up to threefold [31]. Also prokinetic drugs as metoclopramide accelerating gastrointestinal motility may increase lithium absorption and blood concentration [32]. Verapamil metabolites (especially when verapamil is given at >560 mg daily) can reduce renal clearance of lithium; in such patients lithium dosage has to be reduced to prevent AEs [33]. Alcohol should be avoided, and caffeine intake controlled because it increases lithium excretion [29]. Conversely, caffeine discontinuation reduces lithium excretion, and lithium dosage should be decreased as well.
12.3.2 Methysergide
Federigo Sicuteri introduced methysergide, an ergotamine alkaloid derivative as effective headache treatment more than 50 years ago [34]. It has been used as effective CH preventative also in CH [4]. However, no placebo-controlled, double-blind studies are available. Open-label studies showed that between 20% and 73% of patients improve at dosages ranging from 4 to 16 mg daily particularly patients with chronic CH [33].
Usually, methysergide is administered at a daily dose of 4–8 mg starting from 1 mg/day and then increasing 1 mg every 3–5 days up to maximum of 12 mg/day.
Methysergide is indicated for patients with short cluster periods (less than 4 months) [13] as prolonged treatment has been reported to cause retroperitoneal, pulmonary, pleural, and cardiac fibrosis [35, 36]. Laboratory controls including renal function, chest X-ray, electrocardiogram, and abdominal MRI should be undertaken after 4–6 months of treatment.
Methysergide is used much less now because of concerns due to side effects, and its prescription has also been prohibited in several countries (e.g., USA). Methysergide is contraindicated in patients with coronary or peripheral arterial insufficiency and should not be co-administered with triptans because of the synergistic vasoconstrictive effects. Because of the problematic safety profile, methysergide should be used only by experienced practitioners and only as third-line pharmacotherapy.
12.3.3 Topiramate
Topiramate is considered a second-line therapy for CH prophylaxis.
Open-label studies suggest that topiramate in doses ranging from 50 to 200 mg/day is effective in the 70% of patients [37], although one study showed only a minor, if at all, topiramate effect [38].
The recommended starting dose is 25 mg that should be slowly increased by 25 mg every week to minimize adverse effects, to reach at least 100 mg/day. However some authors consider topiramate effective only at higher daily dosages (>100–150 mg/day) or in combination with verapamil and/or lithium.
AEs occur in about 40% of patients, and even if rarely severe, they are a major cause of treatment discontinuation. Topiramate is contraindicated with a history of nephrolithiasis because it may increase the risk of recurrent stones. To prevent nephrolithiasis, patients should be warned to drink at least 2 L of water per day, particularly in warm periods.
Topiramate binding to proteins is quite variable (9–41%) and inversely correlated to its plasmatic concentration [39]. Among 55–97% of administered dose is excreted unchanged in urine. Topiramate may induce the CYP3A4 enzyme leading to a reduction of plasmatic concentrations of oral contraceptive steroids (e.g., ethinylestradiol) [40]. The maintenance of an effective contraception may require higher estrogen doses. Topiramate can have other drug-drug interactions through inhibition of the CYP2C19 enzyme, with consequent decreased clearance of drugs like omeprazole, diazepam, or mephenytoin [41].
12.4 Third-Line Medications
12.4.1 Ergotamine Tartrate
Oral ergotamine has been found to be effective in CH prophylaxis, but its use is limited by the vasoconstrictive properties, variable gastrointestinal absorption, and the potentially threatening AEs associated with ergotism. Ergotism is suggested when limb paresthesia start; in this case the drug must be stopped. Ergot derivatives can be prescribed to hypertensive patients only if arterial blood pressure values are fully controlled.
It is recommended to use this drug category only for short-term treatment courses. Ergotamine tartrate 2 mg per rectum taken at bedtime may help to prevent nocturnal attacks, while 3–4 mg daily in divided doses may be administered for 2–3 weeks as transitional prophylaxis [42].
Dihydroergotamine (DHE) also seems an alternative in CCH patients not responding to other prophylactic drugs. In an open-label study, repeated intravenous (i.v) DHE administration induced remission lasting 12 months in 83% of patients with intractable episodic CH and in 39% of patients with intractable CCH [43].
Because of synergistic side effects, ergot derivatives cannot be administered simultaneously with triptans as for methysergide.
12.4.2 Valproic Acid
Valproic acid has been studied in three small-sample open-label trials that showed efficacy in 54–73% of CH patients, both episodic and chronic [44–46]. A randomized controlled double-blind study did not confirm its efficacy; however, this may have been due to an exceedingly high response rate of 62% in the placebo group, most likely due to spontaneous remission [47].
The clinical experience is that valproic acid is generally ineffective in CH but can be tried as drug of third choice in doses ranging from 500 to 2000 mg daily used alone or in combination with ergots and possibly lithium. Valproic acid may be more effective in CH patients with migrainous features, such as nausea, vomiting, and photo and phonophobia [2]. Regular evaluation of hemogram and liver and pancreatic function are necessary to monitor AEs [19].
Valproic acid is contraindicated in female potentially childbearing patients because of the risk of fatal birth defects [48].
12.4.3 Melatonin
Melatonin is a natural sleep hormone. Cluster patients have reduced serum melatonin levels, and this has the potential to favor CH attacks particularly during the night [49]. This and other observations prompted its use as a CH preventive agent.
In a double-blind, placebo-controlled trial, melatonin 10 mg in regular release tablets was effective to induce cluster remission in five of ten subjects within 5 days while none of the ten subjects randomized to placebo went into remission [50]. A subsequent study that used a 2 mg slow release tablet investigated melatonin efficacy as adjunctive therapy in CH prophylaxis but failed to show benefits [51]. However melatonin can be used with other cluster medications at a starting dose of 10 mg, titrated quickly to 25 mg, and given in the late evening before going to sleep [27].
12.4.4 Pizotifen
One old controlled trial showed that pizotifen exerts some effect [52, 53]. It can be used in one dose of 1.5–3 mg before retiring. Its use is limited by side effects, and it should be used in rare cases as third-line drug [27].
12.4.5 Capsaicin
The effect of repeated capsaicin application to the nasal mucosa in cluster headache has been evaluated in two open [54, 55] and one double-blind, placebo-controlled [56] trial that showed an efficacy in about two-third of the patients. Results from the double-blind study are questionable because of the irritating properties of the active drug [56].
12.4.6 Baclofen
A small open-label study evaluated the efficacy of baclofen 15–30 mg in three divided doses in nine CH patients [57]. Six patients went into remission within a week, and one additional patient improved with cessation of attacks at week 2 [57]. Baclofen should be started at low dosage, increased slowly, and slowly decreased until stopped.
12.4.7 Civamide
A randomized double-blind, placebo-controlled study evaluated the efficacy of intranasal application of civamide for 7 days in 28 CH patients [58]. The primary endpoint was change in frequency of CH attacks per week during posttreatment period (20 days). During the 1st week of the study, civamide was significantly better than placebo in decreasing number of attacks (55.5% vs. 25.9%); a similar trend was present for the entire posttreatment period but did reach statistical significance (61.4% vs. 30.9%; p 0.054). As for capsaicin, blindness is difficult to achieve because of the irritating nature of the nasally applied substance.
12.4.8 Gabapentin
Gabapentin was used in two open-label studies. In the first, 900 mg/day induced remission in eight episodic and four CCH patients within 8 days, with a bout duration reduction ranging from 16 to 40% compared to previous bouts (in episodic cluster headache patients) [59]. In the second study, gabapentin was used as add-on drug in eight patients suffering from CCH refractory to first-line treatment [60]. Six of them responded to treatment, and the longest remission under gabapentin treatment was 18 months.
12.4.9 Clonidine
Clonidine 5–7.5 mg transdermal patch has been studied in two small open-label studies [61, 62]. The first included eight episodic and five chronic CH patients, and all had significant reduction in frequency, intensity, and duration of the attacks [61]. The second study included 16 episodic CH patients but failed to confirm the previous positive results [62].
12.4.10 Botulinum Toxin Type A
Botulinum toxin type A has been tested as add-on therapy in a small open-label study that gave mixed results [63]. Patients with CH (three episodic and nine chronic) received 50 units injected ipsilateral to the headache. One chronic CH patient had remission, other two chronic patients had improvement in attack frequency and severity, and another chronic CH patient had his continuous headache improved but no change in cluster headache attacks. The remaining eight patients had no benefit.
12.4.11 Calcitonin Gene-Related Peptide (CGRP)-Targeted Therapies
Calcitonin gene-related peptide (CGRP)-targeted therapies represent the new frontiers in migraine and CH treatment. At this time, two monoclonal antibodies, galcanezumab (LY2951742 by Eli Lilly) and fremanezumab (TEV-48125 by TEVA), are under evaluation in Phase 3 clinical trials.
Galcanezumab is being studied for both episodic (NCT02397473) [64] and chronic CH (NCT02438826) [65]. The drug is administered subcutaneously every 30 days for 8 weeks and 12 months (in episodic and chronic trial, respectively). In both studies the primary outcome is the mean change in number of weekly attacks, and the secondary outcome is the proportion of participants with ≥30 or ≥50% reduction in number of weekly attacks. Both studies estimate to enroll 162 patients. The estimated completion date for the episodic study is June 2018 and for the chronic one is July 2019. Patients that complete those trials will be invited to participate to a long-term safety and tolerability study [NCT02797951] estimated to be completed in August 2020 [66].
Similarly, fremanezumab in two dose regimens (intravenous/subcutaneous and subcutaneous) is under evaluation for both episodic [NCT02945046] [67] and chronic [NCT02964338] [68] CH prophylaxis. The primary outcome is the mean change in the weekly average number of attacks during the 4-week (for episodic) and the12-week period (for chronic) after administration of the first dose. The secondary outcomes are the mean change from baseline in the number of CH attacks during the 4-week (for episodic) and the 12-week period (for chronic) after the first dose and the proportion of participants with ≥50% reduction in number of weekly attacks during same period. Both studies estimate to enroll 300 patients. The estimated completion date for the episodic study is June 2018 and for the chronic one is November 2018. Patients that complete those trials will be invited to participate to a 68 weeks study to evaluate the long-term safety of fremanezumab [NCT03107052] estimated to be completed in August 2020 [69].
12.5 Transitional Therapies
The transitional medications are usually administered initially together with CH prophylactic treatment until prophylactic treatment effectiveness begins. Transitional therapies are indicated primarily in episodic CH patients with relatively high attacks frequency (>2 attacks/day). This approach aims to quickly stop CH attacks to prevent pain and reduce disability, also reducing use of acute medications. In the meantime dosage of prophylactic medication can be gradually increased up to therapeutic range. Transitional therapies are generally used for 1–3 weeks depending on the prophylactic drug titration and cluster period severity. Occipital nerve blockade with steroids and/or local anesthetics can require only one injection.
12.5.1 Corticosteroids
Corticosteroids as prednisolone, prednisone, and dexamethasone are rapidly effective drugs for CH and are considered the most effective transitional treatment [27]. About 70–80% of all CH patients report headache-free or near headache-free states within 24–48 h from steroid administration, but some patients require prolonged administration as headaches recur once steroid is tapered/stopped [70]. Because of the high risk for side effects, steroids should be used for short-term courses only trying to limit their use as long-term treatment [2].
CH is very likely to relapse when transitional steroid treatment is reduced and stopped unless a nonsteroidal prophylactic therapy as verapamil or lithium has been initiated in the meantime. A steroid course lasting 15–18 days provides time to increase the dose of the prophylactic drug to the expected therapeutic dosage.
There are no adequate randomized, placebo-controlled trials available for the use of corticosteroids in CH. Common dosage of oral prednisone or prednisolone is 60–100 mg given once a day for 5–7 days; the dose should then be tapered every 2–3 days by 10 mg down to zero. The tapering could be slower in CCH because of relapse occurrence. Intravenous corticosteroids (methylprednisolone i.v. 500 mg), sometimes followed by oral steroids, may also be effective [71, 72]. Also dexamethasone, a synthetic corticosteroid used mainly to manage cerebral edema, resulted in a clinical positive response when administered intramuscularly or orally as 4 mg twice a day for 2 weeks followed by 4 mg/day for the subsequent week [71].
12.5.2 Ergot Derivatives
Even though controlled trial data supporting their use are lacking, ergotamine tartrate and DHE may be used for CH transitional prophylaxis. Ergotamine tartrate (3–4 mg/day in divided doses) may be administered for 2–3 weeks [42]. Repetitive intravenous DHE administrations (two or three times a day) stop the attacks within 3 days from initiating therapy in more than 90% of patients [73]. The most practical method of administration for use at home is by SC or intramuscular self-injection. DHE given subcutaneously as 1 mg twice a day or just 1 mg at bedtime can be continued beyond 1 week [74]. DHE nasal spray could theoretically also be used, but not all the medication is absorbed [75], and consequently a higher dose of 2 mg is recommended [76].
12.5.3 Occipital Nerve Block
An effective alternative to steroid oral administration is occipital nerve block injecting local anesthetic and corticosteroid or corticosteroid alone; compared to oral administration, this route has the advantage of not inducing the rebound effect [77].
Blockade of greater occipital nerve (GON) was investigated as CH treatment in several studies, with the majority showing positive results. In a small open-label trial, GON block ipsilateral to the head pain using lidocaine 1% in combination with triamcinolone 40 mg was associated with good or moderate response in 64% of patients [78]. However, triamcinolone should be avoided because of reported risk of cutaneous atrophy and localized alopecia [79]. A prospective open-label study showed a positive response to GON blockade in 57% of CCH patients: 42% of responders were pain free and 15% having a partial benefit [80]. Duration of improvement was 3 weeks (median); efficacy, overall rate, and average duration of response remained consistent with repeated quarterly injections.
Also, suboccipital injection of steroids was effective in a double-blind, placebo-controlled trial [81]. A single injection of a mixture of short- and long-acting betamethasone (12.46 mg betamethasone dipropionate and 5.26 mg betamethasone disodium phosphate mixed with 0.5 mL lidocaine 2%) suppressed cluster attacks in 85% of patients (both episodic and chronic) with 61% remaining attack-free for at least 4 weeks. In another randomized, double-blind, placebo-controlled trial, three suboccipital injections (48–72 h apart) of cortivazol 3.75 mg reduced the number of attacks during the first 15 days after the first injections in both episodic and chronic CH patients [75].
Long-acting preparation of steroids may be more useful for occipital nerve block, and based on the two controlled trials, a relatively high dose can be used [75, 81]. Betamethasone has a five times higher potency than methylprednisolone, so methylprednisolone dosages between 40 and 80 mg in a slow release preparation would be appropriate in case of several repeated injections. In the case of only a single injection, 80 mg of methylprednisolone might be more appropriate than 40 mg.
