International guidelines give verapamil, lithium, methysergide, topiramate, valproate, melatonin, and baclofen as first-line treatments [
2]. In their review, Pereja and Alvarez describe verapamil, lithium, and topiramate as being the standard treatments most commonly in use [
3••]. Below, we shall provide a summary of treatments aside from verapamil, lithium, methysergide, and topiramate (Table
2).
Table 2
Summary of evidence for oral and injectable alternative treatments for cluster headache
Gabapentin |
Leandri et al. [ 6], Schuh-Hofer et al. [ 7] | 20 (12 CCH) | Positive 18/20 | 800–3600 mg daily |
Melatonin |
| 10 (treatment group; 2 CCH), 10 (placebo group) | Treatment group: positive 5/10 treated Placebo group: positive 0/10 Significant difference to placebo (p < 0.03) | 10 mg daily |
| 9 (6 CCH), crossover trial | No significant difference to placebo (p > 0.05) | 2 mg daily for 1 month, placebo for one month |
Baclofen |
| 16 (ECH) | Positive 13/16 | 15–30 mg daily |
Valproic acid |
| 15 (2 CCH) | Positive 11/15 | 600–2000 mg daily |
| 50 (treatment group; 11 CCH), 46 (placebo group; 6 CCH) | Treatment group: positive 25/50 Placebo group: positive 29/50 No significant difference to placebo (p = 0.23) | 1–2 g daily |
Candesartan |
| 24 (treatment group), 16 (placebo group) | No significant difference to placebo for change in attack frequency (p = 0.38). Post hoc analysis significant difference to placebo (p < 0.01, RR 1.3) | 32 mg daily |
Levitracetam |
| 2 | 2 | 1–2 g (unpublished data on further 3 CCH responding) |
Botulinum toxin |
Sostak et al. [ 17], Robbins [ 18], Freund and Schwartz [ 19], Smuts and Barnard [ 20] | 24 (15 CCH) | Positive 11/24 | 24–50 units |
Nerve blocks |
GON |
| 21 (treatment group; 7 CCH), 22 (placebo group; 8 CCH) | Significant difference between groups in mean no attacks a day until day 15 (p < 0.01) No significant difference between groups reaching 50 % reduction of attacks at 15 days (p = 0.06) | Treatment: 3.75 mg cortivazol, 3 injections given 48–72 h apart Placebo: saline |
| 13 (treatment group; 4 CCH), 10 (placebo group; 3 CCH) | Treatment group: positive 11/13 (4 CCH) Placebo group: positive 0/10 Significant difference between groups (p < 0.01) | Treatment: betamethasone and xylocaine Placebo: saline and xylocaine |
| 83 (83 CCH) | Positive 47/83 (first injection), 31/37 (second injection), 27/28 (third injection) | 80 mg methylprednisolone and lidocaine |
SPG |
| 15 (15 CCH) | Positive 8/15 | Triamcinolone acetonide, bupivacane, mepivacane, and 1/100,000 adrenaline injected with endoscopic guidance |
Oral Treatments
Gabapentin is widely used in the treatment of pain and has therefore been trialled in CH with some highly positive data in a limited series of patients. In the series of Leandri et al. [
6], 12 patients undertook an open trial of gabapentin. All reported freedom from pain after 8 days of treatment. Schuh-Hofer et al. [
7] used gapapentin as an adjunctive treatment in eight patients with chronic CH (CCH) who had failed first-line therapies. Six of eight patients reported a more than 50 % reduction in attack frequency, with two claiming pain freedom at the 4-months follow-up. Doses used by this group ranged from 800 to 3600 mg. Long-term data on the use of gabapentin do not exist, but Schuh-Hofer et al. [
7] saw that, over a year, follow-up patients did seem to develop tolerance. Although the authors state that gabapentin is a well-tolerated drug the dosage of which can be rapidly increased over a short period of time, in clinical practice their highly positive rapid-onset results have not been observed. It is relevant to note that although gabapentin was previously considered beneficial for migraine, both a placebo-controlled study by Silberstein et al. [
8] and recent Cochrane review have found no evidence of efficacy [
9].
Melatonin has been tried in CH, but there are contradictory findings. Leone et al. [
10] found a significant reduction in headache frequency in their 2-week randomized placebo controlled trial, with 5/10 patients with episodic CH (ECH) treated reporting cessation of their attacks after 5 days of treatment (10 mg daily) but no effect on patients with CCH. Pringsheim et al. [
11] conducted a placebo-controlled crossover study using 2 mg daily for 1 month in nine patients. They reported no significant difference between melatonin and placebo. Although conflicting evidence exists, melatonin makes for an attractive therapy given its lack of side effects and drug interactions. An argument can be made that the negative trial group used a very low dose and, in practice, our unit recommends a treatment dose of 12–16 mg daily. Further trials with higher doses need to be carried out before clear recommendations can be made.
Baclofen has gamma-aminobutyric acid-ergic actions and is used in a variety of nonheadache-related pain conditions. Its use in CH has been evaluated by Hering-Hanit and Gadoth [
12] in an open-label series of 16 patients with ECH. Patients were treated with a 15–30 mg daily dose of baclofen for a 3-week period. Twelve of the 16 patients reported that their attacks ceased within a week of starting treatment, and one more reported pain freedom by week two. No side effects were reported and the drug seemed to retain its efficacy on repeated use. Tizanadine, an alpha-2 adrenergic agonist, has similar antinociception actions to baclofen in other conditions but is better tolerated. There is no published evidence of its usefulness in CH but our local experience is of a similar efficacy to baclofen. Again, randomized controlled trials are indicated on both drugs.
Valproic acid (valproate) is a drug used in the treatment of migraine and it has also been evaluated in three reports on CH treatment. Hering and Kuritzky [
13] conducted an open-label study on 15 patients using 600 mg–2 g daily of valproate taken until the expected end of their bout (from 2 weeks to 2 months). Eleven patients reacted favorably to treatment; nine were rendered pain free [
13]. Although patients reported typical bouts lasting many weeks, there is a possibility that spontaneous remission accounted for the positive response seen in the group. Therefore, El Amrani et al. [
14] did a multicenter, double-blind, placebo-controlled study of 96 patients given 1–2 g/day of sodium valproate for a 2-week treatment period. No difference was observed between the placebo and treatment groups. The response rate in the placebo group was high (62 %), and authors state that this was likely to be due to spontaneous remission and influenced their ability to draw conclusions about the efficacy of the valproate [
14]. Until further large-scale, randomized studies are conducted, the use of valproate in CH is questionable.
Candesartan was investigated by Tronvik et al. [
15] in a placebo-controlled, multicenter study. Forty patients with ECH were enrolled but the trial was negative [
15]. Given that post hoc analysis showed a difference in the number of attacks in the treatment group, larger studies may prove useful.
Levetiracetam is an antiepileptic drug used for partial and generalized seizures. It has been trialed in neuropathic pain and migraine, with low-quality evidence suggesting its usefulness in both conditions. Recently, Palermo et al. [
16] reported two cases of ECH with attacks lasting several months responding to 1 g daily of levetiracetam given for a 4-month period. Both patients were pain free within a week and remained so 6–8 months following discontinuation of the drug. The same group also reported unpublished data of three patients with CCH responding to 2 g daily of levetiracetam. Our local experience is positive, with 3/5 patients treated over the last 6 months responding well, and two failing to respond owing to an inability to tolerate the drug’s side effects of apparent weight gain and worsening of headaches (unpublished data). Overall, the drug has a very good side effect profile and a low potential for interactions. Although the mechanism of action is unclear, initial open-label data are promising; however, further randomized controlled data are clearly needed.
Injectable Treatments
Botulinum toxin has been reported to relieve pain in a number of conditions, including headache, and has a licence for use in chronic migraine in the USA and Europe. Only one open-label study has looked at the effect of botulinum toxin in CH. In this study, Sostak et al. [
17] treated 12 patients with CH (9 with CCH) with a total of 50 units injected into the temporalis, frontalis, splenium capitis, and trapezius ipsilateral to the headache. A reduction in attack frequency was seen by 3/12 patients, all with CCH, with a response lasting 2–3 months postinjection. Case reports exist in abstract form for 12 patients. These patients were injected with 24–50 units into the temporalis and frontalis muscles [
18‐
20]. Eight patients are reported to have had an improvement, with four patients with ECH having abrupt cessation of their attacks. Although botulinum toxin is an attractive treatment option owing to its potential long action, lack of side effects, and drug interactions, further controlled trials similar to those done in chronic migraine are essential.
Nerve Blocks
Transitional treatments are required when trying to gain rapid control of attacks either during a short bout or until a preventative agent takes effect. The standard option is oral corticosteroids but these should be prescribed with caution (in our unit a maximum of twice a year) owing to the risk of side effects with prolonged or frequent use. The alternative treatment option is peripheral nerve blockade using local anesthetics, often in combination with corticosteroids.
Occipital nerve blocks are the most widely used and evaluated nerve block in the treatment of headache. The greater (GONB) and lesser occipital nerve blocks have been targeted owing to the physiological connections between the upper cervical nerves and the trigeminal nerves in the trigeminocervical complex. The majority of publications are of case reports or observational studies. The most recent of these, by Lambru et al. [
21], looked at the efficacy of GONB in CCH and found that after the first injection of methylprednisolone and lidocaine, 57 % of patients reported a beneficial response lasting, on average, 21 days. These results were reproduced on repeated injections. Transient worsening of headaches was seen in 6 % of patients.
Two groups have published prospective placebo controlled data. Leroux et al. [
22•] randomly allocated 43 patients (15 CCH, 28 ECH) to treatment with three suboccipital injections of steroid given over 72 h or placebo. A significant difference was found between treatment groups in the number of attacks post-treatment, in the time taken to remission, and in patient satisfaction with treatment [
22•]. A reduction in the dose of additional verapamil and rescue medication taken was also seen. Ambrosini et al. [
23•] conducted a blinded placebo-controlled trial on 23 patients. A single injection of suboccipital steroid led to complete attack suppression in 80 % of patients, with remission lasting at least 4 weeks.
Safety data on GONB are, on the whole, favorable; however, it is as yet unclear as to whether the blocks are better given as a series or a single injection. In the routine clinic setting it is often difficult to organize repeated injections, and larger studies would be needed to change the current practice of single injections.
Other sites used for nerve blocks include supraorbital, auriculotemporal and supratrochler blocks, although no controlled evidence exists for their use. Sphenopalatine ganglion (SPG) blockades have been used to terminate CH since the early 1900s but are clinically difficult to perform. Devoghel [
24] published a series of 120 blocks and reported a response rate of 85 %. Pipolo et al. [
25] reported a series of 15 patients undergoing endoscopic SPG block for CH in which 54 % experienced complete remission for between 1 and 28 months. Although not widely used, this and the increasingly positive data emerging from SPG stimulation, may mean that SPG blocks should be considered as part of the treatment arsenal for refractive patients.
Resectional and Ablative Surgery
The disabling nature of CH has led many surgeons to target the trigeminal nerve in a bid for pain control. Trigeminal nerve root section was the traditional option for refractory CCH prior to the advent of neuromodulation. Jarrar et al. [
26] reported that 76 % of their 17 patients with CCH experienced long-term full or near complete pain relief. However, adverse effects were dramatic, with one death, cerebrospinal fluid leaks, and a case of meningitis. Another widely reported adverse outcome of this type of surgery is corneal anesthesia; in the series of Jarrar et al., two patients needed surgery for this complication in order to prevent blindness. Other groups have reported negative outcomes with CH continuing after trigeminal nerve root section [
27].
Kano et al. [
28] reviewed stereotactic Gamma knife radiosurgery of the trigeminal and SPG for CCH in 2011 and concluded that Gamma knife for CCH was a minimally invasive and potentially attractive alternative to nerve root section, with 60 % of patients reporting long-lasting pain relief. However, they found that CCH patients were far more likely to suffer facial sensory disturbances postoperatively than those with trigeminal neuralgia (50 % compared with 10 %) [
28]. A similar review by McClelland et al. [
29] was less positive, finding that any initial benefit regressed with time, leaving none of their nine patients reporting >50 % improvement by 2 weeks–2 years post-treatment, with 50 % of patients suffering some trigeminal nerve dysfunction as a consequence of surgery. However promising the immediate results of trigeminal nerve surgery may appear, the adverse effects and long-term outcomes are consistently poor, and with neuromodulation producing favorable results in terms of safety and follow-up, this sort of surgery should very much be at the bottom of any treatment list, if conducted at all.
Neurostimulation
Occipital nerve stimulation (ONS) is a nondestructive surgical option for refractory CCH with an increasing evidence base of open-label studies. Burns et al. [
30•] first examined the role of ONS in CCH in a series of 14 patients. Ten reported benefit, three a benefit of >90 %, and three of >40 %. Magis et al. [
31] followed up 14 patients over an average of 37 months and reported 11 to be receiving an at least 90 % reduction in attacks. From these and other series available, ONS appears to be safe, with the most frequent adverse effects reported being dependent on surgical experience and battery depletion, which is overcome by the introduction of rechargeable batteries. A number of series report a side-shift in attacks if unilateral stimulation is employed, and so bilateral lead placement is now standard. A review of the current literature on ONS is given by Magis and Schoenen [
32••].
The SPG has also been a target for neuromodulation owing to its links with the trigeminovascular system. Ansarinia et al. [
33] investigated SPG stimulation in six patients and found that complete resolution of pain was seen within 3 mins in 11/18 attacks treated. A larger, multicenter, sham-controlled study was published in 2013 on the use of on-demand SPG stimulation. A novel device was implanted in 28 patients who randomly received full, sham, or subperception stimulation. There was a significant difference in the number of resolving attacks in the treated group. Sixty eight percent of treated patients had clinically significant resolution of attacks. Adverse events were mild, with 81 % reporting transient facial sensory disturbance and only five cases requiring surgical revision for lead migration or explanation [
34••]. Unexpectedly, many patients demonstrated a reduction in attack frequency following regular use of SPG stimulation despite the study being designed to treat acute attacks. Further work is ongoing into the prophylactic efficacy of SPG stimulation.
Deep brain stimulation (DBS) in CCH stems from imaging findings showing the posterior hypothalamus becoming overactive in attacks [
35]. Leone et al. [
36] reported the first case in 2001, and there are now >60 published cases. A recent review of DBS was included in the review by Magis and Schoenen [
32••]. The overall clinical success rate is around 66 % (mean follow-up 2 years) with a mean delay to clinical result of 42 days. The only placebo-controlled trial of DBS randomized 11 patients to active or sham stimulation for 2 months. No difference was found between groups [
37], but, given the findings of other series of time delays to response of 1–86 days, this is thought likely to be due to the short treatment phase. The most commonly reported adverse effects are transient dizziness and visual disturbance associated with amplitude changes.
However, DBS is not without serious risk, with one patient dying from intracerebral hemorrhage postoperatively [
38]. With collated data on DBS for CCH the risk for serious hemorrhage is 3 %, which is within the range reported for DBS for movement disorders [
32••]. Owing to the risks of surgery and lack of controlled evidence, the European Headache Federation has reviewed the use of neuromodulation in CCH. It has recommended that procedures should only be considered when all other medical treatments have failed, should be carried out by tertiary headache centers, and should start with the least invasive methods before considering DBS [
39].