Migraine and CH therapy includes the acute therapy to abort the single attack, and preventive therapy to reduce attack frequency, duration and severity and the use of acute headache medications.
Acute therapy
As in migraine, CH attacks respond well to acute therapy with triptans [
152‐
154]. Nevertheless, differently from migraine, the oral route of administration is not usually recommended in CH, because of the delayed effect compared to subcutaneous or intranasal administration. On the other hand, acetaminophen and non-steroidal anti-inflammatory drugs are only used in the acute therapy of migraine and not in CH [
155]. Shared pathophysiological mechanisms as reviewed in previous sections could explain the efficacy of triptans in both diseases.
Another acute approach for the treatment of CH attacks is inhalation of 100% oxygen through a face mask (with a flow of 12–15 l/min). Interestingly, a recent randomized placebo-controlled clinical trial on 22 patients reported that high-flow oxygen was significantly more effective than air in the acute treatment of migraine attacks [
156], and it has been suggested that this treatment could have greater responses in migraine patients with cranial autonomic symptoms [
157] or migraine-cluster and cluster-migraine variants (these rare phenotypes are not included in the ICHD-3). An inhibition of activated trigeminal nociceptive afferents or the autonomic pathway could be one of the mechanisms explaining its efficacy in both migraine and CH [
158].
Lastly, in patients affected by CH, when oxygen and triptans are ineffective, intranasal lidocaine (sprayed in the ipsilateral nostril) should be considered [
125]. Clinical trials provided conflicting data about its efficacy in migraine [
159‐
161].
Taken together, the previous suggests that, although with different preferable route of administration (for triptans) and response rate (for oxygen inhalation) migraine and CH share responsiveness to some acute strategies (see Table
4).
Table 4
Efficacy of acute therapies in migraine and cluster headache
NSAIDs | | Not effective |
Triptans | Oral route of administration | Subcutaneous sumatriptan/ intranasal sumatriptan or zolmitriptan [ 153, 154] effective |
Inhalatory oxygen | Effective in about 46% of patients [ 156] | Effective: about two-third of patients [ 240] |
Intranasal lidocaine | | |
Preventive therapy
Different drug categories are effective in the prophylactic treatment of patients affected by episodic or CCH, even though, unlike in migraine, few randomized clinical trials have been conducted [
162]. Similarities and differences in migraine and CH preventive therapies are summarized in Table
5.
Table 5
Efficacy of preventive therapies in migraine and cluster headache
Verapamil | | Effective in high-dose (360 up to 960 mg) |
Litihum | No large RCTs; ineffective in small trials; efficacy clues in “cyclic migraine” [ 169] | |
Steriods | Reduced recurrence of attacks in patients coming to emergency department [ 171] | Effective (usual dosage ≥40 mg) |
Antiepileptic drugs | Effective | Efficacy clues in open uncontrolled studies, not confirmed by RCTs. |
GON blockade | Effective in chronic migraine [ 173] | |
Melatonin | 3 mg per day are effective [ 186] | 10 mg per day are effective [ 185] |
High-dose verapamil is the most frequently used in CH preventive therapy [
163]. Interestingly, few studies suggested the efficacy of verapamil in migraine prophylaxis [
164,
165]. Lithium carbonate is mainly used as a prophylactic drug in CCH to reduce the attack frequency in patients [
166,
167]. To date, no randomized clinical trials have studied the efficacy of lithium in migraine prophylaxis. Small open trials reported conflicting results in migraine [
168,
169]. A short term effective therapy for CH is represented by prednisone [
77,
170] which can be used for short-duration episodes or to induce a rapid remission (usually within 3–10 days). Evidences about the use of steroids in the preventive therapy of migraine do not allow precise conclusions. Nevertheless a recent review showed that steroids demonstrated a good efficacy in reducing the recurrence of migraine in patients visiting the emergency department for acute attacks [
171]. Blockade of the greater occipital nerve (GON) ipsilateral to the pain, with injection of corticosteroids and local anesthetic is effective in CH [
172] and was also shown to be effective in treatment of CM [
173].
In migraine, the efficacy of sodium valproate and topiramate has been documented in RCTs [
174,
175]. In CH, even though open uncontrolled studies indicated a good efficacy, RCTs did not show any clinical efficacy of sodium valproate and topiramate [
176‐
180].
Open trials showed clinical efficacy of local injection of onabotulinumtoxin A into the sphenopalatine ganglion (SPG) both in CH [
181] and in refractory CM therapy [
181]. The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 and 2 (PREEMPT 1 and 2) have shown the efficacy of Onabotulinumtoxin A in reduction of headache days in CM, using a specific injection protocol [
182,
183]. The PREEMPT study protocol was also used in a 28 week, open-label trial, with refractory CCH [
184]. A more than 50% reduction in headache minutes was reached in 58.8%, whereas 29.4% experienced a 30–50% of improvement. Mean frequency of headache days dropped from 28 to 12 days at week 24 (
p = .0001). Randomized controlled trials are needed to confirm these encouraging results.
Randomized clinical trials have indicated that melatonin may be effective for the preventive treatment of CH, with a daily dose of 10 mg [
185] and migraine, with a dose of 3 mg [
186].
Anti CGRP monoclonal antibodies (mAbs) are effective in migraine prophylaxis [
135‐
138] and the anti CGRP receptor mAbs erenumab is now approved by Food and Drug Administration (FDA) [
187]. Ongoing trials (NCT02964338, NCT02797951, NCT02397473, NCT02438826) are investigating the efficacy of anti CGRP mAbs in CH. Recently, an Eli Lilly press release announced that a phase 3 study (NCT02797951) showed that galcanezumab reduced weekly attacks in episodic but not CCH patients [
188].
The efficacy of anti CGRP monoclonal antibodies and greater occipital nerve (GON) blockade in both migraine and CH indicates that the activation of the trigeminovascular system (with consequent release of CGRP) and the TCC is a key mechanism involved in the pathogenesis of both migraine and CH. Furthermore, the good response to oral corticosteroids as a transitional treatment may indicate that they may reduce the neurogenic inflammation induced by the activation of the trigeminovascular system in both diseases. The efficacy of melatonin in the prophylactic therapy for both migraine and CH points towards a pathogenetic role for the hypothalamus and the circadian rhythm regulation system in both migraine and CH. The pharmacological effect of verapamil is probably due to the interactions with muscarinic, serotoninergic and dopaminergic receptors, the inhibition of presynaptic adrenergic receptors (with a consequent increase in noradrenaline release) and the modulation of pain pathways. Its efficacy in both migraine and CH could be due to the modulation of brainstem circuitries, the rebalancing of autonomic system and the restoration of the pain control system [
189].
In conclusion, even though the first line strategies for migraine and CH treatment seem to be quite different, most of the drugs used for CH prophylaxis also demonstrated a certain degree of efficacy in migraine prophylaxis, showing that migraine and CH, even with their clinical differences may share some of their basic pathophysiological mechanisms.
Neuromodulation
Invasive neuromodulatory procedures comprise stimulation of the central nervous system, hypothalamic deep brain stimulation (hDBS) and of the peripheral nerves (occipital nerve stimulation, ONS; SPG). Non-invasive variants comprise vagus nerve stimulation (VNS), supraorbital nerve stimulation (SNS), rTMS and transcranial direct current stimulation (tDCS).
The rationale for the use of hDBS is an increased blood flow in the posterior hypothalamus during cluster [
74] and migraine attacks [
190], which was interpreted as neuronal activation of that brain area. hDBS has been shown to be highly effective in CH, with significant reduction of attack frequency and with the ability to change disease course [
22,
191‐
193]. Although the treatment effects seem clinically equal, the side effects of the more invasive hDBS treatment are to be considered [
194]. So far, there is no evidence to support the use of hDBS in CM.
The basis for the use of ONS in headaches came from animal studies showing the convergence of cervical, somatic and dural afferents on second order nociceptors in the trigeminocervical complex [
195,
196]. More or less all these structures are involved in the pathophysiology of CM and CH. For ONS, to date, 3 RCTs have been performed in CM [
197‐
199], and their outcome is overall disappointing. For CH multiple isolated reports, case series, small cohort studies and observational studies suggested a 50% improvement in headache frequency or intensity with ONS [
200,
201].
The SPG is a large extracranial parasympathetic ganglion located in the pterygopalatine fossa. Post-ganglionic parasympathetic fibers from the SPG innervate facial structures such as the salivary and lacrimal glands, the nasopharyngeal mucosa and the cerebral and meningeal blood vessels [
202]. Mainly all these structures are involved in the pathophysiology of CH and partially also in CM. SPG electrical stimulation via an implantable device was proven for effective in a multicentre randomised, double-blind and sham-controlled trial in refractory CCH [
203]. Full stimulation of the SPG versus sham stimulation resulted in a significant pain relief (67%) and a significant reduction in attack frequency (34%) [
203]. Only anecdotal cases have been reported for migraine treatment with SPG, usually reserved for cases of refractory migraine [
204]. SPG has been targeted also with blockade via bupivacaine, which showed, in CM, a sustained reduction of headache frequency in a double-blind, parallel-arm, placebo-controlled, randomized pilot study [
205].
VNS has been shown to be effective in both migraine and CH. Indeed, in small open-label single-arm studies, VNS had good migraine abortive effect, with 43 to 65% of patients obtaining pain relief [
206,
207]. The recent multicenter, double-blind, randomized, sham-controlled PRESTO trial confirmed VNS effective as abortive treatment for migraine attacks, with consistent therapeutic benefit compared to sham stimulation [
208]. In the EVENT trial, a double-blind sham-controlled study on migraine prevention, though not reaching the primary outcome, VNS led to a slight reduction in migraine frequency [
209].
CH patients can also benefit from VNS. In an open-label, prospective, randomized study, a significant reduction in weekly attack frequency was observed among patients with CCH receiving VNS plus standard of care compared to standard of care alone [
210,
211]. Moreover, VNS has been shown to be cost-effective, providing economic benefits as an adjunct treatment to standard of care in CCH [
212].
rTMS has effect as prophylactic treatment in migraine with aura. In a sham controlled randomized trial, single pulse rTMS has been shown to increase in freedom from pain after 2 h when applied early in the treatment of migraine with aura, with substantial benefit for up to 48 h after treatment [
213] Although cortical excitability has been implicated in CH [
82], to date few data exist on rTMS in CH.
In migraine prevention, SNS has been extensively studied and shown to provide a significant reduction of migraine days compared to sham stimulation [
214,
215]. On the contrary, SNS in CH has been poorly investigated, and only isolated reports of possible positive neuromodulation among CH are available [
216].
Overall, few data still exist on neuromodulation strategies in headache disorders. Nevertheless, data from randomised controlled trials seem to suggest safety and effectiveness in both migraine and CH (see Table
6), supporting the concept that these two diseases, despite their differences, might share pathophysiological mechanisms. The common denominator might be the hyperexcitability of brain network, progressive changes in nociceptive thresholds and subsequent central sensitization. For CCH, SPG [
217,
218] or ONS [
197,
219], given the risk/benefit profile of the intervention, might be considered before hDBS. In migraine VNS might be considered as an abortive effective treatment, also able to spare symptomatic drugs. For patients with CM the use of ONS, as well as the application of the non-invasive VNS, tDCS, rTMS, cannot be recommended so far, given the poor amount of controlled data.
Table 6
Efficacy of neuromodulation strategies in migraine and cluster headache
Deep brain stimulation | Isolated reports, no consistent data | no RCT, available case series show significant reduction in attack frequency but with consistent side effects [ 22, 117‐ 119] |
Occipital nerve stimulation | conflicting results from 3 RCT [ 197‐ 199] | no RCT, case series show 50% improvement in frequency and intensity [ 200, 201] |
Sphenopalatine ganglion stimulation | no RCT, only anecdotal case reports available | RCT shows SPG electrical stimulation is effective in reducing intensity and frequency in refractory chronic cluster headache [ 203] |
Vagus nerve stimulation | RCT shows effective as abortive treatment [ 208], slight benefit on migraine frequency in prophylaxis [ 209] | Conflicting results from RCT, more effective on episodic CH than refractory chronic CH |
Transcranial magnetic stimulation | RCT shows benefit on migraine with aura [ 213] | no RCT, no systematic reports available |
Supraorbital nerve stimulation | significant reduction in migraine frequency [ 214, 215] | no RCT, only isolated reports available, possible positive effect [ 216] |