The immense majority of patients with chronic headaches can be controlled with medical treatments. However, there is a subset of them with poor response, and it is for those patients that new therapeutic strategies are being designed. Neuromodulation has been used for chronic pain management in many areas for the past 50 years. The application of these techniques to the treatment of the most refractory chronic headache disorders has offered hope to these patients. There is a large variety of different techniques, each of them particularly suitable to specific types of chronic headaches. The surgically implanted devices are still in use in some particularly recalcitrant cases. Nevertheless, new percutaneous devices allow new treatment strategies. Percutaneous devices do not always show the same effectivity as surgically implanted stimulating devices, but they are user-friendly and have no serious adverse effects. Thus, they are becoming the treatment of choice once the pharmacological means are no longer effective. In case of failure, the surgical procedures would still be available as a last resort.
- chronic headache
- chronic migraine
- cluster headache
Chronic headache is one of the most frequent pain syndromes, affecting 3% of the population. It can be rather disabling [1, 2], particularly for young people who are most affected by it. The International Classification of Headache subdivides headaches into 300 different entities , each of those with a different pathophysiology and involving different anatomical structures. Pain can originate from the central nervous system, the cranium or the cervical area . Primary headaches such as tension headache, migraine (CM), or trigeminal autonomic cephalagias (TACs), show the highest incidence. TACs are particularly incapacitating . Most cases can be controlled with medication and physiotherapy. Abuse of medication is common with these patients, via the dose, the drugs or both . When the pharmacological and conservative treatments fail, surgery may be considered. In the past, ablative surgical techniques have been applied. These techniques have been replaced by neuromodulation techniques. In them, the anatomical structures are not lesioned, but instead the electric impulses block the nervous structures in a reversible fashion . These techniques can be subdivided into two broad categories: non-invasive and invasive . The non-invasive options include transcranial stimulation either electric [8–10] or magnetic [11–13] and transdermal stimulation of occipital [14, 15], supraorbital [9, 14–19] or vagus [20–23] nerves. Invasive procedures include stimulation of occipital [5, 17, 24–35], supraorbital [19, 31, 36], infraorbital  or greater auricular  nerves as well as sphenopalatine ganglion [38–44], cervical spinal cord [45–48], or hypothalamus [4, 25, 27, 49–52].
Non-invasive neuromodulation techniques are user-friendly, have low costs and few and minor side effects [8–15, 19–23]. Unfortunately, their effectivity is lower than their invasive counterparts. Invasive neuromodulation is reserved for the most refractory cases as they are associated with increased aggressiveness, more severe adverse events (AE) and higher costs .
Taking the net expenditure into consideration, some have reported that the reductions in cost are evident at 5 years post-implantation . In any case, invasive neuromodulation must only be used in the most refractory cases and only after all other medical and non-invasive treatments have failed . This is particularly important due to the high incidence of AEs and the possibility of new surgical procedures to solve them [29, 33]. A trial of temporary stimulation is required to evaluate the possible response of a definitive implant [45, 46, 54], to avoid wasting of time and resources.
These techniques present promising new treatment strategies. The available evidence will be analysed, describing the possible future trends.
2. Historical aspects of neuromodulation
Electricity to treat chronic headaches was first used in ancient Rome , but it was not until the 1950s that neuromodulation was used in the treatment of chronic pain disorders [56, 57]. Thalamic stimulation to treat chronic headaches was introduced in 1976  and percutaneous peripheral nerve stimulation a year later . At the beginning of the 1990s, hypothalamic deep brain stimulation (hDBS) was applied to the treatment of some chronic headache syndromes and particularly in TACs . The first report of occipital nerve stimulation (ONS) to treat occipital neuralgia was in 1999 . In the year 2000, the hypothalamic stimulation was applied in the treatment of drug-resistant cluster headache (CH) . The first two cases of supraorbital nerve stimulation (SONS) were reported in 2002 . The first cases of hDBS in the treatment of CH were reported in 2003 . In 2004, the ONS was applied in the treatment of CM . The first case reported with cervical spinal stimulation (SCS) in the treatment of CH was in 2008 . The first report on stimulation of the sphenopalatine ganglion was presented in 2009 . Ever since, there has been an explosion of reports on the effectiveness, indications and AEs of all these techniques. Simultaneously, new devices that allow percutaneous stimulation have reached the market, allowing new solutions to old problems.
3. Indications for neuromodulation
The first step is to diagnose the patient and select an appropriate treatment by an experienced team that is familiarised with all available treatments. Neuromodulation techniques are indicated in cases that have failed all other medical treatments available for this specific headache type. It is also recommended that patients receive a psychological assessment.
The next step is to attempt non-invasive neuromodulation techniques particularly useful in this type of chronic headache. Should all fail, a period of temporary trial stimulation is suitable . Patients showing no response are not implanted and are redirected to other forms of treatment. This temporary stimulation also helps to predict the results to be expected if the definitive implant is attempted [32, 46].
4. Classification of the different techniques
4.1. Non-invasive procedures
4.1.1. Transcranial electric stimulation (TES)
This technique involves applying a low amperage continuous electric stimulation directly to the scalp . In most cases, the electric stimulus spreads out of the area covered by the electrodes . AEs have been moderate, such as skin burns due to inadequate electrode skin contact, fatigue or local prickling and burning sensation during the stimulation [8, 10]. Its effectivity and experience are limited [8, 10].
4.1.2. Transcranial magnetic stimulation (TMS)
A magnetic field is applied to the head. In chronic headache related to mild post-traumatic head injury (MTHI-H), it has showed a 57% improvement in the intensity and frequency of the pain . The left prefrontal cortex is stimulated . A continuous application is required for the effects to be persistent, which can be impractical.
4.1.3. Transcutaneous supraorbital-supratrochlear stimulation
This technique involves a special equipment that looks like a pair of glasses, which has to be worn on the forehead. It provides a 50% chronic headache pain reduction, including CM [14, 16, 18]. When used for CM prevention, it reduces the number of attacks, but not their intensity [16, 18]. In the episodic, CM patients induced a 50% headache frequency reduction in 38.2% of the patients . Although not very effective, the only side effects are local discomfort, redness or temporary skin irritation .
4.1.4. Transcutaneous vagus nerve stimulation (VNS)
The first reports entailed electrodes implanted surgically around the vagal nerve in the neck . However, it never gained acceptance because the procedure was invasive and the results limited. In 2013, a percutaneous VNS device was introduced, showing promising results in the treatment of chronic CM (CM) [20, 23]. Its best advantage is that it is applied directly to the neck by the patient him/herself [21, 23]. Its main drawback is its low effectiveness (22%) [22, 23, 67]. It is well tolerated with minor side effects like neck twitching, raspy voice or redness at the application site [22, 23, 68].
In CH, it is helpful in the episodic but not in the chronic type [67, 68]. In the episodic type, it induces a positive response in 26.7% of the cases . Some have used it in the acute treatment of the chronic variant of this disease with a higher than 50% pain reduction in 40% of the patients . In CM, it provides a 50% or more pain reduction in 22–56.3% of the patients which is better in the episodic than in chronic variant [20, 22, 69]. It has been helpful in a single case of hemicrania continua (HC) unresponsive to indomethacin .
4.2. Invasive procedures
4.2.1. Sphenopalatine ganglion stimulation (SPGS)
The sphenopalatine ganglion has been a target in the treatment of chronic headaches for over a century. Initially, destructive lesions were applied , but since 2009, neuromodulation is also available . It is effective in two thirds of episodic CH cases, preventing at least 50% of attacks, showing a decrease in intensity of at least 50%, or both [38, 41–43, 72, 73]. SPGS is both preventive and therapeutic in acute phases [72, 74]. About 30% of the patients can stop the medication [72, 74]. A transoral technique has been described with a remote powering system that avoids extension leads and the need to replace the batteries , where patients switch-on the stimulation with a handheld remote controller when the pain attack starts . This markedly reduces the incidence of AEs . Some patients use the stimulation continuously to reduce the attack incidence . Bilateral stimulation is more effective than unilateral , but it is not so effective in the chronic variant of this disease . AEs are uncommon and mild, including sensory loss in the maxillary region (81%) , that may last over 1 year (2–28%), epistaxis (13%), facial numbness (25%) and local pain (4%) . SPGS has also been used successfully in CM .
4.2.2. Occipital nerve stimulation (ONS)
ONS is the stimulation of the distal branches of C2 and C3 nerve roots (greater and lesser occipital nerves). The electrodes (one at each side) can be inserted either through a 2-cm midline skin incision at C1 level and tunnelled subcutaneously through a bent Tuohy needle inserted laterally from the mastoid area, or alternatively from a lateral approach with a bilateral mastoid area skin incision and the electrodes inserted from a lateral to medial direction with the Tuohy needle [14, 61, 75]. As ONS only covers 85% of the head leaving the forehead uncovered, some have combined it with SONS [15, 76, 77]. Percutaneous ONS is recommended to foresee the results of a permanent implantation . In any case, a temporary external stimulation must be performed before definitive implantation . Those with no positive response are referred to other treatment modalities.
ONS has been used in chronic CH [5, 24–26, 28, 29, 32–35, 40], CM [29, 32, 33], TACs , hypnic headaches (happening during sleep) , SUNCT/SUNA [80, 81] and occipital neuralgia . In chronic CH, it reduces the attack incidence in over 50% in 70% of patients [5, 24, 25, 28, 33, 40]. In CM, its average success rate is 65.4% in 67.9–80% of the cases [29, 82]. In SUNCT/SUNA, bilateral ONS induced a 69% pain improvement in 77% of the patients [80, 81]. In idiopathic intracranial hypertension, it has been used to treat the associated headache and the residual headache, once the intracranial hypertension is resolved, with higher than 75% pain improvement ; but it requires bilateral stimulation .
AEs plague 33–70% of the cases [24, 25, 29, 33, 83]. Among them are: lead erosion [19, 76], local infection [29, 33], electrode emigration [83, 84], lead breakage [28, 30, 33], hardware-related discomfort , hardware/stimulation dysfunction  and early battery depletion related to high energy consumption [25, 33]. Some technical modifications have been devised to reduce the chance of lead migration , that in some series reaches 24% . These include using silicone glue with silicone anchors , 2-point anchoring stimulator leads with a tension-relief loop , narrow paddle electrodes  and to insert the impulse generator as close as possible to the leads (i.e. supraclavicular area) . Unfortunately, solving the AE entails additional surgical procedures in 26–40.7% of the cases [25, 29].
Simultaneous ONS and SONS in CH provide more than 50% pain reduction in over 70% of patients . This dual stimulation has also been successful in HM  and TACs . Although the results are promising, the number of cases is too small to draw any statistically significant conclusions.
4.2.3. Great auricular nerve stimulation (GANS)
Pain relief was reported using this technique in a single case of persistent MTHI-Ha 90% . Further studies are needed.
4.2.4. Supraorbital nerve stimulation (SONS)
The first case was reported in 2009 in the treatment of CH . In this disorder, SONS produced more than 50% pain reduction in 71% of the patients [19, 36, 77]. In a series of five patients with TACs, it improved the pain in all of them, but the series is too short to draw any conclusions . It can be used alone or associated with ONS [14, 15, 19, 77].
4.2.5. Cervical spinal cord stimulation (SCS)
The electrode is introduced in the epidural space at the upper thoracic level and advanced to the cervical spinal cord until its distal tip is at the C2 level. One or two electrodes are inserted. The leads are connected to a subcutaneous impulse generator inserted at the infra-clavicular area .
SCS has been used in CM [46, 47], SUNA , CH [45, 65] and MTBI-HA , reducing the headache frequency and/or intensity by ≥50% in 71% of the patients [45–47]. In CM, it improves the headache by >30% in 50% of the cases [46, 47, 88]. The AEs are frequent (71%) and usually require system explant and replacement in a second surgery . Among these AEs are infections (13%) and lead rupture or migration (17%) [45–47, 88].
4.2.6. Hypothalamic deep brain stimulation (hDBS)
hDBS was introduced in 2000 to treat drug-resistant CH . It is useful in many types of chronic headache disorders such as HC, CH, SUNCT/SUNA and in TACs [4, 50]. In chronic CH, it results in reduction of ≥50% of the attacks in 60% of the patients [5, 40, 50, 52].The response rate in HC and SUNA is 82% . In TACSs, the improvement rate is >50% in 69.9% of patients .
AEs include incision site pain, subcutaneous dislodgement of the impulse generator, transient gaze disturbance (oscillopsia, diplopia), autonomic disturbances, myosis, dizziness, wound infection, cervical dystonia, intracranial haemorrhage and lead disconnection or rupture [40, 49, 52]. Many of these complications require system explant . hDBS is reserved for those very few cases, in which everything else has failed as death has been reported .
The target was initially in the posterior hypothalamus [89, 90], but other areas have also been used like the mesencephalic grey substance, the red nucleus, the fasciculus retroflexus, the dorsal longitudinal fasciculus, the ansa lenticularis, the medial longitudinal fasciculus or the medial thalamus superficialis . In the latest years, the ventral tegmental area is used to decrease the chance of haemorrhages [49, 52].
5. Indications and results for specific chronic headache disorders
5.1. Cluster headache (CH)
CH consists of bouts of unilateral periorbital pain, lasting between 15 min and 3 h, which follow an annual pattern . It is considered the most painful headache type, with a 0.12% prevalence. About 10% of the cases cannot be controlled with medical treatment . CH has two variants: chronic and episodic . In the episodic, headache periods alternate with others of remission and the attacks last between 7 days and 1 year, with a pain-free period lasting at least 1 month . The chronic variant represents 10–15% of the cases [34, 73] and has pain-free periods shorter than 1 month or attacks that are present non-stop through at least 1 year .
Percutaneous VNS has been used in the acute treatment of the chronic variant of CH with a higher than 50% pain reduction in 40% of the patients [33, 42, 68, 93]. Although not universally effective, it is minimally invasive and with very minor and reversible AEs.
Both ONS [25, 26, 34] and SPGS [40–43, 72] are the first options among the invasive techniques [5, 73]. About 70% of patients respond to these treatments with a 48% of excellent responders [25, 34]. ONS together with SONS has been applied with >50% pain reduction in 71% of the patients . Cervical SCS has also been used with some success . hDBS should be left as the very last resource as its complications are more severe and potentially life threatening [5, 52].
5.2. Hemicrania continua (HC)
It is a continuous and unilateral headache (it only affects one side of the head), associated with autonomic symptoms and episodes of increased headache intensity . Indomethacin is the drug of choice, but some patients do not tolerate it due to side effects such as hypertension, gastrointestinal problems (particularly when combined with aspirin), vascular events or bronchial spasms . In a single case, it was found to respond to non-invasive percutaneous VNS . Others tried repetitive sphenopalatine ganglion block . The data are not statistically significant and no definite conclusions can be drawn.
5.3. Chronic migraine (CM)
The transcranial stimulation has contradictory results, so no recommendations can be offered . The cervical percutaneous VNS shows promising but moderate results, better in the episodic than in chronic variant [20, 97].Transcutaneous SONS reduces the number of attacks but not its intensity [18, 97]. Much more efficient is the ONS via implanted electrodes [5, 24, 29, 46], with a success rate of 65.4% in 67.9–80% of the cases [29, 82]. Unfortunately, 70% of the patients suffer AEs, 40.7% of which require a new surgical procedure . Some have combined the ONS with the SONS with ≥50% pain reduction in >70% of the patients . The SCS has also been applied with 30% pain reduction in 50% of the cases .
5.4. Hemiplegic migraine
It is a very severe migraine variant, refractory to most known therapies and that often evolves to a very debilitating state. It has been treated with combined SONS and ONS with a 92% average decrease in the number of attacks . The number of cases is limited, so further studies are needed.
5.5. Trigeminal autonomic cephalalgias (TACs)
TACs are a group of headache disorders characterised by unilateral headache accompanied by cranial autonomic symptoms. Although SONS has been attempted , ONS is the first option , reserving the hDBS to the most recalcitrant cases [49, 50, 52].
5.6. Short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
These consist of primary headache attacks associated with cranial autonomic dysfunction. In refractory cases, bilateral ONS induced a 69% pain improvement in 77% of the patients [80, 81]. Deep brain ventral tegmental area stimulation achieved a 78% headache rate improvement in almost all patients, but with frequent AEs that at times required to explant the system .
5.7. Mild traumatic head injury related headache (MTHI-H)
MTHI-H represents about 4% of the chronic headaches . Transcranial magnetic stimulation has shown a 57% improvement in the intensity and frequency in this disorder [11–13]. SCS or GANS  stimulation has been used, stimulating the left prefrontal cortex . In both cases, there was a 90% headache frequency reduction. Unfortunately, only two case reports exist and no conclusions can be drawn.
6. Availability and usefulness of ambulatory techniques that can be practiced at home
All non-invasive procedures can be safely practiced at home. Their only drawback is low effectiveness, but they induce no harm in those in whom no beneficial results are obtained. Further studies are necessary. The AEs are minor and completely reversible once the device is no longer used. The biggest problem may arise from the economical point of view, as health providers could choose not to pay for treatments that show moderate response.
Although the immense majority of chronic headache disorders can be controlled with pharmacological means, there is a subset of patients that are refractory to all of them. A thorough diagnosis of the specific headache subtype is essential to provide an effective treatment. For those few refractory patients to the current available drugs, there are other treatment possibilities. We have now a wide array of non-invasive techniques that can be tried as a first attempt. In case of failure, surgically implanted stimulating systems can be of help. We should choose the more suitable option to the specific headache variant, keeping in mind the effectivity possible incidence of AEs of each treatment. hDBS should be considered the very last resource as it is associated with some serious AEs, and potentially to death.
Appendices and nomenclatures
|GANS||Great auricular nerve stimulation|
|hDBS||Hypothalamic deep brain stimulation|
|MTHI-H||Mild traumatic head injury related headache|
|ONS||Occipital nerve stimulation|
|SCS||Spinal cord stimulation|
|SONS||Supra-orbital nerve stimulation|
|SPGS||Sphenopalatine ganglion stimulation|
|SUNA||Short-lasting unilateral neuralgiform headache attacks with autonomic symptoms|
|SUNCT||Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing|
|TACs||Trigeminal autonomic cephalagias|
|TMS||Transcranial magnetic stimulation|
|tSNS||Non-invasive transcutaneous supraorbital neurostimulation|
|VNS||Vagus nerve stimulation|