A novel therapy for cluster headache

Electric stimulation has been used since ancient times to treat medical disorders, including pain syndromes. The Roman physician Scribonius Largus recommended in De compositione medicamentorum (47 AD), the use of local application of a torpedo fish to treat various pain syndromes including severe headache. With increasing knowledge, new treatment modalities were developed using non-biological electrical sources, and pioneers in electrophysics, such as Benjamin Franklin, Luigi Galvani and Michael Faraday, have been connected with electrotherapeutic methods.

 

During the 20th Century, the focus was more on pharmacology and a large number of pharmaceutical agents were developed against various disorders, whereas the interest in electrotherapy diminished. However, pioneering work in the 1960s by Melzack, Wall, Sweet and Shealy inspired a new interest in the latter and stimulation of peripheral nerves and the dorsal column was introduced.

 

Recently, a new concept in electrotherapy has emerged and the term ‘electroceutical’ has been coined. Miniaturised stimulators designed to fit the local anatomy are used to treat specific disorders and to give precise effects, avoiding general systemic side effects, which are almost ubiquitous when pharmaceutical therapy is used. One example from this new generation of neuromodulators is the PulsanteTM Microstimulator, which is CE marked to treat cluster headache.

 

 

Cluster headache

Cluster headache is a highly disabling chronic neurological condition with a prevalence of 0.12%, similar to the prevalence of other neurological disorders such as Parkinson’s disease and multiple sclerosis. It is characterised by intense stabbing pain around the eye accompanied by parasympathetic symptoms such as conjunctival injection, tearing, ptosis and nasal congestion. The patient is usually restless or agitated. The pain is recognised as among the most severe known to humans, with attacks lasting from 15 to 180 minutes often several times per day (see Table 1). Cluster headache can be episodic with pain-free periods of one month or longer every year or chronic with pain for more than one year without remission.^1,2 The disorder causes a major impact on daily life of most patients with absence from work, lifestyle changes and psychiatric comorbidity including suicidal tendencies.^3,4 The cost for society for cluster headache in Germany has been estimated.⁵ Over a six-month period, one patient with chronic cluster headache costs €10,985 and a patient with episodic cluster headache costs €2583.

 

Medical treatment

Medical treatment is offered to patients with cluster headache both to abort acute attacks and for prophylaxis (Table 1). For the acute treatment, sumatriptan and/or 100% high flow oxygen are the first choices, whereas for prophylaxis, a number of drugs are effective, such as verapamil, lithium, topiramate and steroids. However, oxygen treatment can be cumbersome for the patient and the drugs have significant side effects. For example, sumatriptan can cause vascular side effects and is contraindicated in patients with ischaemic heart disease. Sumatriptan injections are limited to two per day, which is often insufficient for patients with severe cluster headache. Still, the cost for multiple sumatriptan injections can be a burden for the patient. Drugs used for prophylaxis are also known for their side effects, exemplified by cardiac arrhythmias and confusion caused by verapamil and lithium, respectively.⁶

 

Alternative treatments

Neuromodulation is an alternative treatment for patients with cluster headache. There are non-invasive transcutaneous or transcranial methods using electrical current or magnetic stimulation. There are also more invasive methods with implantation of peripheral nerve stimulators affecting the occipital nerves and the vagal nerve and deep brain stimulation of the posterior hypothalamus.^7,8 Although there are case reports describing positive effects of these methods against cluster headache, randomised controlled trials verifying these observations are still lacking. However, there is one study where there was no significant effect of deep brain stimulation of the posterior hypothalamus during the four-week study period but a significant response (50% reduction of attacks) of stimulation during a subsequent open-label period.⁹

 

Microstimulation

Recently, the Pulsante™ Microstimulator, which represents a new generation of nerve stimulators, was introduced. These are miniaturised devices designed to modulate specific targets. The PulsanteTM Microstimulator is designed to modulate the sphenopalatine ganglion (SPG), which is a parasympathetic nerve cell ganglion situated in the pterygopalatine fossa.^10,11

 

There are data strongly suggesting that the SPG is involved in the generation of headaches including cluster headache and SPG interventions have been used against cluster headache for more than 100 years. In 1908, cocaine was injected in the vicinity of the SPG and thereafter alcohol, corticosteroids and lidocaine have been injected into this area, and other destructive methods, such as ganglionectomy, cryosurgery, stereotactic radiosurgery and radiofrequency lesioning have been used to inhibit the effect of the ganglion. However, all these methods only gave temporary effects, providing an unmet need for an alternative treatment providing long-term effects.

 

Fig. 1: The Pulsante Microstimulator, CE-Marked for treatment of cluster headache.

 

The PulsanteTM Microstimulator is inserted trans-orally and designed to fit the facial anatomy. It comprises a lead with six electrodes, a plate for fixation and a stimulation unit containing the electronics and in which the stimulation programmes are stored (Figure 1). The stimulator is activated by a handheld remote control, which is also used to program the device (Figure 2). The remote control communicates with the stimulator using radiofrequency.

 

Fig. 2: The Pulsante Microstimulator is activated by the patient with a handheld remote control during attacks of cluster headache. The remote control communicates with the Microstimulator using radiofrequency and is also used to program the device.

 

The Microstimulator is inserted through an incision in the gingiva and is placed medial to the zygoma above the wisdom teeth (Figure 3). The lead is positioned adjacent to the SPG in the pterygopalatine fossa by following the posterior wall of the maxillary sinus through the pterygomaxillary fissure. The procedure is aided by the fluoroscope and surgical tools specifically designed for the procedure. The quality of the imaging is essential for the procedure because bony anatomical landmarks are used in an often challenging anatomical region (Figure 4). The device is fixed in the maxillary bone by using three titanium screws through the holes of the plate.¹² With the patient still on the operating table, before suturing the incision, we perform a cone beam CT to verify the exact location of the lead in all three dimensions.

 

 

The first multicentre randomised sham-controlled study of the PulsanteTM Microstimulator (CH-1 study) was published in 2013.¹³ It was a study of 32 patients with chronic cluster headache, of which 28 completed the study. The primary endpoint was pain relief at 15 minutes following the start of stimulation. During the three-week long experimental period, which was about two months after surgery, a total of 566 cluster headache attacks were treated. 

 

Pain relief after 15 minutes was observed in 67.1% and pain freedom in 34.1% of the attacks, as compared with sham (pain relief in 7.4% and pain freedom in 1.5% of the attacks). However, during the trial many patients also had a substantial reduction in headache frequency. Therefore, the patients were divided into two groups. 

 

 

Acute responders achieved 50% pain relief or more in at least five headache attacks. Frequency responders had at least a 50% reduction in headache frequency. Twelve out of 28 patients were frequency responders with an average reduction of 88% of the number of attacks. Fourteen patients did not have enough attacks to be analysed for acute response, of which nine were frequency responders. Of the remaining 14 patients who treated at least five attacks, nine were acute responders. 

 

Overall, 19 of 28 patients (68%) were responders during the randomised controlled experimental period (Figure 5a). Of these, nine were acute responders and 12 were frequency responders (two patients were both acute and frequency responders). Fewer attacks required the use of rescue medication with full stimulation (31.0% of attacks) as compared to sham stimulation (77.4% of attacks).

 

To analyse the consistency of SPG stimulation over time, 33 patients with chronic cluster headache were enrolled in the CH-1 long-term follow-up study and completed two years; 20 of the 33 patients (61%) were responders at two years (Figure 5b). Of these, 15 were acute responders and 10 frequency responders (five patients were both acute and frequency responders). The acute responders effectively treated 78% of their attacks and the frequency responders experienced an 83% reduction in attack frequency. Nine of the 20 responders (45%) stopped using preventive medication altogether.¹⁴ Thus, SPG stimulation is a consistent treatment for chronic cluster headache in the majority of the patients for at least two years.

 

Ten of the 33 patients with chronic cluster headache in the CH-1 long-term follow-up study experienced remission defined as pain-free periods lasting 28 days or longer.¹⁵ All remissions started after the start of the SPG stimulation and lasted from 28 to 268 days (average 111 days). Thus, a substantial portion of chronic cluster headache patients effectively converted to the episodic form of the disease. Long-term benefits of SPG stimulation in cluster subjects with remission suggest that the therapy may also be beneficial during episodic subjects’ cluster bouts. 

 

In addition, an open-label registry study with a five-year follow-up has been started. An interim analysis after six months of this prospective, single-arm, multicentre, post-market registry demonstrates that 61% of the patients are responders. The acute responders treated 88% of their attacks. The frequency responders experienced an 89% reduction in attack frequency, from an average of 20 attacks per week at baseline to two/three attacks per week after six months therapy. 

 

Thus, the results from the open-label post-market study are consistent with the data from the double-blind randomised control study. Also, additional questionnaires show that the patients are satisfied with SPG stimulation, where 80% found SPG stimulation useful in treating headache, 86% would make the same decision again and 97% would recommend the therapy to someone else. Regarding side effects of the therapy, 82% found the surgery tolerable, and all patients found the stimulation sensation tolerable and for 87% the device is comfortable.

 

Safety

The safety of the PulsanteTM Microstimulator has been analysed in more detail in 99 patients included in the CH-1 and the post-market open-label studies.¹² It appears to be well tolerated with an acceptable safety profile. The procedure leaves no visible scars and the Microstimulator cannot be seen. However, as with other oral maxillofacial procedures, a majority of the patients experience expected discomfort to a varying degree postoperatively. During the first 30 days after surgery, 67% of patients experienced sensory disturbance and 34% had pain and swelling in the surgical area. 

 

A number of more rare adverse events, for example, trismus (3%), infection (2%) and haematoma (1%) were observed in 63% of the patients. Adverse events after 30 days occurred but were more rare. Two thirds of all side effects resolve on average within 70 days. They are typically mild and do not have an effect on patient’s daily activities and are comparable to those reported for other oral procedures. Revisions or explants were carried out in 19 of the 99 patients (19%). 

 

Explants can be carried out under local anaesthesia as an outpatient procedure. The most common cause of revision was ineffective therapy due to improper initial lead position in ten patients, a finding that may be mitigated with advances in surgical training, preoperative planning and improvements in surgical instrumentation. No late lead migrations or breakages occurred. In three other patients, the microstimulator was explanted because of neuropathic pain and in one patient an explant was carried out because of wound infection.

 

A model-based analysis of the Pathway CH-1 study found that SPG stimulation with the PulsanteTM Microstimulator is a cost effective or cost-saving treatment plan. Cost savings were primarily realised by reduction in acute abortive medications over a conservative five years.¹⁶

 

Conclusions

The PulsanteTM Microstimulator is a new tool to treat cluster headache by specifically modulating the parasympathetic sphenopalatine ganglion, which is an important part of the neural network driving cluster headache pain. Randomised controlled studies and registry studies have demonstrated that the PulsanteTM Microstimulator has a dual effect and can both decrease the intensity of the pain and reduce the number of attacks. The effect is consistent over time and the procedure is safe and is well tolerated by patients.

 

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