A case of cluster headache treated with rotigotine: Clinical and neurophysiological correlates

Abstract

Background

Chronic cluster headache (CCH) is characterized by recurrent bouts of facial pain lasting up to 180 minutes in the absence of a long remission period.

Case

We report the case of a 43-year-old male patient with treatment-resistant CCH, who improved with administration of transdermal rotigotine. We also evaluated the nociceptive blink reflex habituation that was reduced before the treatment (as is usual in CH patients) and normalized by transdermal rotigotine.

Conclusions

We suggest that rotigotine could represent a further therapeutic option in the treatment of drug-resistant CCH.

Introduction

Cluster headache (CH) is a severe form of primary headache characterized by trigemino-autonomic system activation. The pain is strictly unilateral, preferentially localized in orbital, supraorbital and/or temporal sites and associated with at least one autonomic symptom (conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, eyelid edema) and restlessness or agitation. Bouts, lasting 15–180 minutes, occur from once to eight times a day, for a period (cluster period) persisting for weeks or months, followed by a full remission. However, about 10%–15% of patients have no remission periods and their CH is defined as chronic (CCH) (1).

Oxygen therapy and subcutaneous or intranasal triptans are the first-choice acute treatments, with a good responder rate (2). By contrast, preventive treatments can be ineffective or poorly tolerated, particularly in chronic forms (3). In the case of a poor preventive outcome, patients search for more invasive treatments, such as interventional and surgical treatment (2), or alternative drugs, such as illegal psychoactive drugs with hallucinogenic effects (4).

Here we report the case of a patient affected by refractory CCH, planning to try hallucinogens, who underwent a complete and sustained response to transdermal rotigotine. Further, a modification in the typical CH electrophysiologic phenotype was also observed during the treatment.

Case report

A 43-year-old male patient, already known to be affected by CCH and treated at our Headache Clinic for eight years, requested that we help him start preventive treatment with hallucinogenic drugs.

He had a history of CH with onset at the age of about 30, chronic for eight years. In the first year of chronification (a mean of three bouts per day), verapamil 360 mg/day was effective to stop the cluster (which reappeared at each attempt to reduce the drug dosage), but starting from the second year he experienced, despite continuous prophylaxis, further active periods, treated with progressive verapamil increases (up to 780 mg/day) and add-on treatments (topiramate, valproate, gabapentin, lithium, amitriptyline, steroids, melatonin, tryptophan, pizotifen, lidocaine, capsaicin). Each treatment modification gave a transient improvement of symptoms, but became ineffective in the following reactivations (approximately every six months, with two to four bouts per day). Also, great occipital nerve block was twice tried (effective on the first attempt, ineffective on the second). Dihydroergotamine (DHE) was effective, but it was discontinued because of blood pressure reduction, abdominal pain and nausea. Against medical advice, he covertly re-introduced DHE; however, an episode of chest pain (with no enzymatic signs of myocardial infarction) induced him to definitively suspend the treatment. Over the years, each attempt to discontinue or reduce verapamil during the inactive periods, to verify if CH had reverted to the episodic form, caused recurrence of bouts. During one of these periods of verapamil discontinuation, a nociceptive blink reflex (nBR) recording, a measure of trigeminal nucleus caudalis activation, was performed according to already published methods (5), showing a lack of habituation of the R2 component to repetitive right supraorbital region stimuli. Over the last two years, despite the default treatment of verapamil 360 mg/day, he had two three-month reactivation periods per year (characterized by two to four bouts per day), absolutely unresponsive to verapamil 780 mg/day and multiple add-on treatments (topiramate 200 mg/day and lithium 1200 mg/day taken together, with and without transient steroid therapy).

At the time of the visit, the patient had been suffering a reactivation for one week, with three bouts per day of 120 minutes of severe periorbital pain, accompanied by conjunctival injection, lacrimation, eyelid edema and rhinorrhea, all treated with subcutaneous sumatriptan. Clinical neurological examination was, as usual, normal. Over the past eight years, brain magnetic resonance imaging (MRI) was performed twice with normal results.

We were not in a condition to satisfy his request and, not fully convinced of the good therapeutic index of hallucinogen treatment, thus proposed him an off-label therapy with transdermal rotigotine, a non-ergolinic D3-like and 5HT1A agonist (6): a pharmacological profile not very dissimilar to DHE, but without its vascular side effects. Once the patient’s written informed consent was obtained, the treatment was started with a 2 mg patch every 24 hours. After three days of treatment he noted a reduction in pain intensity (mean visual analog score (VAS) reduced from 9 to 6) at the same bout frequency. Once he reached 4 mg/day he experienced only some rare “shadows” (preliminary sensations of pain in the general area of attack) not evolving into bouts, thus doses of rotigotine were not further increased. During the treatment, verapamil was slowly tapered until discontinuation, with recurrence of multiple daily shadows; rotigotine was increased up to 6 mg and symptoms disappeared. After three months of follow-up (coinciding with the presumable end of the most severe cluster period), during an attempt to reduce the dose, the patient again experienced shadows and mild attacks with 2 mg of rotigotine, thus it was decided to increase the dose again to 4 mg, with full disappearance of symptoms. After six months of treatment (coinciding with the expected new period of the most severe cluster period), daily shadows appeared again and a further increase of rotigotine up to 6 mg was again effective to avoid recurrence of pain. The patient required maintenance at 6 mg and that the dose not be reduced again and, after one year, he remained pain free in the absence of any side effects (Figure 1). Up till now, treatment has not been discontinued. During that period of 6 mg treatment, the nBR was recorded again to verify whether the lack of habituation found in the absence of treatment would be modified by rotigotine. Indeed, at the second nBR we observed a normalization of habituation of the R2 component, with a normal reducing response to repeated stimulation (Figure 2).

Figure 1.

Twenty-four-month cluster headache diary recording: number of bouts, in brackets; number of “shadows,” in gray, period of rotigotine treatment.

Figure 2.

R2 component area-under-the-curve (AUC) of the nociceptive-specific blink reflex (nBR) in three successive blocks of five sweeps elicited by stimulating the supraorbital branch of the right trigeminal nerve before (a) and after (b) rotigotine. Note the baseline AUC increase with time, i.e. lack of habituation (a), whereas after rotigotine the response normalized and then a normal reducing response, i.e. habituation, was restored (c).

Discussion

We have described a patient affected by CCH who, after eight years, has discontinued treatment with verapamil and has stopped having his refractory cluster reactivations following therapy with the dopamine agonist rotigotine. In addition, the normal habituation of nBR was restored.

Rotigotine is a non-ergoline D3-like receptor agonist, characterized by high clearance and a relatively short effect duration. These last two characteristics made this drug ideal for transdermal administration, providing continuous dopaminergic stimulation. In a recent prospective study, transdermal rotigotine was generally well tolerated for up to six years. Most common adverse events were: somnolence, falls, peripheral edema, nausea and application site reactions (7).

Although CH is a rare primary headache condition, in any headache clinic there are cases untreatable with common pharmacological therapies for which patients require invasive interventions, such as surgical neural lesion procedures and deep brain stimulation of the posterior inferior hypothalamus (2), or attempts with hallucinogenic substances, in particular lysergic acid diethylamide (LSD) and psilocybin (8). The patient we describe falls into this group of intractable cases, and he experienced severe distress due to the pain and needed to obtain rapid improvement. The sense of hopelessness induced our patient to desire to try treatment with an illicit substance. An off-label attempt was the only chance to fulfill his needs, before a surgical procedure that the patient has always refused. The decision to try rotigotine derived from some considerations. As mentioned above, rotigotine has a pharmacological profile not very dissimilar to DHE, the only drug apparently effective in this case, but without its vascular side effects. Moreover, rotigotine shares with LSD and psilocybin the 5HT1A agonism that induces an analgesic effect (9), perhaps by activity of receptors in the dorsal raphe nucleus that have been shown to inhibit the release of substance P (10). Lastly, a case of the effectiveness of a non-ergolinic dopamine agonist (pramipexole) in CCH was already previously reported (11). However, this effectiveness was not confirmed by a further report (a case of CH recurrence with pramipexole) (12), even if that report does in any case suggest a possible relationship between the dopaminergic system and CH (because pramipexole would have induced headache). A link between CH and the dopaminergic system is still now unknown, although dopaminergic impairment has already been shown in CH patients (13). To reduce the risk that our observation could be due to chance, we also performed a neurophysiologic examination to explore the behavior of the response to repetitive stimuli. In healthy subjects the nBR response progressively decreases during stimulus repetition (habituation), whereas in CH subjects during the bouts outside the attacks a reduced habituation was observed (5). Our patient, consistent with his condition as a CH sufferer, showed this altered behavior of response in an active, drug-free phase of disease, while normal habituation was restored by rotigotine. The drug-induced effect of normalization observed in this case could reveal an interference with CH pathophysiology exerted by rotigotine. Interestingly, consistent with this hypothesis, dopamine is known to inhibit nociception in the trigeminovascular system (14), a phenomenon that could explain the double effect we have observed of rotigotine on CH exacerbations and nBR habituation.

Our awareness that this reported response to rotigotine might in any case have occurred randomly does not, however, reduce the evidence that this case might open the way again to consider new pharmacological treatment strategies in chronic CH prophylaxis, and suggests another drug that could be tried to reduce the number of untreatable chronic CH patients.

Clinical implications

Drug-resistant chronic cluster headache is a clinical challenge for physicians.

In our patient, rotigotine has proven to be effective in treating chronic cluster headache and normalizing trigeminal system excitability.