Abstract
This study was designed to evaluate the efficacy of gabapentin (GBP) in the treatment of SUNCT syndrome on a relatively large sample of Persian patients. Eight patients with SUNCT syndrome underwent a 4-week, open-label, daily treatment of 600-900 mg GBP. The frequency, intensity and duration of attacks were compared before and after the trial. After 4 weeks of treatment, intensity, duration and frequency of headaches were significantly (P< 0.05) reduced. In addition, five patients (62.5±) were completely relieved from headaches, and in the other three patients the mean intensity, frequency and duration of headaches were decreased notably. In this study, GBP was well tolerated and no unfavourable side-effects were reported. After the end of the trial all patients continued the medication, and after 3 months none reported undesired side-effects or return of the headaches to the pre-treatment status. Our patients had a significant response to GBP, and considering other case reports on the effectiveness of GBP in the treatment of SUNCT syndrome, we propose that, taking into account the good side-effect profile and lack of interactions of GBP, this drug could be considered as an option for the treatment of SUNCT.
Introduction
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) was first described by Sjaastad et al. in 1989 (1). SUNCT is predominant in men (2, 3), with a mean onset age of nearly 50 years (4); and for the most part, the aetiology and pathogenesis remain unknown.
The attacks are strictly unilateral, generally with the pain confined to the orbital or periorbital area and accompanied by ipsilateral cranial autonomic symptoms (mostly lacrimation and conjunctival injection) (1, 3, 5). Most attacks of pain are moderate to severe in intensity, and burning, stabbing or electrical in quality (1, 5). The paroxysms reach maximum intensity within 2–3 s (6) and have a short duration, which mostly ranges from 5 to 250 s; attacks lasting 3 h have also been described (2). During active periods, the frequency of attacks may vary from fewer than one attack per day to > 30 attacks per hour (5).
This debilitating disease has been regarded as the most refractory to treatment of all primary headache disorders (2). As a result of the extreme burden it causes, all reasonable treatment alternatives should be attempted (5). However, some studies have suggested that intravenous lidocaine (7, 8), lamotrigine (5, 7–13), gabapentin (5, 7, 8, 14–16), topiramate (5, 7, 8, 17, 18) and oxcarbazepine (19) could be useful in the treatment of SUNCT syndrome.
Gabapentin [1-(aminomethyl) cyclohexane acetic acid; GBP] is an antiepileptic drug and was initially developed as a gamma-aminobutyric acid-mimetic agent to treat spasticity. It was later shown to be an effective anticonvulsant drug, and soon after it even proved to be helpful in the treatment of chronic pain syndromes, particularly neuropathic pain (20).
This study was designed to evaluate the efficacy of GBP in the treatment of SUNCT syndrome in a relatively large sample of Iranian patients.
Patients and methods
Patients were recruited from the university hospital out-patient neurology clinics in Isfahan, Iran, from February 2002 to January 2007. Eight patients with SUNCT syndrome were identified who fulfilled the diagnostic criteria of SUNCT syndrome recommended by International Classification of Headache Disorders, 2nd edn (21). These criteria require ≥ 20 attacks of unilateral orbital, supraorbital or temporal stabbing or pulsating pain lasting for 5–240 s, and accompanied by ipsilateral conjunctival injection and lacrimation. The attacks should occur with a frequency of 3–200 per day and should not be attributed to another disorder.
Inclusion criteria were the diagnosis of SUNCT syndrome and an age range of 18–75 years, in whom routine headache treatments such as aspirin, indomethacin, ibuprofen, prednisone, valporate, carbamazepine, propranolol, topiramate and amitriptyline had not led to relief of their headache attacks. Exclusion criteria were abuse of simple analgesics (corresponding to > 50 g of aspirin/month), regular intake of opiates or benzodiazepines, serious somatic or psychiatric diseases and intake of prophylactic headache medications.
Prior to the trial all identified participants were consulted by a neurologist about the trial and all gave informed consent. Patients underwent a general and neurological examination and completed a diagnostic headache diary during a 1-week run-in period. Throughout the study, patients kept a headache diary to record the intensity, duration and frequency of attacks and experienced side-effects. In addition, all patients had a magnetic resonance imaging (MRI) test carried out.
This study was designed as a ‘before–after’ trial, in which the characteristics of headaches in the week before the treatment were compared with those of week 4 of treatment. The study medications were capsules containing 300 mg of GBP (Razak® Laboratories, Tehran, Iran). The drug was prescribed at 600 mg/day (300 mg twice a day). In the case of patients who still experienced headaches after 1 week of treatment (although reduced in intensity, duration and frequency), the prescription was augmented to 900 mg/day (300 mg three times a day). Follow-up visits were planned weekly, and on each visit the headache diary was checked and the medication was handed over in an open-label fashion.
Intensity was recorded on an 11-point verbal rating scale, where 0 indicates the headache-free condition, 5 a moderate headache and 10 the worst headache condition possible. To compare mean values, paired sample t-test and Wilcoxon's test were used, and P < 0.05 was considered to be significant.
Results
Of the eight SUNCT patients, six were male and two female. Their ages ranged from 21 to 67 years (mean 41.3 years). Seven patients (88%) were suffering from the chronic SUNCT syndrome and only one (12%) had the episodic form of SUNCT. The patient with the episodic form reported that he had experienced the bouts for nearly 3 months each year, it being in remission for the rest of the year. This patient was included in the study when his bouts had just started 2 weeks before the trial began. Brain MRI in all patients was normal, including the posterior and middle fossa, and neurological and general examination revealed no other neurological disorder in these patients.
Among the patients only one became headache free after the first week of trial (with 600 mg/day GBP), and we had to augment the prescription dose to 900 mg/day in the remaining seven patients (including the patient with episodic SUNCT). All included patients successfully finished the trial period, and the characteristics of headaches before and after 4 weeks of treatment are shown in Table 1. In comparison with baseline values, after 4 weeks of treatment with GBP all identified patients responded to the treatment and paired sample t-test showed that mean intensity (9.06 ± 0.7 vs. 1.1 ± 1.5, P < 0.001), duration (60 ± 41.7 vs. 10.3 ± 17.4, P = 0.002) and frequency (4.75 ± 6.3 vs. 0.375 ± 0.5, P = 0.047) of headaches were significantly reduced; Wilcoxon's test also demonstrated significance (P = 0.01).
Headache characteristics before and after treatment with gabapentin
Calculated by paired sample t-test. Wilcoxon's test also demonstrated a significance level of P = 0.01.
HD, headache duration (second); HF, headache frequency (per day); HI, headache intensity (verbal rating scale).
Of note, five patients (63%) were completely relieved of headaches (including the episodic SUNCT sufferer), and in the remaining three patients (37%) intensity, duration and frequency of headaches were notably reduced. In the case of these three patients, the mean intensity of headaches was reduced from 9.2 to 3, the mean frequency of headaches was reduced from 3.4 to 1 per day and the mean duration of headaches was reduced from 75 to 27.5 s by the end of week 4 of the trial. In this study, GBP was well tolerated and no unfavourable side-effects were reported.
After the end of the trial, all patients continued the medication with the prescribed dose (in none of the patients was the drug stropped or reduced in dose) and, when contacted after 3 months, none reported undesired side-effects or the recurrence of headaches similar to that of pretreatment status. At this stage, patients were recommended to try reducing their dosage, since it has been suggested that with reduction in the dosage possible remission may be revealed and as a result further chronic therapy may not be required anymore (22). Among our patients, only the five who had become headache free during the trial accepted a reduction of their dosage and, upon returning after 45 days for the new prescription, all reported the recurrence of headaches within 24 h of reducing the dosage.
Discussion
SUNCT was believed to be highly refractory to treatment, since various treatments (sumatriptan, indomethacin, prednisone, aspirin, carbamazepine and many other drugs) (2), used for other short-lasting headaches and migraines, have failed in the treatment of this type of headache. Some single reports have recently suggested some hopeful treatments. Among these, lamotrigine is reported to be the most effective and is recommended as the choice treatment for SUNCT (5). Other treatment options include gabapentin, topiramate, intravenous lidocaine and intravenous phenytoin (5).
There are few case reports on the success of GBP in the treatment of SUNCT. In 2000, Graff-Radford (14) reported a 48-year-old man suffering from SUNCT. Initially indomethacin was tried, without significant effect. GBP was then started with improvement at 1800 mg/day. The patient was then lost to follow-up for 3 years, and when he returned having stopped the GBP, reported the immediate recurrence of pain. Once more GBP was prescribed and at 900 mg three times a day he has been pain free for 12 months. In 2002 Porta-Etessam et al. (16) reported a 55-year-old woman suffering from SUNCT, who had tried daily non-steroidal anti-inflammatory drugs, serotonin re-uptake inhibitors and flunarizine without significant improvement. The patient was treated with GBP 300 mg three times a day. After 1 month, the attacks had ceased, and 3 months later GBP was stopped without any recurrence of the pain. In the same year Hunt et al. (15) reported a 35-year-old woman with SUNCT, who initially had received indomethacin 50 mg three times a day, and the severity of attacks was reduced but their frequency had remained unchanged. The medication was then changed to GBP 400 mg daily. The headaches were completely resolved within 4 days, and after 15 months the patient reported no other headache. However, in this case when the patient tried to reduce the dosage in anticipation of stopping the medication, the pain recurred. In 2007 Cohen, in a study carried out on a large sample of SUNCT patients, reported that among the 22 patients receiving GBP up to 3600 mg/day, 10 (45%) responded to the treatment (7). Recently, Rocha Filho et al. have presented two women diagnosed with SUNCT who responded to GBP with 600 and 1200 mg/day, respectively. The first was a 75-year-old woman who after multiple failed therapies had her pain controlled by GBP 600 mg/day. The second was 82 years old and had a partial response to carbamazepine (600 mg/day) and chlorpromazine (15 mg/day). Then the administration of GBP (1200 mg/day) led to complete resolution of the pain attacks, but the patient continued to have episodes of conjunctival injection (23).
In our study, GBP was well tolerated and no unfavourable side-effects were reported. In addition, GBP significantly reduced the intensity, frequency and duration of headaches in a short period and successfully terminated headaches in five patients (63%). It is less likely that the effect of GBP should be attributed to spontaneous remission, because the bouts of the only patient with the episodic form of SUNCT had started just before the beginning of the trial, and it seems unlikely that this patient has gone into spontaneous remission; furthermore, the headaches recurred soon after the drug dosage was reduced in five (63%) patients. Finally, all recruited patients responded to the treatment in a short period.
Since our study was open-label, the placebo effect cannot be excluded (24, 25). Nevertheless, our study, in line with other case reports about the success of GBP in the treatment of SUNCT syndrome (7, 8, 14–16, 23), suggests that GBP is an effective treatment for SUNCT and, taking into account its relative lack of interactions and severe side-effects (20), this drug could be considered as an option for the treatment of this kind of headache.