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Open Access Full Text Article Case Series : successful antiepileptic drug combination therapy in three refractory cases

Lara Prisco1 Abstract: Antiepileptic drug combination therapy remains an empirical second-line treat- Mario Ganau2 ment approach in trigeminal neuralgia, after treatment with one antiepileptic drug or other Federica Bigotto1 nonantiepileptic drugs have failed. The results in three patients followed in our clinic are not Francesca Zornada1 sufficient to draw definitive conclusions, but suggest the possibility of developing this type of therapeutic approach further. 1Department of Anaesthesiology, Intensive Care and Emergency Keywords: trigeminal neuralgia, antiepileptic drugs, combination therapy Medicine, University Hospital of Cattinara, 2Graduate School of Nanotechnology, University Introduction of Trieste, Italy The annual incidence of trigeminal neuralgia is approximately 12.6 new cases per 100,000 people per year, with a female to male preponderance of 3:2.1 Trigeminal neuralgia is defined by the International Classification of Headache Disorders as paroxysmal attacks of pain (strong, sharp, superficial, or stabbing) lasting from a fraction of a second to 2 minutes, precipitated by stimulation of “trigger zones” or triggers with involvement of one or more divisions of the trigeminal nerve. The age of onset is 40–60 years for classic trigeminal neuralgia (idiopathic, not attributed to another disorder) and 30–40 years for symptomatic trigeminal neuralgia (secondary to compression of the trigeminal ganglion or to a demyelinating disorder). Several studies have investigated , , and for their effectiveness in the treatment of trigeminal neuralgia.2–4 Currently, the combina- tion of antiepileptic drugs in the treatment of trigeminal neuralgia is a “second-line approach.” Antiepileptic drug treatment is sometimes considered when a combination of nonantiepileptic drugs fails. We report here three patients with trigeminal neuralgia who were successfully treated using a combination of antiepileptic drugs after failure of first-line and other therapeutic strategies.

Case series The records of three patients (A, B, and C) diagnosed with trigeminal neuralgia and attending the Clinic for Pain Therapy at our institution were retrospectively reviewed, and appropriate information was collected. These patients were chosen as cases to report because of their refractory typical trigeminal neuralgia symptoms. Patients who Correspondence: Lara Prisco did not require a combination of antiepileptic drugs to treat their symptoms were not Via San Francesco 12, Trieste 34133, Italy included. The patients provided written consent for their information to be used for Tel +39 34 0229 3558 clinical research. Two patients were found to have trigeminal neuralgia secondary Fax +39 040 823375 Email [email protected] to ganglion compression (A and B) and the third patient had an idiopathic form (C).

submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2011:3 43–45 43 Dovepress © 2011 Prisco et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/DHPS.S22385 which permits unrestricted noncommercial use, provided the original work is properly cited. Prisco et al Dovepress

The pathophysiological characteristics and therapeutic management of the patients are summarized in Table 1. The VAS afterVAS CT VAS 0 VAS 0 two patients with secondary trigeminal neuralgia underwent VAS 1 neurosurgical decompression of the trigeminal ganglion and + + +

other minimally invasive treatment (nerve block and infiltra- tion), in addition to several sessions of acupuncture which did not change either in intensity or type of pain. In a differ- CT with AED AED with CT (duration) CBZ 100 mg GBP 100 mg (1 month) CBZ 100 mg PGB 75 mg (1 month) CBZ 300 mg GBP 100 mg (7 months) ent tertiary clinic, all three patients had in the first instance taken antiepileptic monotherapy using various combinations of nonantiepileptic drugs for a period of 7 months to 8 years VAS before before VAS CT VAS 6 VAS 5 without obtaining satisfactory results in terms of pain relief, VAS 4 but experiencing various side effects due to the use of anti- depressants (drowsiness), opioids (nausea and constipation),

and nonsteroidal anti-inflammatory drugs (epigastralgia). × 2/day × 3/day The three patients were subsequently prescribed a com- bination of antiepileptic drugs for a period of 1–7 months.

Carbamazepine was prescribed with gabapentin or pregaba- × 2/day lin, taking advantage of the different actions of these agents Non-AEDs Non-AEDs pharmacologic treatment Doxepine 10 mg/day 4% 5 g/day 10 mg/day Lormetazepam 0.25% Alphalipoic acid + vitamins 400 mg 150 mg/day E toricoxib 90 mg/day 20 gtt/day Oxycodone 10 mg I ndomethacin 100 mg/day Tizanidine 4 mg/day 25 mg/day at various receptor levels. The dosages of all the drugs were Tramadol 100 mg

lower (see Table 1) than the therapeutic dose of each drug when used alone, without the need for initial titration, thereby decreasing the potential risk of side effects. All patients × 3/day + 25 mg/day underwent regular blood investigations to ensure consistent carbamazepine levels, which were always within the thera- Single AED treatment (duration) CBZ 200 5 mg/day (8 years) PGB 75 mg (1 year) peutic range (4–12 mg/L). GBP 100 mg (7 months)

All patients showed a marked clinical improvement on combination therapy (carbamazepine + gabapentin or ­carbamazepine + pregabalin) and decided voluntarily to reduce or suspend treatment after remission of pain

­symptoms, and have not reported recurrence of symptoms since their last follow-up visits in our clinic at 1 year. There have been no side effects reported following the combination therapy. Only one patient complained of dizziness, which predated the start of the antiepileptic drug combination.

Discussion Nonpharmacologic treatments Decompressive neurosurgical treatment Acupuncture (12 sessions) Trigeminal blockade with local anesthetic and cortisone transoral) with local anesthetic and clonidine point injections with local anesthetic Trigger and clonidine T E NS and laser sessions in trigeminal territory Trigeminal neuralgia causes episodes of paroxysmal pain treatment neurosurgical Decompressive Dental treatment (20 sessions) Acupuncture Sphenopalatine ganglion blockade (transnasal/ transoral) and infraorbital nerve blockade that are short-lasting but intense in nature. The intervals between the paroxysms are generally free from painful symptoms, but a constant dull pain persists in some cases.5 Medical treatment of trigeminal neuralgia includes the use of Trigeminal Trigeminal branch involved I , II III II III antiepileptic drugs (carbamazepine, gabapentin, pregabalin, ) and nonantiepileptic drugs (baclofen, , Age Age (years) 70 67 pimozide, ­, amitriptyline, tizanidine, propa- 48 racaine). The most studied antiepileptic drugs in trigemi- A E D, antiepileptic drug; CT, combination therapy; VAS, visual analog scale (0–10); GBP, gabapentin; CBZ, carbamazepine; PGB, pregabalin; T NS, Transcutaneous lectrical Nerve Stimulation. nal neuralgia are carbamazepine, baclofen, lamotrigine, Characteristics and treatments used in three patients with trigeminal neuralgia Gender F M and pimozide.6 Recent studies have suggested the use of F Table 1 Abbreviations: A B other antiepileptic drugs in trigeminal neuralgia, such as C

44 submit your manuscript | www.dovepress.com Drug, Healthcare and Patient Safety 2011:3 Dovepress Dovepress Antiepileptic combination therapy in trigeminal neuralgia gabapentin and pregabalin.2,7 No study has ever compared Disclosure antiepileptic drug monotherapy with combination therapy The authors report no conflicts of interest in this work. of two antiepileptic drugs, exploiting their different actions at the synaptic level, although in one study polypharmacy References has been used successfully as second-line treatment after 1. Koopman J, de Vries L, Dieleman J, et al. A nationwide study of three invasive treatments for trigeminal neuralgia. Pain. 2011;152:507–513. 2 eight weeks of unsuccessful monotherapy. It is assumed that 2. Obermann M, Yoon MS, Sensen K, et al. of pregabalin in the carbamazepine controls paroxysmal pain by suppression of treatment of trigeminal neuralgia. Cephalalgia. 2008;28:174–181. 3. Taylor JC, Brauer S, Espir ML, et al. Long term treatment of trigeminal ectopic neuronal transmission, ie, blocking synaptic sodium neuralgia with carbamazepine. Postgrad Med J. 1981;57:16–18. channels, whereas gabapentin and pregabalin interact with 4. Magnus L. Nonepileptic uses of gabapentin. Epilepsia. 1999;40(S): the α δ subunit of voltage-gated calcium channels by increas- S66–S72. 2 5. Headache Classification Committee of the International Headache ing the brain concentration and rate of synthesis of gamma Society. The International Classification of Headache Disorders. 2nd ed. aminobutyric acid.8,9 Cephalalgia. 2004;24:1–160. 6. Gronseth G, Cruccu G, Alksne J, et al. Practice parameter: The diagnostic There are no randomized trials demonstrating the effec- evaluation and treatment of trigeminal neuralgia (an evidence-based tiveness of a combination of anticonvulsants compared with review): Report of the Quality Standards Subcommittee of the American monotherapy or following unsuccessful monotherapy in their Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008;71:1183–1190. study of pregabalin. In their study of pregabalin, Obermann 7. Rozen TD. Antiepileptic drugs in the management of cluster headache et al2 added carbamazepine 600–1200 mg/day or lamotrigine and trigeminal neuralgia. Headache. 2001;41:S25–S32. 8. Guay DR. Pregabalin in neuropathic pain: A more ‘pharmaceutically 50–200 mg/day after eight weeks of pregabalin monotherapy. elegant’ gabapentin? Am J Geriatr Pharmacother. 2005;3:274–287. Although their research did not investigate the efficacy of 9. Taylor CP, Gee NS, Su TZ, et al. A summary of mechanistic hypotheses combination therapy, the results showed a marked reduction of gabapentin pharmacology. Epilepsy Res. 1998;29:233–249. of pain in two patients treated with anticonvulsants. The three patients followed in our clinic are not sufficient to draw any kind of conclusion, but suggest the possibility of further investigation of this type of therapeutic approach.

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