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Erectile dysfunction associated with pregabalin add-on treatment in patients with partial seizures: Five case reports
Epilepsy & Behavior 8 (2006) 418–421 www.elsevier.com/locate/yebeh
Erectile dysfunction associated with pregabalin add-on treatment in patients with partial seizures: Five case reports Nikolas Hitiris a, Jeannette A. Barrett b, Martin J. Brodie a
a,*
Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow, Scotland, UK b Pfizer Global Pharmaceuticals, Pfizer Inc., New York, NY, USA Received 19 October 2005; revised 8 December 2005; accepted 9 December 2005
Abstract Sexual dysfunction has been reported in both men and women with epilepsy. Associated factors are diverse but include, among others, antiepileptic drugs. We present the cases of 5 men who reported mild to moderate erectile dysfunction or impotence for the first time when treated with the new antiepileptic drug pregabalin as add-on therapy. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Pregabalin; Epilepsy; Erectile dysfunction; Side effect
1. Introduction Erectile dysfunction (ED) is a common disorder. An estimated 52% of American men aged 40–70 years suffer from some form of ED [1]. The prevalence of complete ED in the Massachusetts Male Aging Study was 10% overall, with 5% affected at age 40 years increasing to 15% at age 70 years. Increasing age was the strongest predictor of ED followed by concomitant medical disorders such as diabetes, heart disease, and hypertension. ED has been reported with many drugs including thiazide diuretics, beta blockers, benzodiazepines, phenothiazines, antidepressants, and anticholinergics [1,2]. In patients with epilepsy, sexual disorders are reported in both men and women [3,4]. Outpatient and community-based studies have suggested that sexual dysfunction is present in 8–57% of men with epilepsy [5–7]. In a recent study by Herzog et al., 20% of men with localisation-related epilepsy were reported to have sexual dysfunction [8]. In contrast, two additional studies have not found significant differences in sexual dysfunction between persons with epi-
*
Corresponding author. Fax: +44 141 334 9329. E-mail address: [email protected] (M.J. Brodie).
1525-5050/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2005.12.001
lepsy and controls [6,9]. It should be noted, however, that these types of studies tend to involve small numbers of patients attending specialist clinics. An accurate estimate of the prevalence of sexual disorders for people with epilepsy will require larger, community-based studies across the complete spectrum of the epilepsies. The aetiology for sexual dysfunction in patients with epilepsy remains unclear and is likely to be multifactorial. Epilepsy has been most commonly associated with hyposexuality and ED has been reported in several case studies [3,10]. Impotence and reduced libido have been described with older antiepileptic drugs (AEDs) such as carbamazepine (CBZ), phenobarbital, phenytoin, and primidone [11,12]. A number of studies have reported reproductive endocrine abnormalities in men and women treated with enzyme-inducing AEDs, but most have not correlated this with sexual desire or function [3]. Two studies described a correlation between reduced free testosterone (FT) and low sex drive in male patients with epilepsy [13,14]. However, this low FT may be within the normal physiological range and further studies did not demonstrate any significant difference in FT between affected patients with epilepsy and control groups [6,9]. It has been hypothesised that men with epilepsy might have a premature aging of the reproductive system [15]. Consistent with this concept,
N. Hitiris et al. / Epilepsy & Behavior 8 (2006) 418–421
Herzog et al. [8] noted a significantly greater age-related decline in bioavailable testosterone in men with localisation-related epilepsy than among controls. Case reports have described anorgasmia and ejaculatory failure with CBZ [16] and gabapentin (GBP) [17,18]. Erectile dysfunction has been reported with topiramate (TPM) [19]. Pregabalin (PGB) is a new AED recently licensed in Europe and US as adjunctive therapy for partial epilepsy and as treatment of neuropathic pain in adults. It is structurally related to GBP, although PGB is more potent. Both drugs bind to the a2d subunit of voltage-dependent calcium channels and, thereby, modulate the release of a range of neurotransmitters [20]. The efficacy of PGB as add-on therapy in patients with refractory partial seizures has been demonstrated in four multicentre, double-blind, randomised, placebo-controlled trials [21–24]. Adverse events commonly reported in patients taking PGB comprised dizziness, somnolence, ataxia, asthenia, weight gain, blurred vision, diplopia, and tremor. We describe five cases of mild to moderate ED associated with PGB add-on treatment in patients with partial seizures. All patients were taking part in randomised clinical trials or open-label (OL) studies with the drug. All patients spontaneously reported inability or reduced ability to achieve tumescence adequate for penetration after initiating PGB therapy. 2. Case reports 2.1. Patient 1 A 64-year-old man experienced complex partial and secondary generalised seizures for 9 years. Brain magnetic resonance imaging (MRI), routine electroencephalography (EEG), and sleep deprived EEG were all reported as normal. The seizures persisted despite treatment with CBZ 1000 mg daily in divided doses. He was enrolled in a double-blind, placebo-controlled, and add-on titration study with PGB and was randomised to placebo. After successfully completing the trial, he commenced on PGB 300 mg daily as part of an OL extension. He reported moderate impotence on the first day of OL therapy on which he received his first dose of PGB (150 mg/day). Further investigation and treatment for ED were declined. Treatment with PGB was continued in view of the excellent seizure control. 2.2. Patient 2 A 58-year-old man was entered into an OL extension study starting on PGB 300 mg daily. He was already taking CBZ 800 mg/day and clomipramine 100 mg/day for depression. He also had a previous history of alcohol abuse. He had reported complex partial and secondary generalised seizures for 17 years. Brain MRI showed left mesial temporal sclerosis. Repeated EEGs were normal. PGB was gradually increased to 600 mg/day with improve-
419
ment in his seizure control. The patient had received PGB for 466 days when he first reported mild ED, 53 days after his dose of PGB was increased to 600 mg/day. PGB was discontinued 83 days later. Other adverse events that were reported as ongoing for up to 54 weeks at the time ED was reported included parasthesia, anxiety, word finding difficulties, and memory problems, all of which were reported to be mild in intensity. The ED rapidly resolved on PGB withdrawal. 2.3. Patient 3 This 48-year-old man had a history of intermittent generalised tonic-clonic seizures from the age of 19 years. His control deteriorated 3 years previously with the development of complex partial seizures with occasional secondary generalisation. Brain MRI and routine EEG were normal. His seizures were not controlled with CBZ 1200 mg daily in divided doses. He was started on 300 mg/day PGB as part of a randomised pregabalin add-on study. He first mentioned moderate impotence 18 days after commencing 300 mg PGB. Additional concomitant medications for this patient included zopiclone, rofecoxib, and fluoxetine for the ongoing treatment of insomnia, shoulder pain, and depression. The patient reported mood swings approximately 2 weeks after he first reported impotence. He was entered into the OL extension after 35 days of double-blind treatment where he continued to receive PGB 300 mg daily. ED had not resolved and the patient discontinued PGB on day 66 of OL treatment. The patient reported rapid resolution of ED once he discontinued PGB. 2.4. Patient 4 A 37-year-old man had a history of complex partial and tonic-clonic seizures since the age of 3 years. An EEG showed focal interictal discharges from the right temporal region. Brain MRI showed abnormal signals in both hippocampi. His seizures remained refractory despite treatment with sodium valproate 1000 mg daily and lamotrigine 150 mg daily. In addition, the patient was taking cocodamol and thyroxine for the treatment of post-ictal headaches and hypothyroidism. He entered a double-blind, placebo-controlled, dose-escalation study with PGB in which he was randomised to the flexible dose group of PGB (150–600 mg/day). Five days after commencement of treatment (PGB 150 mg/day) he complained of moderate ED for the first time. Following the completion of the double-blind trial, he entered into the OL extension. He received PGB 300 mg daily and continued to experience ED for 151 days. The ED resolved while the patient was receiving PGB 425–450 mg day. The patient reported the recurrence of mild ED 93 days later while receiving 400 mg/day PGB. The ED resolved after 121 days. He judged his seizure control to have substantially improved and elected to continue on treatment with PGB.
420
N. Hitiris et al. / Epilepsy & Behavior 8 (2006) 418–421
2.5. Patient 5 This 39-year-old man with fascioscapulohumoral dystrophy had a history of complex partial and secondary generalised seizures for 19 years. Brain MRI showed left mesial temporal sclerosis and EEG showed frequent interictal sharp wave discharges over the left anterior temporal region. His seizures remained refractory to treatment with sodium valproate 1000 mg daily, lamotrigine 200 mg, and 10 mg diazepam daily. Concurrent medical conditions included migraine, arthritis, and dyspepsia. Diazepam was withdrawn 3 days prior to taking part in a randomised, double-blind, placebo-controlled add-on trial of PGB. He was randomised to PGB 600 mg/day and reported moderate impotence after 7 days which lasted a total of 88 days. Several days prior, the patient reported mild hand tremor (although this was noted during the neurological examination performed at the baseline visit), paresthesia and ‘‘mood subdued.’’ After completing the entire double-blind trial (84-day duration), he entered into the OL extension and began receiving 300 mg PGB at which time his initial report of ED resolved 6 days later. He again complained of impotence the next day when commencing PGB 450 mg/day. This was not reported to have resolved while he remained in the study for the next 1800 days during which his PGB dosage was increased to 600 mg/day daily and he became seizure free. Nearly 2 years after he reported impotence the second time, he received sildenafil (25 mg prn) for approximately 2 months. Nearly 1.5 years later he began taking tadalafil for the remainder of the study. He persisted with PGB treatment and has been seizure free for over 5 years. 3. Trial data In the placebo-controlled trials of PGB in epilepsy, 363 males received PGB and 156 males received placebo. Impotence was reported by 11 (3.0%) men taking PGB and three (1.9%) on placebo (Fisher’s exact test, p = 0.57). Across all placebo-controlled trials for all indications, a total of 2428
males have received PGB, 71 (2.9%) of whom reported the adverse event of impotence. In these same trials, 1099 males received placebo with eight patients (0.7%) reporting impotence (Table 1). Sexual dysfunction was not reported by female patients with epilepsy receiving treatment with PGB during the epilepsy trials and only in 3 patients (0.1%) across the entire population treated with PGB. 4. Discussion PGB has been demonstrated to be an effective treatment for partial seizures [21–24]. In the placebocontrolled epilepsy trials, the difference in reporting rates of ED between PGB and placebo did not reach statistical significance. We report 5 cases of new-onset ED in men aged 37–64 years, of mild to moderate severity, occurring 1–466 days after commencement of treatment with PGB. Most were taking high doses of the drug when ED was first reported. Most of the patients also had risk factors for ED in addition to their epilepsy such as age, depression, and hypothyroidism. All patients were taking 1–2 additional AEDs as well as concomitant medications that included antidepressants and analgesics. Three of the 5 patients chose to continue to take PGB because of a substantial improvement in their seizure control, with 2 of the patients achieving seizure freedom. In one of these patients ED was successfully treated with tadalafil for over 3 years after the initial report. In the remaining 2 patients the ED was reversible, resolving rapidly with discontinuation of PGB. ED has been reported in men with epilepsy treated with enzyme-inducing AEDs such as phenobarbital, phenytoin, and CBZ [11]. Though the mechanism of ED with these medications is unclear, it is possibly related to AED-induced perturbations of reproductive hormone levels [3]. However, other factors related to epilepsy and ED such as depression are likely to be involved [25]. A few case reports of ED involving the use of non-enzyme inducing AEDs, such as GBP and TPM, have been published. The pathophysiological mechanisms
Table 1 Sexual dysfunction in randomised, placebo-controlled studies with pregabalin Placebo
Epilepsy Impotence Libido decreased Anorgasmia Abnormal ejaculation
All indications* Impotence Libido decreased Anorgasmia Abnormal ejaculation *
Pregabalin
Male N = 156
Female N = 138
Male N = 363
Female N = 395
3 0 0 0
0 0 0 0
11 1 0 0
0 1 1 0
(1.9%) (0%) (0%) (0%)
(0%) (0%) (0%) (0%)
(3.0%) (0.3%) (0%) (0%)
(0%) (0.3%) (0.3%) (0%)
Male N = 1099
Female N = 1191
Male N = 2418
Female N = 2804
8 6 0 1
0 1 1 0
73 58 21 36
3 (0.1%) 21 (0.7%) 17 (0.6%) 0 (0%)
(0.7%) (0.5%) (0%) (0.1%)
(0%) (0.1%) (0.1%) (0%)
Includes studies in epilepsy, neuropathic pain and generalised anxiety disorder.
(2.9%) (2.3%) (0.8%) (1.4%)
N. Hitiris et al. / Epilepsy & Behavior 8 (2006) 418–421
of sexual dysfunction for all AEDs remain unclear and merit further investigation. References [1] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54–61. [2] Kirby RS. Impotence: diagnosis and management of male erectile dysfunction. BMJ 1994;308:957–61. [3] Lambert MV. Seizures, hormones and sexuality. Seizure 2001;10:319–40. [4] Morrell MJ. Sexual dysfunction in epilepsy. Epilepsia 1991;32(Suppl 6):S38–45. [5] Murialdo G, Galimberti CA, Fonzi S, Manni R, Costelli P, Parodi C, et al. Sex hormones and pituitary function in male epileptic patients with altered or normal sexuality. Epilepsia 1995;36:360–5. [6] Jensen P, Jensen SB, Sorensen PS, Bjerre BD, Rizzi DA, Sorensen AS, et al. Sexual dysfunction in male and female patients with epilepsy: a study of 86 outpatients. Arch Sex Behav 1990;19:1–14. [7] Toone BK, Edeh J, Nanjee MN, Wheeler M. Hyposexuality and epilepsy: a community survey of hormonal and behavioural changes in male epileptics. Psychol Med 1989;19:937–43. [8] Herzog AG, Drislane FW, Schomer DL, Pennell PB, Bromfield EB, Dworetzky BA, et al. Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy. Neurology 2005;65:1016–20. [9] Duncan S, Blacklaw J, Beastall GH, Brodie MJ. Antiepileptic drug therapy and sexual function in men with epilepsy. Epilepsia 1999;40:197–204. [10] Smaldone M, Sukkarieh T, Reda A, Khan A. Epilepsy and erectile dysfunction: a review. Seizure 2004;13:453–9. [11] Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313:145–51. [12] Rattya J, Turkka J, Pakarinen AJ, Knip M, Kotila MA, Lukkarinen O, et al. Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy. Neurology 2001;56:31–6.
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[13] Toone BK, Wheeler M, Nanjee M, Fenwick P, Grant R. Sex hormones, sexual activity and plasma anticonvulsant levels in male epileptics. J Neurol Neurosurg Psychiatry 1983;46:824–6. [14] Fenwick PB, Mercer S, Grant R, Wheeler M, Nanjee N, Toone B, et al. Nocturnal penile tumescence and serum testosterone levels. Arch Sex Behav 1986;15:13–21. [15] Rodin E, Subramanian MG, Gilroy J. Investigation of sex hormones in male epileptic patients. Epilepsia 1984;25:690–4. [16] Leris AC, Stephens J, Hines JE, McNicholas TA. Carbamazepinerelated ejaculatory failure. Br J Urol 1997;79:485. [17] Labbate LA, Rubey RN. Gabapentin-induced ejaculatory failure and anorgasmia. Am J Psychiatry 1999;156:972. [18] Brannon GE, Rolland PD. Anorgasmia in a patient with bipolar disorder type 1 treated with gabapentin. J Clin Psychopharmacol 2000;20:379–81. [19] Holtkamp M, Weissinger F, Meierkord H. Erectile dysfunction with topiramate. Epilepsia 2005;46:166–7. [20] Fink K, Dooley DJ, Meder WP, Suman-Chauhan N, Duffy S, Clusmann H, et al. Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 2002;42:229–36. [21] Arroyo S, Anhut H, Kugler AR, Lee CM, Knapp LE, Garofalo EA, et al. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia 2004;45:20–7. [22] French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA. Doseresponse trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 2003;60:1631–7. [23] Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA. Safety and efficacy of two pregabalin regimens for addon treatment of partial epilepsy. Neurology 2005;64:475–80. [24] Elger CE, Brodie MJ, Anhut H, Lee CM, Barrett JA. Pregabalin add-on treatments in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, Placebo-Controlled Study. Epilepsia 2005;46:1926–36. [25] Araujo AB, Johannes CB, Feldman HA, Derby CA, McKinlay JB. Relation between psychosocial risk factors and incident erectile dysfunction: prospective results from the Massachusetts Male Aging Study. Am J Epidemiol 2000;152:533–41.
Erectile dysfunction associated with pregabalin add-on treatment in patients with partial seizures: Five case reports Nikolas Hitiris a, Jeannette A. Barrett b, Martin J. Brodie a
a,*
Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow, Scotland, UK b Pfizer Global Pharmaceuticals, Pfizer Inc., New York, NY, USA Received 19 October 2005; revised 8 December 2005; accepted 9 December 2005
Abstract Sexual dysfunction has been reported in both men and women with epilepsy. Associated factors are diverse but include, among others, antiepileptic drugs. We present the cases of 5 men who reported mild to moderate erectile dysfunction or impotence for the first time when treated with the new antiepileptic drug pregabalin as add-on therapy. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Pregabalin; Epilepsy; Erectile dysfunction; Side effect
1. Introduction Erectile dysfunction (ED) is a common disorder. An estimated 52% of American men aged 40–70 years suffer from some form of ED [1]. The prevalence of complete ED in the Massachusetts Male Aging Study was 10% overall, with 5% affected at age 40 years increasing to 15% at age 70 years. Increasing age was the strongest predictor of ED followed by concomitant medical disorders such as diabetes, heart disease, and hypertension. ED has been reported with many drugs including thiazide diuretics, beta blockers, benzodiazepines, phenothiazines, antidepressants, and anticholinergics [1,2]. In patients with epilepsy, sexual disorders are reported in both men and women [3,4]. Outpatient and community-based studies have suggested that sexual dysfunction is present in 8–57% of men with epilepsy [5–7]. In a recent study by Herzog et al., 20% of men with localisation-related epilepsy were reported to have sexual dysfunction [8]. In contrast, two additional studies have not found significant differences in sexual dysfunction between persons with epi-
*
Corresponding author. Fax: +44 141 334 9329. E-mail address: [email protected] (M.J. Brodie).
1525-5050/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2005.12.001
lepsy and controls [6,9]. It should be noted, however, that these types of studies tend to involve small numbers of patients attending specialist clinics. An accurate estimate of the prevalence of sexual disorders for people with epilepsy will require larger, community-based studies across the complete spectrum of the epilepsies. The aetiology for sexual dysfunction in patients with epilepsy remains unclear and is likely to be multifactorial. Epilepsy has been most commonly associated with hyposexuality and ED has been reported in several case studies [3,10]. Impotence and reduced libido have been described with older antiepileptic drugs (AEDs) such as carbamazepine (CBZ), phenobarbital, phenytoin, and primidone [11,12]. A number of studies have reported reproductive endocrine abnormalities in men and women treated with enzyme-inducing AEDs, but most have not correlated this with sexual desire or function [3]. Two studies described a correlation between reduced free testosterone (FT) and low sex drive in male patients with epilepsy [13,14]. However, this low FT may be within the normal physiological range and further studies did not demonstrate any significant difference in FT between affected patients with epilepsy and control groups [6,9]. It has been hypothesised that men with epilepsy might have a premature aging of the reproductive system [15]. Consistent with this concept,
N. Hitiris et al. / Epilepsy & Behavior 8 (2006) 418–421
Herzog et al. [8] noted a significantly greater age-related decline in bioavailable testosterone in men with localisation-related epilepsy than among controls. Case reports have described anorgasmia and ejaculatory failure with CBZ [16] and gabapentin (GBP) [17,18]. Erectile dysfunction has been reported with topiramate (TPM) [19]. Pregabalin (PGB) is a new AED recently licensed in Europe and US as adjunctive therapy for partial epilepsy and as treatment of neuropathic pain in adults. It is structurally related to GBP, although PGB is more potent. Both drugs bind to the a2d subunit of voltage-dependent calcium channels and, thereby, modulate the release of a range of neurotransmitters [20]. The efficacy of PGB as add-on therapy in patients with refractory partial seizures has been demonstrated in four multicentre, double-blind, randomised, placebo-controlled trials [21–24]. Adverse events commonly reported in patients taking PGB comprised dizziness, somnolence, ataxia, asthenia, weight gain, blurred vision, diplopia, and tremor. We describe five cases of mild to moderate ED associated with PGB add-on treatment in patients with partial seizures. All patients were taking part in randomised clinical trials or open-label (OL) studies with the drug. All patients spontaneously reported inability or reduced ability to achieve tumescence adequate for penetration after initiating PGB therapy. 2. Case reports 2.1. Patient 1 A 64-year-old man experienced complex partial and secondary generalised seizures for 9 years. Brain magnetic resonance imaging (MRI), routine electroencephalography (EEG), and sleep deprived EEG were all reported as normal. The seizures persisted despite treatment with CBZ 1000 mg daily in divided doses. He was enrolled in a double-blind, placebo-controlled, and add-on titration study with PGB and was randomised to placebo. After successfully completing the trial, he commenced on PGB 300 mg daily as part of an OL extension. He reported moderate impotence on the first day of OL therapy on which he received his first dose of PGB (150 mg/day). Further investigation and treatment for ED were declined. Treatment with PGB was continued in view of the excellent seizure control. 2.2. Patient 2 A 58-year-old man was entered into an OL extension study starting on PGB 300 mg daily. He was already taking CBZ 800 mg/day and clomipramine 100 mg/day for depression. He also had a previous history of alcohol abuse. He had reported complex partial and secondary generalised seizures for 17 years. Brain MRI showed left mesial temporal sclerosis. Repeated EEGs were normal. PGB was gradually increased to 600 mg/day with improve-
419
ment in his seizure control. The patient had received PGB for 466 days when he first reported mild ED, 53 days after his dose of PGB was increased to 600 mg/day. PGB was discontinued 83 days later. Other adverse events that were reported as ongoing for up to 54 weeks at the time ED was reported included parasthesia, anxiety, word finding difficulties, and memory problems, all of which were reported to be mild in intensity. The ED rapidly resolved on PGB withdrawal. 2.3. Patient 3 This 48-year-old man had a history of intermittent generalised tonic-clonic seizures from the age of 19 years. His control deteriorated 3 years previously with the development of complex partial seizures with occasional secondary generalisation. Brain MRI and routine EEG were normal. His seizures were not controlled with CBZ 1200 mg daily in divided doses. He was started on 300 mg/day PGB as part of a randomised pregabalin add-on study. He first mentioned moderate impotence 18 days after commencing 300 mg PGB. Additional concomitant medications for this patient included zopiclone, rofecoxib, and fluoxetine for the ongoing treatment of insomnia, shoulder pain, and depression. The patient reported mood swings approximately 2 weeks after he first reported impotence. He was entered into the OL extension after 35 days of double-blind treatment where he continued to receive PGB 300 mg daily. ED had not resolved and the patient discontinued PGB on day 66 of OL treatment. The patient reported rapid resolution of ED once he discontinued PGB. 2.4. Patient 4 A 37-year-old man had a history of complex partial and tonic-clonic seizures since the age of 3 years. An EEG showed focal interictal discharges from the right temporal region. Brain MRI showed abnormal signals in both hippocampi. His seizures remained refractory despite treatment with sodium valproate 1000 mg daily and lamotrigine 150 mg daily. In addition, the patient was taking cocodamol and thyroxine for the treatment of post-ictal headaches and hypothyroidism. He entered a double-blind, placebo-controlled, dose-escalation study with PGB in which he was randomised to the flexible dose group of PGB (150–600 mg/day). Five days after commencement of treatment (PGB 150 mg/day) he complained of moderate ED for the first time. Following the completion of the double-blind trial, he entered into the OL extension. He received PGB 300 mg daily and continued to experience ED for 151 days. The ED resolved while the patient was receiving PGB 425–450 mg day. The patient reported the recurrence of mild ED 93 days later while receiving 400 mg/day PGB. The ED resolved after 121 days. He judged his seizure control to have substantially improved and elected to continue on treatment with PGB.
420
N. Hitiris et al. / Epilepsy & Behavior 8 (2006) 418–421
2.5. Patient 5 This 39-year-old man with fascioscapulohumoral dystrophy had a history of complex partial and secondary generalised seizures for 19 years. Brain MRI showed left mesial temporal sclerosis and EEG showed frequent interictal sharp wave discharges over the left anterior temporal region. His seizures remained refractory to treatment with sodium valproate 1000 mg daily, lamotrigine 200 mg, and 10 mg diazepam daily. Concurrent medical conditions included migraine, arthritis, and dyspepsia. Diazepam was withdrawn 3 days prior to taking part in a randomised, double-blind, placebo-controlled add-on trial of PGB. He was randomised to PGB 600 mg/day and reported moderate impotence after 7 days which lasted a total of 88 days. Several days prior, the patient reported mild hand tremor (although this was noted during the neurological examination performed at the baseline visit), paresthesia and ‘‘mood subdued.’’ After completing the entire double-blind trial (84-day duration), he entered into the OL extension and began receiving 300 mg PGB at which time his initial report of ED resolved 6 days later. He again complained of impotence the next day when commencing PGB 450 mg/day. This was not reported to have resolved while he remained in the study for the next 1800 days during which his PGB dosage was increased to 600 mg/day daily and he became seizure free. Nearly 2 years after he reported impotence the second time, he received sildenafil (25 mg prn) for approximately 2 months. Nearly 1.5 years later he began taking tadalafil for the remainder of the study. He persisted with PGB treatment and has been seizure free for over 5 years. 3. Trial data In the placebo-controlled trials of PGB in epilepsy, 363 males received PGB and 156 males received placebo. Impotence was reported by 11 (3.0%) men taking PGB and three (1.9%) on placebo (Fisher’s exact test, p = 0.57). Across all placebo-controlled trials for all indications, a total of 2428
males have received PGB, 71 (2.9%) of whom reported the adverse event of impotence. In these same trials, 1099 males received placebo with eight patients (0.7%) reporting impotence (Table 1). Sexual dysfunction was not reported by female patients with epilepsy receiving treatment with PGB during the epilepsy trials and only in 3 patients (0.1%) across the entire population treated with PGB. 4. Discussion PGB has been demonstrated to be an effective treatment for partial seizures [21–24]. In the placebocontrolled epilepsy trials, the difference in reporting rates of ED between PGB and placebo did not reach statistical significance. We report 5 cases of new-onset ED in men aged 37–64 years, of mild to moderate severity, occurring 1–466 days after commencement of treatment with PGB. Most were taking high doses of the drug when ED was first reported. Most of the patients also had risk factors for ED in addition to their epilepsy such as age, depression, and hypothyroidism. All patients were taking 1–2 additional AEDs as well as concomitant medications that included antidepressants and analgesics. Three of the 5 patients chose to continue to take PGB because of a substantial improvement in their seizure control, with 2 of the patients achieving seizure freedom. In one of these patients ED was successfully treated with tadalafil for over 3 years after the initial report. In the remaining 2 patients the ED was reversible, resolving rapidly with discontinuation of PGB. ED has been reported in men with epilepsy treated with enzyme-inducing AEDs such as phenobarbital, phenytoin, and CBZ [11]. Though the mechanism of ED with these medications is unclear, it is possibly related to AED-induced perturbations of reproductive hormone levels [3]. However, other factors related to epilepsy and ED such as depression are likely to be involved [25]. A few case reports of ED involving the use of non-enzyme inducing AEDs, such as GBP and TPM, have been published. The pathophysiological mechanisms
Table 1 Sexual dysfunction in randomised, placebo-controlled studies with pregabalin Placebo
Epilepsy Impotence Libido decreased Anorgasmia Abnormal ejaculation
All indications* Impotence Libido decreased Anorgasmia Abnormal ejaculation *
Pregabalin
Male N = 156
Female N = 138
Male N = 363
Female N = 395
3 0 0 0
0 0 0 0
11 1 0 0
0 1 1 0
(1.9%) (0%) (0%) (0%)
(0%) (0%) (0%) (0%)
(3.0%) (0.3%) (0%) (0%)
(0%) (0.3%) (0.3%) (0%)
Male N = 1099
Female N = 1191
Male N = 2418
Female N = 2804
8 6 0 1
0 1 1 0
73 58 21 36
3 (0.1%) 21 (0.7%) 17 (0.6%) 0 (0%)
(0.7%) (0.5%) (0%) (0.1%)
(0%) (0.1%) (0.1%) (0%)
Includes studies in epilepsy, neuropathic pain and generalised anxiety disorder.
(2.9%) (2.3%) (0.8%) (1.4%)
N. Hitiris et al. / Epilepsy & Behavior 8 (2006) 418–421
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