Anorgasmia During Pregabalin Add-On Therapy for Partial Seizures

Home , Anorgasmia, Delayed ejaculation

doi:10.1684/epd.2013.0592 et al., 2005; et al., 2010), leve- et al., 2006) may cause et al., 2009; Coebergh and Epileptic Disord, Vol. 15, No. 3, September 2013 Calabrò Waldinger, 2012),(OXC) (Calabrò oxcarbazepine tiracetamBramanti, (LEV) 2013), gabapentin(Clark (Calabrò (GBP) andand Elliott, and Struck, 1999; 2011),(PGB) (Hitiris Kaufman and pregabalin SD throughunderstood complex pathomechanisms, pos- andsibly poorly involving,hormonal changes, beyond an imbalance sexual et al.,effects of 2011),such new as the erectileand AEDs anorgasmia, dysfunction sexual have (table (ED) described (Calabrò, been side 2011a). 1), rarely In particular,gest a few thattopiramate reports (Holtkamp new sug- AEDs, including et al., 2010). anorgasmia, pregabalin, sexual dysfunction – Anorgasmia is the inability to reach orgasm during sexual Epileptic Disord 2013; 15 (3): 358-61 Clinical commentary Anorgasmia is the inability toorgasm reach during sexualeven intercourse, with appropriateIn stimulation. males,related the to delayed condition ejaculation, typi- cally is causing often sexualis frustration. estimated It anorgasmia that problems aroundto 90% are psychological of related sexual issues, dysfunction although be (SD) can causedproblems, also by such as differentpathy, diabetic pelvic neuro- trauma, medical multiplerosis, scle- spinalcations cord from injury, genitalhormonal compli- imbalances, surgery, or and genic be in origin (Rowland iatro- Although the relationship between older antiepileptic drugs (AEDs) and SD has long been known (Calabrò Anorgasmia during pregabalin add-on therapy for partial seizures Rocco Salvatore Calabrò, Rosaria DePlacido Luca, Bramanti Patrizia Pollicino, IRCCS Centro Neurolesi “Bonino-Pulejo” Messina, Italy Received April 10, 2013; Accepted July 5, 2013 ABSTRACT intercourse, and, although itproblems is are believed related thatdrugs, to around including psychological 90% issues, antidepressants ofmon the anorgasmia and cause use atypical of ofdrug, antipsychotics, situational structurally serotoninergic related is anorgasmia. to gabapentin, a Pregabalintherapy and commonly for com- is used partial as a adjunctive epilepsyHerein, new and we treatment antiepileptic describe ofanorgasmia three neuropathic after pregabalin pain men add-on in treatment. with adults. epilepsy, who experiencedKey severe words: 358 Correspondence: Rocco Salvatore Calabrò IRCCS Centro Neurolesi “Bonino-Pulejo”, SS 113, Contrada Casazza 98124, Messina, Italy Pregabalin-induced anorgasmia

Table 1. AED-related sexual dysfunction.

Sexual side effects

Old AEDs

enzyme-inducing AEDs hyposexuality, erectile dysfunction, (carbamazepine, phenytoin, phenobarbital) delayed ejaculation, anorgasmia

valproic acid retrograde ejaculation

New AEDs

topiramate erectile dysfunction, anorgasmia

oxcarbazepine anorgasmia, ejaculatory failure, retrograde ejaculation

lamotrigine hypersexuality

levetiracetam loss of libido, hypersexuality

zonisamide erectile dysfunction

gabapentin anorgasmia

pregabalin erectile dysfunction, delayed ejaculation, anorgasmia

in central nervous system neurotransmission with plete restoration of the patient’s sexual performance. regard to dopamine and serotonin rate. At two years of follow-up, sporadic partial seizures Herein, we describe three male individuals with without SD were reported. epilepsy presenting with clear drug-related anorgasmia after pregabalin add-on treatment. Patient 2 A 24-year-old man was evaluated in our epilepsy Case studies centre following episodes of complex partial seizures without generalisation. Family history Patient 1 was positive for epilepsy (his uncle and one of his cousins were affected by undetermined epilepsy), A healthy 35-year-old man had partial seizures with whereas personal history was unremarkable. EEG secondary generalisation since the age of 10 years. showed interictal sharp waves over the right Family history was unremarkable, however, he had a anterior temporal region. Neurological exami- history of febrile convulsions. General and neurolog- nation and brain MRI were normal. Treatment with ical examinations were normal as well neuropsycho- carbamazepine was started and gradually titrated up logical testing, while brain MRI showed left mesial to 1,800/day with moderate seizure control. Thus, since temporal sclerosis. Interictal EEG showed frequent the patient had a concomitant generalised anxiety dis- focal epileptiform discharges from the left fronto- order, PGB was introduced and seizures disappeared temporal region. His seizures remained refractory when a dosage of 300 mg/day was reached. Nonethe- despite treatment with OXC (up to 1,800/day) and less, the patient progressively complained of severe valproate (up to 2,000/day). After PGB was gradually anorgasmia, followed by loss of libido and, sometimes, titrated at a dosage of 300 mg/day, he progressively secondary erectile dysfunction. Medical and sexual started complaining of delayed ejaculation and anor- history, as well as general, psychiatric and urological gasmia, which caused severe sexual dissatisfaction. His examinations, were normal. The patient was not taking sexual history was unremarkable and he had never any other medication, alcohol or illicit drugs. Haema- experienced similar SD before. He denied using other tological tests, including a complete sexual hormonal medications, alcohol, or substances of abuse. More- panel, as well as urological examination, were within over, urological evaluation and blood sexual hormonal the normal range. Thus, PGB was gradually withdrawn proﬁle, as well as psychiatric examination, were within and LEV introduced up to 3,000 mg/day with no other the normal range. Thus, PGB was gradually withdrawn reported seizures or sexual problems at 12 months of and lacosamide introduced up to 400 mg/day with com- follow-up.

Epileptic Disord, Vol. 15, No. 3, September 2013 359 R.S. Calabrò, et al.

Patient 3 man, affected by post-traumatic epilepsy, who experienced severe delayed ejaculation, sometimes with Following a brain trauma, an otherwise healthy 28-year- anorgasmia, secondary to PGB monotherapy. old young man experienced several complex partial Our patients presented with anorgasmia, very likely, seizures, sometimes followed by secondary generali- as a direct effect of PGB add-on treatment. Indeed, sation. Neurological examination, as well as brain MRI, the onset and termination of anorgasmia was closely were normal. EEG revealed moderate slow activity related in time to the exposure to PGB, moreover, and epileptiform discharges over the right fronto- all other potential causes of sexual dysfunction were temporal region. The patient was started on OXC up ruled out. to 1,600/day, with improvement in his seizure con- PGB is a new AED licensed in Europe and US as adjunc- trol (2-4 seizures/month). However, as PGB was added, tive therapy for partial epilepsy and treatment for although the patient was nearly seizure-free, he pro- neuropathic pain in adults. It is structurally related to gressively started to complain of anorgasmia, which GBP and both drugs bind to the ␣ ␦ subunit of voltage- caused distress within the relationship and high levels 2 dependent calcium channels and, thereby, modulate of sexual dissatisfaction. Sexual history, psychologi- the release of a range of neurotransmitters (Sills, 2006). cal and urological evaluation, as well as blood tests Orgasm refers to the subjective experience of plea- (including hormonal levels), were unremarkable. Thus, sure associated with somatic phenomena occurring PGB was gradually withdrawn and LEV introduced, during ejaculation, such as the rhythmic contractions up to 2,000 mg/day, with a remarkable improvement of the genital and reproductive organs, cardiovas- in seizure control and complete restoration of the cular and respiratory changes, and the release of patient’s sexual performance at 18 months of follow- sexual tension. Interestingly, orgasm is achieved up. only in the expulsion phase of the ejaculation pro- cess when both sympathetic and parasympathetic Discussion cerebral tension-releasing processes occur together, due to the multifaceted neural networks between Although the use of serotoninergic drugs, including spinal and supraspinal (particularly hypothalamic) antidepressants and atypical antipsychotics, is a com- centres (Argiolas and Melis, 2003; Rowland et al., mon cause of situational anorgasmia in both men and 2010). Human sexual response involves a complex women, anorgasmia related to new AEDs has been interplay between many neurotransmitters including rarely reported (Serretti and Chiesa, 2011). Conversely, dopamine, serotonin, norepinephrine, acetylcholine, emerging evidence shows that GBP-related anorgas- ␥-aminobutyric acid, oxytocin, opioids, and nitric mia could be an overlooked and under-reported oxide, as well as neuromodulators. In particular, problem (Calabrò, 2011b). Since GBP and PGB are simi- whereas dopamine appears to promote sexual desire lar with regards to structure and mechanism of action, and arousal, serotonin has an inhibitory effect on it is also possible that PGB-induced SD may be under- sexuality, especially on orgasm (Argiolas and Melis, estimated. 2003). Because of the wide distribution of calcium To this end, Hitiris et al. (2006) reported the cases channels in the central and peripheral nervous sys- of ﬁve men who experienced mild-to-moderate erec- tems, it is likely that they control neuronal, and thus tile dysfunction for the ﬁrst time when treated sexual, function at many sites. Therefore, the inhibition with the new antiepileptic drug PGB as add-on of calcium currents induced by PGB (as well as by GBP) therapy. Notably, all patients were taking part in ran- may lead to a decrease in neurotransmitter release and domised clinical trials or open-label studies with attenuation of postsynaptic excitability. Since excita- the drug. Indeed, in the placebo-controlled trials tory transmission is necessary for sexual arousal and, of PGB in epilepsy patients, erectile dysfunction was consequently, for achieving orgasm, it is possible that reported by 11 (3.0%) men taking PGB and three (1.9%) PGB may exert a negative effect on sexuality by reduc- with placebo. Moreover, the same authors, in their ing central nervous system excitatory transmission (via interesting study,showed that erectile dysfunction was calcium channel inhibition) and by unbalancing the reported by 71 of a total of 2,428 male patients (around dopamine/serotonin ratio. 3%) who received the new AED across all PGB placebo- In conclusion, given that individuals with epilepsy controlled trials for all indications, whereas only 8 of may not spontaneously complain of sexual dysfunc- 1,099 male patients (0.7%) who received placebo expe- tion, physicians should always discuss sexual issues rienced erectile dysfunction. Sexual dysfunction was with their patients since sexual dysfunction, including not reported by female patients with epilepsy receiv- anorgasmia, related to AEDs may continue to be an ing treatment with PGB during the epilepsy trials. overlooked and underestimated problem, even with Interestingly, we have recently described a 35-year-old new AEDs.

360 Epileptic Disord, Vol. 15, No. 3, September 2013 Pregabalin-induced anorgasmia

Disclosures. Calabrò RS, Marino S, Bramanti P. Sexual and reproductive None of the authors has any conﬂict of interest or ﬁnancial sup- dysfunction associated with antiepileptic drug use in men port to disclose. with epilepsy. Expert Rev Neurother 2011; 11: 887-95. Clark JD, Elliott J. Gabapentin-induced anorgasmia. References Neurology 1999; 53: 2209. Coebergh JA, Waldinger MD. Reversible anorgasmia with Argiolas A, Melis MR. The neurophysiology of the sexual topiramate for migraine prophylaxis. J Neuropsychiatry Clin cycle. J Endocrinol Invest 2003; 26: 20-2. Neurosci 2012; 24: E30-1.

Calabrò RS. Sexual disorders related to new antiepileptic Hitiris N, Barrett JA, Brodie MJ. Erectile dysfunction asso- drugs: a need for more studies! Epilepsy Behav 2011a; 20: 734- ciated with pregabalin add-on treatment in patients with 5. partial seizures: ﬁve case reports. Epilepsy Behav 2006; 8: 418-21.

Calabrò RS. Gabapentin and sexual dysfunction: an Holtkamp M, Weissinger F, Meierkord H. Erectile dysfunction overlooked and underreported problem? Epilepsy Behav with topiramate. Epilepsia 2005; 46: 166-7. 2011b; 22: 818. Kaufman KR, Struck PJ. Gabapentin-induced sexual dysfunc- Calabrò RS, Bramanti P. Levetiracetam-induced sexual disor- tion. Epilepsy Behav 2011; 21: 324-6. ders. Seizure 2013; 22: 329. Rowland D, McMahon CG, Abdo C, et al. Disorders of orgasm Calabrò RS, Bramanti P, Italiano D, Ferlazzo E. Topiramate- and ejaculation in men.JSexMed2010; 7: 1668-86. induced erectile dysfunction. Epilepsy Behav 2009; 14: Serretti A, Chiesa A. Sexual side effects of pharmacologi- 560. cal treatment of psychiatric diseases. Clin Pharmacol Ther 2011; 89: 142-7. Calabrò RS, Ferlazzo E, Italiano D, Bramanti P. Dose- dependent oxcarbazepine related anorgasmia. Epilepsy Sills GJ. The mechanisms of action of gabapentin and prega- Behav 2010; 17: 287-8. balin. Curr Opin Pharmacol 2006; 6: 108-13.

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