Treatment of premature ejaculation with paroxetine hydrochloride

Transcription

1 with paroxetine hydrochloride CG McMahon 1 * and K Touma 1 1 Australian Centre for Sexual Health, St. Luke's Hospital, Sydney, Australia International Journal of Impotence Research (1999) 11, 241±246 ß 1999 Stockton Press All rights reserved /99 $ Aims of this study: To evaluate the ef cacy of chronic and `on demand' administration of paroxetine hydrochloride in the drug treatment of premature ejaculation (PE). Materials and methods: Ninty-four normally potent men, aged 18 ± 61 y (mean 39 y) with premature ejaculation were treated between January 1996 and March 1997, with oral paroxetine hydrochloride, a selective serotonin re-uptake inhibitor (SSRI). All men were either married or in a stable relationship. Sixty-four out of ninety-four men (Group A) were initially treated with paroxetine hydrochloride 20 mg administered once daily. Those men who responded with improved ejaculatory control within four weeks, were then treated with `on-demand' paroxetine hydrochloride (20 mg) administered 3 ± 4 h prior to planned intercourse. The remaining 33 out of 94 men (Group B) were initially treated with `on-demand' paroxetine hydrochloride 20 mg administered 3 ± 4 h prior to planned intercourse. Results: The mean pre-treatment ejaculatory latency time (ELT) of both group A and B was 0.4 min (range 0 ± 1 min) in 205 intercourses at a frequency of 0.4 intercourses PEr week. In group A after four weeks of daily administration of paroxetine, the mean ELT was 4.5 min (range 1- anejac.) in 761 intercourses at a frequency of 2.4 intercourses per week. Fifty-three out of sixty-one men in group A regarded their ejaculatory control as improved and were then treated with `ondemand' paroxetine, achieving an ELT of 3.9 min (range 0 ± 10) in 608 intercourses at a frequency of 2.6 intercourses per week. Thirty-six men in this group of 53 regarded that they had maintained improved ejaculatory control with a mean ELT of 5.5 min (range 2 ± 20 min) after a further four weeks of treatment (P < 0.001). The remaining 17 men reported a recurrence of poor ejaculatory control with a mean ELT of 0.7 min (range 0 ± 2 min). In group B with initial `on-demand' paroxetine after a mean of 4.5 weeks of treatment, the mean ELT was 1.5 min (range 0 ± 5 min) in 298 intercourses at a frequency of 2.2 intercourses per week. Adverse effects were only recorded in men taking daily paroxetine and included anejaculation in 5 out of 61, inhibited orgasm in 3 out of 61 and reduced libido on 3 out of 61. Erectile dysfunction was not reported and `on demand' paroxetine was not associated with any adverse effects. Conclusions: Paroxetine hydrochloride appears to be a useful agent in the pharmacological treatment of premature ejaculation when administered on a chronic, an `on-demand' basis following chronic treatment or initial `on demand' basis. Keywords: premature ejaculation; paroxetine; anti-depressant drugs Introduction *Correspondence: Dr CG McMahon, Australian Centre for Sexual Health, St. Luke's Hospital, Sydney, Australia. Received 26 August 1998; accepted in revised form 10 September 1999 Premature ejaculation (PE) is the most common male sexual disorder, affecting perhaps as many as 75% of men at some stage in their sexual lives. Premature ejaculation is invariably psychogenic due to performance anxiety, fear or psychological trauma and has historically been treated predominantly by psychosexual counselling. However, many men decline or fail to complete a trial of psychosexual counselling as treatment for PE for a variety of reasons. Men may decline treatment with psychosexual counselling as a result of their non-acceptance of counselling as a valid treatment due to incorrectly assumed social stigma associated with attending a psychiatrist or psychologist. Some men may be unable or not prepared to devote the time required to attend several counselling sessions. Other men may demand a quicker response than psychosexual counselling is reported to offer. Optimal results with psychosexual counselling are highly dependant on the cooperation of the sexual partner of the man in attending and actively participating in the counselling sessions. Many men do not have a current sexual partner or may have a non-compliant sexual partner. Clearly, a signi cant treatment `hiatus' exists in the management of PE which may be lled by alternate noncounselling treatment methods. Delayed ejaculation is a common adverse effect of many psychotropic and antidepressant drugs which

2 242 act centrally and=or locally to retard the psychoneurological control of ejaculation and subsequent orgasm. Animal studies have shown that the central neurotransmitter serotonin has an inhibitory effect on sexual function, while dopamine is generally stimulatory. 1 Sexual effects can occur through any shift in this serotonin-dopamine balance by an increase or decrease in either or both neurotransmitter. The serotonin re-uptake inhibitors (SSRI) should reduce sexual arousal and have a bene cial effect on premature ejaculation. There have been multiple reports in the literature regarding the sexual adverse effects of antidepressant drugs and their potential use as treatment for PE. Deveaugh-Geiss et al 2 in a multi-centre study reported failure of ejaculation in 42% of 520 men treated for depression with 200 mg chlomipramine=d. Monteiro et al 3 reported a double blind study which showed even greater sexual dysfunction in depressed men treated with chlomipramine, among 17 men, ejaculation was delayed in three and absent in 14. Girgis et al 4 and Althof et al 5 reported success in the actual treatment of PE with chlomipramine. Patterson 6 noted retarded or absent ejaculation in 45 out of 60 male men treated with 20 mg=d uoxetine for depression. Kara et al 7 in a double blind placebo controlled study of uoxetine demonstrated a seven fold increase in the ejaculatory interval which was noted as early as one week after initiation of treatment. Crenshaw 8 reported a dose related improvement in ejaculatory control in 46 men with uoxetine treatment of PE. He noted that some men maintained improved ejaculatory control after withdrawal of uoxetine after 3 ± 6 months of treatment. Waldinger et al, 9,10, Giammusso et al 11 and Ludovico et al 12 reported signi cant improvement in ejaculatory control with paroxetine. McMahon, 13 Swartz 14 and Mendels et al 15 have all reported a consistently bene cial effect of sertraline in the treatment of premature ejaculation. This paper reports the results of a prospective open label dose study of the ef cacy of paroxetine hydrochloride (Aropax 1, SmithKline Beecham International-Pharmaceuticals) administered chronically and `on-demand' in the treatment of PE. Materials and methods Ninety-four normally potent men suffering from PE were enrolled in a prospective study to assess the ef cacy and tolerance of paroxetine hydrochloride (Aropax 1 ) in the management of PE. All of the study group were heterosexual, had no other sexual disorders and were either married or in a stable relationship. Baseline pre-treatment ELT was determined as the mean of measurements at a minimum of two intercourses (mean 2.2, range 2 ± 3) prior to commencement of the study using a stop watch operated by the patient. All patients enrolled in the study had an ELT less than 1 min and were regarded as having severe PE. Premature ejaculation was regarded as ejaculation that occurred within 60 s of intromission. Men with erectile dysfunction, reduced sexual desire, inhibited male orgasm, chronic psychiatric or physical illness, alcohol or substance abuse and the use of medication, including psychotropic medication were excluded from the trial. Men were asked not to use condoms, topical penile anaesthetic creams or sprays. None of the men received any formal psychosexual counselling. Men in this study were enrolled into two groups, group A and group B. Men enroled in group A initially received paroxetine 20 mg daily for four weeks (Phase 1). Men in Group A who responded with improved ejaculatory control were then treated with a single dose of paroxetine (20 mg) administered `on demand' 3 ± 4 h prior to planned intercourse (Phase 2) for a further four weeks. Men enrolled in group B received only a single dose of paroxetine (20 mg) administered `on demand' 3 ± 4 h prior to all intercourses during a period of four weeks. Men were supplied with an ejaculation diary and were asked to record their frequency of coitus, quality of erection and orgasm, and to measure and record their ejaculatory latency time using a stopwatch. Men were required to attempt coitus on at least two occasions each week. Statistical analysis A Student's t-test was used to compare the ELT before and after treatment with paroxetine in Groups A and B Results The mean age of the 94 men studied was 39 y (range 18 ± 61 y). The mean pre-treatment ejaculatory latency time was 0.4 min (range 0 ± 1 min). The pretreatment frequency of intercourse was 0.4 times= week. Fifty- ve men (59%) had lifelong premature ejaculation, the remaining 39 men (41%) describing acquired premature ejaculation with previous acceptable ejaculatory control. Of the 55 men with lifelong premature ejaculation, 10 men (18%) had severe lifelong premature ejaculation and had never achieved intravaginal ejaculation. Group A comprised 61 men with a mean age of 40 y (range 22 ± 61), 37 men having lifelong PE and the remaining 24 having acquired PE. Group B comprised 33 men with a mean age of 37 y (range

3 18 ± 56), 18 men having lifelong PE and the remaining 15 having acquired PE. Both groups had the same mean pre-treatment ELT of 0.4 min (range 0 ± 1 min) and frequency of intercourse (0.4 times= week). In group A-phase 1,761 intercourses were recorded (Table 1). The mean ELT was 1.1 min after one week of treatment, 1.6 min after two weeks, 3.5 min at three weeks and 4.5 min at four weeks. The ELT was statistically superior to pre-study levels at 2, 3 and 4 weeks (all P < 0.001). The mean frequency of intercourse was 2.4 times=week. Fiftythree men in this group (87%) regarded their ejaculatory control as signi cantly better and had an ELT after four weeks of treatment of 5.1 min (range 2 ± 17 min) and a frequency of intercourse of 2.5 times=week. The remaining 8 out of 61 men regarded that they had not achieved improved control and had a mean ELT of 0.6 min (range 0 ± 2 min) at four weeks and a frequency of intercourse of 1.7 times=week. Lifelong PE was present in 6 men in the cohort of 8 who failed to respond to daily paroxetine. The ELT for the 53 out of 61 men who regarded their ejaculatory control as improved was statistically higher than the remaining 8 out of 61 men who thought that they had not achieved improved control (P < 0.001). Of the 53 men in group a who achieved improved ejaculatory control and continued with `on demand' paroxetine (Phase 2), 608 additional intercourses were recorded with a mean ELT of 3.9 min (range 0 ± 10) and a frequency of 2.6 times=week (Table 1) after a mean follow-up of 4.4 weeks of treatment, one patient was lost to follow up. Thirty-six men (69%) regarded that they had maintained improved ejaculatory control after four weeks of additional treatment with `on-demand' paroxetine, recording 391 intercourses with a mean ELT of 5.5 min (range 2 ± 10) and a frequency of 2.4 intercourses=week. The remaining 16 out of 53 men (31%) who regarded that they had failed to maintain improved ejaculatory control recorded 229 intercourses with a mean ELT of 0.6 min (range 0 ± 2 min) at four weeks and a frequency of 2.8 intercourses=week. Lifelong PE was present in 11 men in the cohort of 16 who failed to respond to `ondemand' paroxetine. The mean ELT for Group A overall was statistically greater than the pre-study Table 1 Results of treatment of premature ejaculation with chronic dosing and `on-demand' dosing with paroxetine (20 mg) n n Frequency Study group men intercourses intercourse ELT (min) Pre-Treatment Group A Ð Phase (20 mg) Group A Ð Phase (on demand 20 mg) Group B (on demand 20 mg) ELT (P < 0.001). The mean ELT for men in group Phase 1 and Phase 2 of group a were not statistically different. The ELT for the 36 out of 53 men who regarded that they had maintained improved ejaculatory control was statistically higher than the remaining 16 out of 53 men who felt that they had not maintained improved ejaculatory control (P < 0.001). In Group B, 298 intercourses were recorded with a mean ELT of 1.5 min (range 0 ± 5 min) and a frequency of 2.2 intercourses=week after a mean follow-up of 4.1 weeks of treatment (Table 1). This was statistically greater than the pre-treatment ELT (P < 0.05) and statistically less than the mean ELT for Group A-phase 2 (P < 0.001). Fourteen out of thirty-three men regarded their ejaculatory control as signi cantly better and these men had a mean ELT of 2.7 min (range 2 ± 5 min) and a frequency of 2.4 intercourses=week. This ELT was statistically superior to the pre-treatment interval (P < 0.05). The remaining 19 out of 33 men reported no change in ejaculatory control with a mean ELT of 0.4 min (range 0 ± 2 min) and a frequency of 2.0 intercourses=week. Lifelong PE was present in 15 men in the cohort of 19 who failed to respond to `on-demand' paroxetine. This ELT was not statistically superior to the pre-study ELT (P > 0.05). Intra-vaginal ejaculation was achieved for the rst time in 10 out of 10 men with severe lifelong premature ejaculation who had never previously achieved intra-vaginal ejaculation, including four men in Group B. The drug was, in general well tolerated. Most side effects were minor and only one patient withdrew from the study as a result of anejaculation. Drowsiness and anorexia occurred in 1 out of 61 men, minor gastrointestinal upset in 2 out of 61 men, reduced libido in 3 out of 61, inhibited orgasm despite achieving ejaculation in 3 out of 61 and anejaculation after prolonged intercourse in 5 out of 61 in Group A-Phase 1 (chronic dosing). The mean age of the ve men who experienced anejaculation was 26 y (range 19 ± 47) and their mean pre-treatment ELT was 0.9 min. Ejaculation was restored with a lesser dose of paroxetine [(5 mg (n ˆ 3), 10 mg (n ˆ 1)] in four men with a mean ELT of 18.4 min following dose titration. The remaining man remained unable to ejaculate despite reducing the dose to 5 mg and withdrew from the study. None of the men taking `on demand' paroxetine (Group A- Phase 2, Group B) reported an adverse effect including anejaculation (Table 2). Erectile dysfunction was not reported. Discussion Paroxetine has a relatively long half life of 24 h allowing once daily dosing. Peak plasma levels are 243

4 244 Table 2 Incidence of adverse effects in men treated for premature ejaculation with chronic dosing and `on-demand' dosing with paroxetine (20 mg). Some men experienced more than one adverse effect Adverse effect Group A Ð Phase 1 Group A Ð Phase 2 Group B Anorexia 1 Ð Ð Anejaculation 5 Ð Ð Gastointestinal upset 2 Ð Ð Drowsiness 1 Ð Ð Reduced libido 3 Ð Ð Inhibited orgasm 3 Ð Ð 12/61 (20%) 0/53 0/33 usually achieved within 2 ± 8 h with steady state systemic levels occurring after 7 ± 14 d. 16 It undergoes extensive rst pass metabolism principally to conjugates with glucuronic acid and sulphate which have no more than 1=50 the potency of their parent compound at inhibiting serotonin uptake. The only reported contraindication to use of paroxetine, apart from known hypersensitivity, is the concurrent use of monoamine oxidase inhibitors. Paroxetine selectively inhibits serotonin (5-HT) uptake in brain neurons, but unlike sertraline has little af nity for dopamine receptors and central b-adrenergic receptors. 17 The most common side effects are sexual and gastrointestinal but a very occasional patient will experience the agitation and tremor seen with uoxetine. Drug interactions with warfarin, tryptophan, dilantin have been reported. This study demonstrates that paroxetine prolongs the ejaculatory latency time when it is administered chronically or `on-demand'. Although this study did not employ an inventory of sexual satisfaction for either the men studied or their partners, the observed improved ejaculatory control and increased frequency of intercourse suggest improved sexual response and satisfaction. Delayed ejaculation and as a consequence, improved ejaculatory control, appears to occur within 1 ± 2 weeks of initiating treatment. This acute effect is due to paroxetine's direct blocking effect on central serotonergic re-uptake and cannot be attributed to a decrease in psychopathology since none of the men were clinically depressed. Furthermore, the antidepressant effect of paroxetine has not been reported to occur within 1 ± 2 weeks. It is possible that some of the improved ejaculatory control and any sustained long term improvement after withdrawal of paroxetine could be related to a reduction in performance anxiety due to improved patient= partner perceived sexual success. Paroxetine administered on a daily basis appears more ef cacious than `on-demand' paroxetine in the treatment of PE. Only 14 out of 33 men (42%) in group B treated with initial `on-demand' paroxetine (group B) achieved improved ejaculatory control as opposed to 53 out of 61 men (87%) in group A who were treated with daily paroxetine. In addition, the ELT of the latter (5.1 min) is statistically superior to the former (2.7 min) (P < 0.05). Clearly, paroxetine administered on a daily basis produces signi cantly better ejaculatory control in signi cantly more patients than does `on-demand' paroxetine. However, `on-demand' use of paroxetine appears more ef cacious after initial chronic dosing. of the 53 men in group A treated with `on-demand' paroxetine after initial daily administration for four weeks, 36 (68%) reported sustained ejaculatory control with an ELT of 5.5 min which was not signi cantly different from that achieved during the initial daily dosing phase (5.1 min). Overall, 59% of men in group a (36 out of 61) achieved and maintained improved ejaculatory control with treatment of PE with a combination of initial daily paroxetine followed by `on-demand' paroxetine. A failure to respond to paroxetine treatment in any form is more likely in men with lifelong PE. The observation that initial loading with paroxetine produces `ejaculatory recruitment' may be related to the non-linear pharmacokinetics of paroxetine. As a result of rstpass metabolism which is almost exclusively mediated by the P450 2D6 enzyme, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract. 18 ± 20 However, paroxetine is also a potent inhibitor of this enzyme, thereby effectively inhibiting it's own metabolism and demonstrating nonlinear pharmacokinetics. Therefore, as paroxetine concentration increases with multiple dosing, the P450 2D6 activity decreases thus prolonging drug clearance and resulting in a disproportionately greater increase in its concentration with every dose. 21 On the basis of these results, initial treatment with daily paroxetine for four weeks followed by a trial of `on-demand' paroxetine is the preferred approach in that it offers 59% of men improved ejaculatory control with minimal adverse effects. However, treatment `conversion' from daily to `ondemand' paroxetine may be associated with a recurrence of PE. in a signi cant number of those men who initially responded to daily paroxetine (32% in this study) prompting continuation of daily paroxetine. Patients should be informed of this risk if and when `conversion' to `on-demand' treatment is planned. Initial `on-demand' paroxetine although having no reported adverse effects, is effective in only 42% of men and is most appropriate in those men troubled by the adverse effects of daily paroxetine particularly anejaculation or retarded ejaculation. `On-demand' paroxetine has particular appeal in those men who have less severe PE, have intercourse infrequently and=or prefer to avoid taking daily medication. Paroxetine appears to be reasonably well tolerated by the men enrolled in this study although treatment with 20 mg paroxetine=d was associated

5 with anejaculation in 5 out of 61 (8%) men and inhibition of orgasm despite achieving ejaculation in 3 out of 61 (5%) men. One man who experienced anejaculation declined further treatment with paroxetine, the remaining 4 out of 5 men achieving ejaculation with a reduced dose of 5 ± 10 mg. These ve men had a mean pre-study ELT of 0.9 min which is higher than that the entire study group (0.4 min) and as such, one would expect a lesser incidence of anejaculation in men with more severe PE especially if lower doses were employed. The occurrence of anejaculation with sertraline, another member of the SSRI class of anti-depressants, has been reported as dose related. McMahon 22 reported that whilst all men in a study group of 46 treated with 25 mg sertraline=d managed to ejaculate during intercourse, 4 out of 46 (9%) men treated with 50 mg sertraline=d and 10 out of 46 men (22%) treated with 100 mg sertraline=d were unable to ejaculate after prolonged intercourse. No correlation has been reported between dose of paroxetine and it's antidepressant effect and the incidence of adverse effects. Crenshaw and Goldberg 23 reported that in their limited clinical experience, the incidence of retarded ejaculation in men treated with paroxetine for depression is dose related, mainly occurring above 20 mg. This parallels the experience of the authors and dose-response studies are currently being conducted. Eight of the 10 men with severe lifelong PE who achieved intravaginal ejaculation for the rst time in their sexual life with treatment with paroxetine, had previously undergone and failed to respond to one or more trials of treatment with psychosexual counselling. These men must be considered as suffering from severe and refractory PE, and previous treatment failures. Paroxetine drug treatment salvaged them from life long ejaculatory dysfunction and its relationship sequella. Conclusions Paroxetine appears to be a useful and reasonably well tolerated oral treatment for premature ejaculation with improved ejaculatory control usually occurring within 1 ± 2 weeks and subsequent increased frequency of intercourse. On demand administration of paroxetine improves ejaculatory control but appears more ef cacious after initial chronic dosing. References 2 Deveaugh-Geiss J, Landau P, Katz R. Preliminary results from a multicentre trial of chlomipramine in obsessive compulsive disorder. Psychopharmacol Bull 1989; 25: 36 ± Monteiro WO, Noshirvani HF, Marks IM, Elliott PT. Anorgasmia from chlomipramine in obsessive-compulsive disorder: A controlled trial. Br J Psychiatry 1987; 151: 107 ± Girgis SM, El-Haggar S, El-Hermouzy S. A double blind trial of chlomipramine in premature ejaculation. Andrologia 1982; 14: Althof S et al., The role of chlomipramine in the treatment of premature ejaculation. J Urol 1994; 151 (Suppl): 345A. 6 Patterson WM. Fluoxetine induced sexual dysfunction (Letter to the editor). J Clin Psychiatry 1993; 54: Kara H et al. The ef cacy of uoxetine in the treatment of premature ejaculation: A double-blind placebo controlled study. J Urol 1996; 156: 1631 ± Crenshaw R. with uoxetine. In: proceedings of American Psychiatric Association Meeting, May Waldinger MD, Hengeveld MW, Zwinderman AH. Paroxetine treatment of premature ejaculation: a double-blind randomized, placebo-controlled study. Am J Psychiatrus 1994; 151: Waldinger MD, Hengeveld MW, Zwinderman AH. Ejaculation-retarding properties of paroxetine in men with primary premature ejaculation: a double-blind, randomized, doseresponse study. Br J Urol 1997; 79: 592 ± Gammusso B, Morgia G, Spampinato A, Motta M. Paroxetine in the treatment of premature ejaculation Italian. Archivio Italiano di Urologia, Andrologia 1997; 69: 11 ± Ludovico GM et al., Paroxetine in the treatment of premature ejaculation. Br J Urol 1996; 77: 881 ± McMahon CG. with sertraline hydrochloride: A single-blind placebo controlled crossover study. J Urol 1998; 159: Swartz DA. Sertraline hydrochloride for premature ejaculation. J Urol 1994; 151 (Suppl): 345A. 15 Mendels J, Camera A, Sikes C. Sertraline treatment for premature ejaculation. J Clin Psychopharmacol 1995; 15: 341 ± Hiemke C. Paroxetine: pharmacokinetics and pharmacodynamics [German]. Fortschritte der Neurologie-Psychiatrie 1994; 62 (Suppl 1): 2 ± Koe BK, Lebel A, Burkhart CA, Schmidt AW. Sertraline: a potent inhibitor of ( )[ 3 H]3-PPP binding to brain sigma (o-) receptors. Soc Neurosci Abstracts: 19th Meeting 1989; 15: (Pt 2) Preskorn S. Targeted pharmacotherapy in depression management: comparative pharmacokinetics of uoxetine, paroxetine and sertraline. Int Clin Psychopharm 1994; Jn 9 (Suppl 3): 13 ± Bloomer JC et al. The role of cytochrome P450 2D6 in the metabolism of paroxetine by human liver microsomes. Br J Clin Pharmacol 1992; 33: 532 ± Preskorn S. Pharmacokinetics of anti-depressants: why and how they are relevant to treatment. J Clin Psychiatry 54 (Suppl 9): 14 ± Kaye CM et al. A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand 1991; 80 (Suppl.350): 60 ± McMahon CG. with sertraline. In: Proceedings of the V Asia Paci c Meeting in Impotence, Asia Paci c Society of Impotence Research. Perth WA, Australia, Crenshaw TL, Goldberg JP. Sexual Pharmacology Ð Drugs That Affect Sexual Function. WW Norton & Co.: New York, McIntosh TK, Bar eld RJ. Brain monoaminergic control of male reproductive behavior. II. Dopamine and the postejaculatory refractory period. Behav Brain Res 1984; 12: 267 ± 273.