Female Urology 144 ANDROLOGY Comparison of Dapoxetine /Tadalafil and Paroxetine/Tadalafil Combination Therapies for the Treatment of the Premature Ejaculation: A Randomized Clinical Trial Hamed Mohseni Rad1, Telma Zahirian Moghadam2, Ali Hosseinkhani3,* Nima Soluki4, Firouz Amani5 Purpose: The purpose of this study was to compare the effectiveness of Dapoxetine, and Paroxetine as well as Dapoxetine/Tadalafil and Paroxetine/Tadalafil combinational therapies, for the treatment of patients with prema- ture ejaculation. Materials and Methods: In this clinical trial study, 120 patients with premature ejaculation were randomly divided into 4 groups: The first group was treated with Paroxetine (Pa), while the second group received Dapoxetine(Da). The third group received Paroxetine combined with Tadalafil(PT) whereas the fourth group's treatment involved the use of Dapoxetine and Tadalafil(DT) for one month. In the next 2 and 4 weeks, the cases were evaluated in terms of ejaculation duration, frequency of intercourse per week, and drug side effects. Results: The mean age of the Da, Pa, PT, DT groups was 32 ± 6.9, 32.4 ± 7.2, 31.6 ± 1.9, and 32.9 ± 7.7 years, respectively. There was a significant difference between the Da and DT groups (p = .029) in the ejaculation latency in the 4-week follow-up. In the two weeks follow-up, a significant difference was observed between DA and DT (p = 0.043), Pa and PT (p = 0.006), and Pa and DT groups (p = 0.004) in terms of ejaculation latency. Four weeks after the intervention, a significant difference was detected in the intercourse frequency of Da and PT groups (p =0.033), Pa and PT groups (p = 0.043), Pa and DT groups (p = 0.02), and Da and DT groups (p = 0.016). Conclusion: Combination therapy (Tadalafil plus Paroxetine or Dapoxetine) was more effective in IELT (Intra ejaculation latency time) than mono-therapy especially in younger patients despite its slightly more side effects. Keywords: dapoxetine; paroxetine; premature ejaculation; tadalafil; treatment 1Department of Surgery, School of Medicine, Imam Reza Hospital, Ardabil University of Medical Sciences, Iran. 2Social Determinants of Health Research Center, Ardabil University of Medical Sciences, Iran. 3Department of Surgery, School of Medicine, Imam Reza Hospital, Ardabil University of Medical Sciences, Iran 4Department of Surgery, School of Medicine, Imam Reza Hospital, Ardabil University of Medical Sciences, Iran. 5School of Medicine, Ardabil University of Medical Sciences, Iran. *Correspondence: Department of Surgery, School of Medicine and Allied Medical Sciences, Imam Reza Hospital, Ardabil University of Medical Sciences, Ardabil, Iran. E-mail: sirhamed2@gmail.com. Received January 2021 & Accepted November 2021 INTRODUCTION The average time to reach orgasm in men is 4 min-utes (1,2). In most sources, premature ejaculation re- fers to cases in which ejaculation occurs in less than one minute from the onset of intercourse. Some others con- sider ejaculation sooner than two minutes as abnormal and premature ejaculation. It should be noted that this definition is limited to intercourses through the vagina (3,4). According to the statistics, premature ejaculation af- fects more than one-third of men. The rate of prema- ture ejaculation is 31% in the United States and 66% in Germany(3). Extensive studies on the anatomy of animal nerves and neuropharmacology have concluded that different regions control ejaculation rate through neuro- transmitters such as serotonin and dopamine(5,6). Dapoxetine is one of the specific serotonin reuptake inhibitors (SSRIs) on the market that has no place in the treatment of depression. Thanks to its unique for- mulation and kinetics with rapid effect and short half- life, it could be applied in the treatment of premature ejaculation on-demand. Paroxetine has been also used in various studies to treat premature ejaculation(7,8). The duration of erection seems to be one of the main con- cerns of patients with premature ejaculation(9,10). PDE5 inhibitor (Tadalafil) is the gold standard first-line treat- ment for erectile dysfunction capable of prolonging the ejaculation duration(11,12). However, some studies prefer single-drug therapy due to the high side effects of com- bination drugs(6,13). MATERIALS AND METHODS Study Population In this parallel clinical trial study, 120 patients with premature ejaculation referring to the urology clinic in Imam Reza Hospital, Ardabil, Iran were selected. These patients were selected from those with the complaint of premature ejaculation. The subjects were married with the age range of 20-50. All the selected patients had IELT (Intra ejaculation latency time) of less than 2 minutes. They had sexual intercourse at least once a week. The sample size was calculated to be equal to 120 items using G * Power 3.1.9.2 software considering the alpha and study power values of 0.05 and 0.8 for each group and with an effect size of 0.7, respectively. Urology Journal/Vol 19 No. 2/ March-April 2022/ pp. 138-143. [DOI: 10.22037/uj.v18i.6644] Vol 19 No 2 March-April 2022 100 Patients were selected by simple sampling and entered into study groups by distributing cards in four colors each assigned to one drug group. The study addressed 4 groups and each group consisted of 30 people. These four colors were written on four separate papers and the papers were placed inside a black bag. The participants were asked to pick up one piece of paper. Inclusion and exclusion criteria Exclusion criteria were having an underlying disease including diabetes, heart disease, high blood pressure, thyroid disease, sexually transmitted diseases, psychi- atric illnesses treated with any psychiatric medication, and erectile dysfunction. Patients who did not tolerate the side effects of drugs were also excluded from the study Procedures Data were collected using a designed checklist. No pla- cebo was used in this study and all treatment groups were according to the guidelines for premature ejacula- tion treatment, thus no blinding was performed in this study. Patients were randomly divided into 4 groups: All groups followed a one-month treatment period. The first group (control) received Dapoxetine 30 mg tab- lets (Shafa Pharmaceutical Company) orally one hour before sexual intercourse. The second group received Paroxetine 20 mg tablets (Tehran Shimi Company) orally once a day. The third group received Paroxetine 20 mg tablets (Tehran Shimi Company) orally once a day combined with Tadalafil 10 mg tablets (Rozdaro Pharmaceutical Company) orally one hour before sex- ual intercourse. The fourth group used Dapoxetine 30 mg tablets (Shafa Pharmaceutical Company) and 10 mg Tadalafil tablets (Rosedaro Pharmaceutical Company) orally one hour prior to sexual intercourse. Patients' in- formation including their age, IELT, and intercourses frequency in a week were recorded in researcher-made checklists before treatment. Patients were contacted by the researcher for follow-up in the second and fourth weeks after treatment. The checklists including IELT, drug side effects (headache, hot flashes, sleep distur- bance, nausea, vomiting, dizziness, and fatigue), and the number of intercourses per week were studied. Evaluations The conditions of the study were fully explained to the patients and they consciously signed a written consent form to participate in the study. Patients completely voluntarily took part in the study and they were assured that could leave the study at any time. Their information was strictly kept confidential and recorded without their name or address. The study procedure was approved by the Ethics committee of Ardabil University of medical sciences (NO: IR.ARUMS.REC.1398.315) with IRCT NO (20190528043747n1) and adhered to the tenets of the declaration of Helsinki. Statistical Analysis The collected data were encoded in SPSS software ver- sion 21 using descriptive-analytical statistical methods as number, percentage, and mean values. Various sta- tistical tests such as ANOVA and Tukey’s post hoc test were applied to compare the two groups while the chi- square test was employed to examine their relationship. Concerning the side effects, different drugs were sepa- rately analyzed at different times. RESULTS In this study, patients in the four groups did not signif- icantly differ in terms of age (P > .05). The mean age of members of the Dapoxetine, Paroxetine, Paroxetine/ Tadalafil, and Dapoxetine/Tadalafil groups was 32 ± 6.9, 32.4 ± 7.2, 31.1 ± 6.9, and 32.9 ± 7.7 years, re- spectively. The four treatment regimes caused a signif- icantly different effect on the ejaculation latency. The latency time for first, second, third, and fourth groups after 4-week treatment were 204.4 ± 82, 208.8 ± 65.1, 269.9 ± 100.4, and 259.3 ± 83.4 s, respectively. Table 1. Comparison of ejaculation time (IELT) and number of sexual intercourses per week Based on Table 1, two and four weeks after the inter- vention, the latency time increased in all groups, how- ever, the longest ejaculation latency was observed in the third group (Dapoxetine combined with Tadalafil). Us- ing the Tukey test for the dual study of the groups four weeks after the intervention, a significant difference was found between Da and DT groups (P = .029), while the other groups did not show a significant difference. Even two-week treatment by Tadalafil in these groups significantly prolonged the latency time (Comparing Da with DT (P = .043), Pa with PT (P = .006), and Pa with DT (P = .004)). The effects of Dapoxetine, Paroxe- tine, Dapoxetine/Tadalafil, and Paroxetine/Tadalafilon on premature ejaculation were different in terms of the weekly frequency of intercourse. Regarding the weekly frequency of intercourse, there was a significant difference between the groups in the two-week and four-week follow-ups. Two weeks after the intervention, the mean frequency of intercourse per week was slightly higher in the PT group compared to Treatment of premature ejaculation- Mohseni Rad et al. Time groups ejaculation time P-value number of relationships P-value per week (Sex Frequency) Before the intervention Dapoxetine 57.8 ± 34.2 0.9 2.04 ± 0.85 0.9 Paroxetine 59.4 ± 32 2.08 ± 1 Dapoxetine + Tadalafil 56.1 ± 31 2 ± 0.8 Paroxetine + Tadalafil 54.6 ± 30.9 1.93 ± 0.8 Two weeks after the intervention Dapoxetine 166.7 ± 67.3 0.001 2.1 ± 0.8 0.036 Paroxetine 146.4 ± 69.5 2.1 ± 1 Dapoxetine + Tadalafil 230 ± 112.6 2.63 ± 0.8 Paroxetine + Tadalafil 227.1 ± 90 2.64 ± 0.9 Four weeks after the intervention Dapoxetine 204.4 ± 82 0.007 2.2 ± 0.8 0.002 Paroxetine 208.8 ± 65.1 2.2 ± 0.7 Dapoxetine + Tadalafil 269.9 ± 100.4 2.9 ± 0.9 Paroxetine + Tadalafil 259.3 ± 83.4 2.8 ± 0.9 Table 1. Comparison of ejaculation time and number of relationships per week (Sex Frequency in the studied groups at different times Vol 19 No 2 March-April 2022 139 Andrology 140 the others. Four weeks after the intervention, groups treated with Tadalafil plus arms exhibited statistical- ly significant more intercourse frequencies, although the mean frequency of intercourses in the DT and PT groups was almost the same. Using the Tukey test, the results of binary comparison of the groups in the four- week follow-ups showed significant differences among the groups regarding intercourse frequency (Da and PT (P =.033), Pa and PT (P = .043), Pa and DT (P = .022), Da and DT (P = .016)). Table 2. Comparison of the drugs in terms of complica- tions two and four weeks post-intervention. The mentioned treatments caused significantly differ- ent side effects. According to Table 2, two weeks after the intervention, there was a significant difference in complications such as headache and hot flashes, but no significant difference was detected between the groups in terms of other side effects. PT and DT groups with 10 cases of headache and 5 cases of hot flashes had the most complications. The groups were significantly different in terms of hot flashes and sleep problems after four weeks of interven- tion. Regarding hot flashes, 5 people in each of the PT and DT groups had the most complications. Concerning sleep disorders, the most complications were in the PT and DT groups with 12 people in each group. The effects of dapoxetine, paroxetine, dapoxetine/tada- lafil, and paroxetine/tadalafil in the treatment of pa- tients with early ejaculation are significantly different based on the patients’ age. Table 3. Comparison of IELT medicinal based on the age group According to Table 3, after two and four weeks of the medical intervention in the age groups of 20-30, there was a significant difference between the drug groups in terms of ejaculation latency. Two and four weeks post-intervention, the combined DT group had a longer IELT duration with average values of 240.5 ± 117 and 286.112 ± 2.7 s, which was significantly different from the other groups. No significant difference was observed between the groups in the age group of 31-40 and 41-50 in terms of (IELT) two and four weeks after the intervention as compared to the condition before the intervention. DISCUSSION Our study showed that adding Tadalafil to Paroxetine or Dapoxetine fortifies ejaculation latency time. Zhang X et al. compared the combination therapy of silde- nafil and sertraline versus sertraline monotherapy for the treatment of premature ejaculation. They showed that combination therapy was more efficient than mo- no-therapy with fewer side effects(14). However, in our study combination therapy exhibited a mild increment of headache and hot flashes. Premature ejaculation has a prevalence of 20-30 % in the male population. Tadalafil may be efficient in improv- ing (IELT) even in combination with the pause-squeeze technique or glandular local anesthesia. Dell'Atti L et al. compared Tadalafil with local anesthetics and re- ported the efficacy and tolerability of Tadalafil in pre- mature ejaculation(15). Our study did not show a considerable difference in efficacy or side effects of Dapoxetine and Paroxetine. However, Jern P. et al. reported a higher rate of discon- tinuation for Dapoxetine compared to Paroxetine. Par- oxetine was more effective and tolerable than Dapox- etine(16). Moudi E et al. compared Tadalafil plus Paroxetine with Paroxetine only in the treatment of premature ejacula- tion. They showed that Tadalafil could moderately in- crease intravaginal ejaculation latency time (IELT) and might be used to treat premature ejaculation in com- bination with Paroxetine(1). This confirms our results that a combination of SSRI and PDE5 inhibitors could outperform monotherapy for the treatment of premature ejaculation. In the study of Muhammad Abu al-Hamd, the combination of Sildenafil plus Dapoxetine led to the best response(17). In a meta-analysis, Martyn-St James M et al. reported that although monotherapy by SSRI and PDE-5 inhibi- tors did not cause much difference in latency time, their combination therapy can make a significant difference (18). ANOVA test was applied to compare the IELT of the four groups. The results showed that before the interven- tion, the groups were the same in terms of ejaculation time. Two and four weeks later, dapoxetine/Tadalafil and paroxetine/Tadalafil groups exhibited significant- ly longer ejaculation latency time than the two groups of dapoxetine and paroxetine groups with the longest belonging to the dapoxetine/Tadalafil group. These re- sults indicate that combination therapies of Dapoxetine/ Tadalafilor and Paroxetine/Tadalafil had more effect on increasing ejaculation latency time in patients with premature ejaculation rather than single Dapoxetine or Paroxetine. In a clinical trial by McMahon et al., the use of Dapox- etine 1 to 2 hours before intercourse at doses of 30 mg and 60 mg enhanced the ejaculation latency by 2.5 and 3 times, respectively(19). Pryor et al. also reported that Table 2. The testis weight of mice in different treated groups and control after treatment complications First group second group Third group Fourth group dapoxetine paroxetine dapoxetine+tadalafil paroxetine+tadalafil two weeks after four weeks after two weeks after four weeks two weeks four weeks two weeks four weeks treatment treatment treatment after treatment after treatment after treatment after treatment after treatment Headache 11.1 11.1 12 16 38 37 35.7 35.7 Flushing 0 0 0 0 18.5 18.5 17.9 17.9 sleep disorder 7.4 11.1 12 16 14.8 44.4 17.9 42.9 nausea 11.1 11.1 16 12 22.2 25.9 28.6 32.1 Vomit 0 0 0 8 3.7 3.7 3.6 0 Vertigo 7.4 7.4 0 0 3.7 3.7 14.3 10.7 Fatigue 7.4 7.4 0 0 0 0 0 3.6 Treatment of premature ejaculation- Mohseni Rad et al. Vol 19 No 2 March-April 2022 100 receiving Dapoxetine 1 to 2 hours before intercourse caused more control over ejaculation, reduced stress, and increased satisfaction(20). Dapoxetine was effec- tive in both sustained and acquired premature ejacu- lation(21-23). In 2018, Li et al. conducted a meta-analy- sis study addressing the effects of Dapoxetine on the treatment of premature ejaculation, they concluded that doses of 30 mg and 60 mg were more effective than placebo for ejaculation latency time(24). In some studies, Paroxetine incremented mean IELT from 0-1 minute to an average of 4.5 minutes after 4-week treatment which was raised to 5.5 minutes after another 4-week therapy(25-27). On the contrary, some studies reported no difference between the combined treatment of Paroxetine-Tada- lafil compared with Paroxetine. They showed that the mean IELT after 3 months and even 6-month of treat- ment were not significantly different(28-30). So it seems that combination therapy has not been regarded as a standard treatment for premature ejaculation yet. However, Polat EC et al. showed that the use of com- bination therapy with serotonin re-uptake inhibi- tors (SSRI) and phosphodiesterase type 5 inhibitors (PDE5-inhibitors) (combination therapy of Paroxetine + Tadalafil) can lead to a significantly better effect on increasing IELT than the single use of these drugs(31). In the present study, the combined groups exhibited a greater increase in ejaculation latency time than the single therapy groups. Concerning the frequency of intercourse per week, there was no difference between the groups. Two and four weeks after the intervention, however, the frequency of intercourses significantly increased. The Dapoxetine/Tadalafil and Paroxetine/ Tadalafil groups sowed almost at the same conditions in terms of the average frequency of intercourses per week; they exhibited, however, significantly higher intercourse frequency compared to Dapoxetine and Paroxetine groups. The combination therapy groups had longer ejaculation times, leading to more sexual satisfaction and desire compared to single drug groups which raised the intercourse frequency(32,33). Side effects of Dapoxetine include nausea and vomit- ing, diarrhea, dizziness, headache, and insomnia. Side effects of Paroxetine have been reported as the inability to ejaculate, and a decreased libido(31,34). In this study, common side effects were headaches and hot flashes that were more common in Tadalafil plus groups. Other side effects were sleep disorders, nausea, vom- iting, dizziness, and fatigue. The results indicated that two weeks after the intervention, there was a significant difference between the groups in terms of headache and hot flashes. However, no significant difference was found between the groups concerning other complica- tions. These side effects were greater in the Dapoxe- tine/Tadalafil and Paroxetine/Tadalafil groups than the Dapoxetine and Paroxetine groups. After 4 weeks, hot flashes and sleep problems were significantly more common. Younger patients showed better responses to prema- ture ejaculation treatment. In the age group of 20-30, Dapoxetine/Tadalafil had the greatest effect on the (IELT), but there was no significant difference in the (IELT) after the intervention compared to the start of the intervention the age groups of 31-40 and 41-50. According to the results of this study, more studies are recommended on the treatment of premature ejacula- tion with the combination therapy of dapoxetine/tada- lafil and paroxetine/ tadalafil with a larger sample size and longer follow-up period. The sample size of this study was about 26 people in each group. It seems that more sample size could raise the accuracy of the results. Another limitation of the present study was the lack of control over the correct use of prescribed drugs during treatment, which may disturb the results. Satisfaction of individuals who can determine the outcome of drug tolerance and the effect of treatment was not examined in this study, which is another limitation of this study. CONCLUSIONS Combination therapy (Tadalafilpl us Paroxetine or Dapoxetine) is more effective in IELT than monothera- py especially in younger patients although it may cause slightly more side effects. ACKNOWLEDGEMENT The authors trully appreciate managers and staffs of the Imam Reza Hospital in Ardabil, for their contribution in the research. CONFLICT OF INTEREST The authors report no conflicts of interest. REFERENCES 1. Moudi E, Kasaeeyan AA. Comparison between tadalafil plus paroxetine and paroxetine alone in the treatment of premature ejaculation. NU monthly. 2016;27:32-48. 2. Mirone V, Arcaniolo D, Rivas D, et al. Results from a prospective observational study of Table 3. The mean serum testosterone, FSH and LH levels in different treated groups and control after treatment. time to study drug group age group of 20-30 P-value age group 31-40 P-value age group 41-50 P-value before the intervention dapoxetine 53.07 ± 23.4 0.7 61.4 ± 43.2 0.9 65 ± 48.2 0.9 paroxetine 58.8 ± 32.94 54.4 ± 34.9 69 ± 29.2 paroxetine + tadalafil 47.1 ± 24.1 63 ± 35.2 60 ± 42.4 dapoxetine + tadalafil 49.6 ± 23.2 51.7 ± 31.02 81 ± 41.9 two weeks after the intervention dapoxetine 161.5 ± 66.6 0.009 174.6 ± 78.02 0.7 160 ± 34.6 0.3 paroxetine 125 ± 54 142.5 ± 55 204 ± 100.4 paroxetine + tadalafil 210 ± 93.4 240 ± 93.8 255 ± 75.5 dapoxetine + tadalafil 240 ± 117.5 176.7 ± 77.1 300 ± 127.3 four weeks after the intervention dapoxetine 184.6 ± 71.3 0.006 212.7 ± 94.3 0.14 260 ± 69.3 0.5 paroxetine 185 ± 40.1 180 ± 45.4 312 ± 26.8 paroxetine + tadalafil 235.7 ± 76.1 270 ± 90.6 315 ± 75.5 dapoxetine + tadalafil 286.2 ± 112.7 213.3 ± 74.2 324 ± 68.4 Treatment of premature ejaculation- Mohseni Rad et al. Vol 19 No 2 March-April 2022 141 Andrology 142 men with premature ejaculation treated with dapoxetine or alternative care: the PAUSE study. Eur Urol. 2014;1:733-9. 3. Reza KB, Safarinezhad M. A survey of prevalence of sexual disorders and risk factors in patient who referred in urology ward in 501 hospital 2004-05. Ann Mil Health Sci Res. 2007;4:1041-5. 4. Tanagho EA, McAninch JW. Smith's general urology. McGraw Hill. 2008;1:345-9 5. Sangkum P, Badr R, Serefoglu EC, et al. Dapoxetine and the treatment of premature ejaculation. Transl Androl Urol. 2013;2:301- 11. 6. Montorsi F, Adaikan G, Becher E, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med. 2010;7:3572- 88. 7. Waldinger MD, Schweitzer DH. The use of old and recent DSM definitions of premature ejaculation in observational studies: A contribution to the present debate for a new classification of PE in the DSM‐V. J Sex Med. 2008;5:1079-87. 8. Buvat J. Pathophysiology of premature ejaculation. J Sex Med.. 2011;8:316-27. 9. Yang X, Gao M, Zhang L, et al. Central neural correlates during inhibitory control in lifelong premature ejaculation patients. Front Hum Neurosci. 2018;12:206-15. 10. Peeters M, Giuliano F. Central neurophysiology and dopaminergic control of ejaculation. Neurosci Biobehav Rev. 2008;32:438-53. 11. Corona G, Mannucci E, Jannini EA, et al. Original research–endocrinology: Hypoprolactinemia: A New Clinical Syndrome in Patients with Sexual Dysfunction. J Sex Med. 2009;6:1457-66. 12. Patrick DL, Rowland D, Rothman M. Ejaculatory Disorders: Interrelationships Among Measures of Premature Ejaculation: The Central Role of Perceived Control. J Sex Med. 2007;4:780-8. 13. Paço JS, Pereira BJ. New therapeutic perspectives in premature ejaculation. Urology. 2016;88:87-92. 14. Zhang X, Tang D, Yang J, et al. Combination of sertraline and sildenafil versus sertraline monotherapy in the treatment of acquired premature ejaculation without concomitant diseases. Andrology. 2014;3:2167-250. 15. Dell'Atti L, Galosi AB, Ippolito C. A randomized single-center study to compare the efficacy and tolerability of tadalafil once daily plus lidocaine anesthetic spray on premature ejaculation. Eur Rev Med Pharmacol Sci. 2017;21:1036-40. 16. Jern P, Johansson A, Piha J, et al. Antidepressant treatment of premature ejaculation: discontinuation rates and prevalence of side effects for dapoxetine and paroxetine in a naturalistic setting. Int J Impot Res. 2015;27:75-80. 17. Abu El‐Hamd M, Abdelhamed A. Comparison of the clinical efficacy and safety of the on‐demand use of paroxetine, dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients with premature ejaculation: A randomised placebo‐controlled clinical trial. Andrologia. 2018;50:128-39. 18. Martyn-St James M, Cooper K, Ren S, et.al. Phosphodiesterase type 5 inhibitors for premature ejaculation: a systematic review and meta-analysis. Eur Urol Focus. 2017;3:119- 29. 19. McMahon CG, Althof SE, Kaufman JM, et.al. Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials. J Sex Med. 2011;8:524-39. 20. Pryor JL, Althof SE, Steidle C, et.al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet. 2006;368:929-37. 21. Giuliano F, Patrick DL, Porst H, et al. Premature ejaculation: results from a five- country European observational study. Eur Urol. 2008;53:1048-57. 22. Castiglione F, Albersen M, Hedlund P, et al. Current pharmacological management of premature ejaculation: a systematic review and meta-analysis. Eur Urol. 2016;69: 904-16. 23. Safarinejad MR. Comparison of dapoxetine versus paroxetine in patients with premature ejaculation: a double-blind, placebo- controlled, fixed-dose, randomized study. Clin Neuropharmacol. 2006;29:243-52. 24. Li J, Liu D, Wu J, et al. Dapoxetine for the treatment of premature ejaculation: a meta- analysis of randomized controlled trials with trial sequential analysis. Ann Saudi Med. 2018;38:366-75. 25. McMAHON CG, Touma K. Treatment of premature ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo controlled crossover studies. Urol. 1999;161:1826-30. 26. AkgÃl T, Karakan T, Ayyildiz A, et al. Comparison of sertraline and citalopram for treatment of premature ejaculation. Urol. 2009;5:41-5. 27. Simsek A, Kirecci SL, Kucuktopcu O, et al. Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation. Asian J. Androl. 2014;16:700-25. 28. Moudi E, Kasaeeyan AA. Comparison between tadalafil plus paroxetine and paroxetine alone in the treatment of premature ejaculation. NU monthly. 2016;8:234-45. 29. Hutchinson K, Cruickshank K, Wylie K. A benefit-risk assessment of dapoxetine in the treatment of premature ejaculation. Drug Saf. 2012;35:359-72. 30. McMahon CG. Dapoxetine: a new option in the medical management of premature ejaculation. Ther Adv Urol. 2012;4:233-51. 31. Polat EC, Ozbek E, Otunctemur A, et al. Combination therapy with selective serotonin reuptake inhibitors and phosphodiesterase‐5 inhibitors in the treatment of premature ejaculation. Andrologia. 2015;47:487-92. Treatment of premature ejaculation- Mohseni Rad et al. Vol 19 No 2 March-April 2022 100 32. Gameel TA, Tawfik AM, Abou-Farha MO, et al. On-demand use of tramadol, sildenafil, paroxetine and local anaesthetics for the management of premature ejaculation: a randomised placebo-controlled clinical trial. Arab J Urol. 2013;11:392-7. 33. Lee WK, Lee SH, Cho ST, et al. Comparison between on‐demand dosing of dapoxetine alone and dapoxetine plus mirodenafil in patients with lifelong premature ejaculation: Prospective, randomized, double‐blind, placebo‐controlled, multicenter study. J Sex Med. 2013;10:2832-41. 34. F Lasker G, Halis F, Gokce A. Selective serotonin reuptake inhibitors for premature ejaculation: review of erectile and ejaculatory side effects. Curr. Drug Saf. 2014;9:118-26. Treatment of premature ejaculation- Mohseni Rad et al. Vol 19 No 2 March-April 2022 143