Accepted: 6 February 2018

DOI: 10.1111/and.13005

ORIGINAL ARTICLE

Efficacy and safety of daily use of tadalafil in treatment

of patients with premature ejaculation: A randomised ­
placebo-­controlled clinical trial

M. Abu El-Hamd

Department of Dermatology, Venereology

and Andrology, Faculty of Medicine, Sohag Summary
University, Sohag, Egypt The study aimed to evaluate the efficacy and safety of the once-­daily use of 5 mg
Correspondence tadalafil in the treatment of patients with premature ejaculation (PE). In a single-­blind
Mohammed Abu El-Hamd, Department of placebo-­controlled clinical study, it was carried out on 100 patients with PE. All pa-
Dermatology, Venereology and Andrology,
Faculty of Medicine, Sohag University, tients were randomised equally divided into two groups (50 patients each). Group 1
Sohag, Egypt. was given placebo in the form of oral multivitamin tablet once a day for 6 weeks.
Email: [email protected]
Group 2 was given 5 mg tadalafil once a day for 6 weeks. All patients were asked to
complete Arabic Index of Premature Ejaculation (AIPE) before and after the treat-
ment. This study showed that there were no statistically significant differences be-
tween patients in the placebo and tadalafil groups regarding the mean values of the
seven questions and total scores of the AIPE questionnaire before treatment (p value
>.05). The mean values of the seven questions and total scores of AIPE questionnaire
in the tadalafil group were significantly higher than the placebo group after treat-
ment (p value = .001). This study concluded that once-­daily use of 5 mg tadalafil for
6 weeks was effective and well tolerated in the treatment of patients with PE.

KEYWORDS
PDE5 inhibitors, premature ejaculation, sildenafil, tadalafil

1 | I NTRO D U C TI O N dysfunction (ED) (Jannini, Lombardo, & Lenzi, 2005) and prostatitis
(Screponi et al., 2001).
Premature ejaculation (PE) is one of the most common male sexual The main therapies for PE include a behavioural/psychotherapy,
dysfunctions with a prevalence of 9%–30% (Karabakan et al., 2016; a pharmacotherapy and a combination of these therapies. The main
Porst et al., 2007). PE can be classified into two types, either primary drugs are selective serotonin reuptake inhibitors (SSRIs) (e.g., dapox-
or secondary (Althof et al., 2014). etine, paroxetine, citalopram, sertraline or fluoxetine), phosphodies-
The aetiology of PE is still obscure, but it can be divided into psy- terase type 5 inhibitors (PDE5 inhibitors) (sildenafil and vardenafil)
chogenic causes such as performance anxiety (Schapiro, 1943) and and topical desensitising agents (prilocaine or lidocaine) (Althof et al.,
organic causes as hypersensitivity of the glans penis (Xin, Choi, Rha, 2014; Castiglione et al., 2016).
& Choi, 1997), genetic factors (Jern et al., 2009), central serotonergic Several studies have been found that on-­demand use PDE5 inhibitors
neurotransmission disturbance (Waldinger, Berendsen, Blok, Olivier, was effective in the treatment of PE (Aversa et al., 2009; Mathers, Klotz,
& Holstege, 1998), thyroid disorders (Carani et al., 2005), erectile Roth, Lummen, & Sommer, 2009; Mattos, Marmo Lucon, & Srougi, 2008).

Andrologia. 2018;e13005. wileyonlinelibrary.com/journal/and © 2018 Blackwell Verlag GmbH | 1 of 5

https://doi.org/10.1111/and.13005
2 of 5 | ABU EL-HAMD

This study evaluated the efficacy and safety of the once-­daily PE. Response to each question was scored on a scale from 1 to 5.
use of 5 mg tadalafil in the treatment of patients with PE. Patients were scored as follows: those with scores 7–13 were con-
sidered as severe PE; those with scores 14–19 were considered as
moderate PE; those with scores 20–25 as mild–moderate PE; those
2 | PATI E NT S A N D M E TH O DS with scores 26–30 as mild PE; and those with scores 31–35 as not
having PE (Arafa & Shamloul, 2007). All patients were instructed to
In a single-­blind placebo-­controlled clinical study, it was carried out enlist any adverse effects after drug administration.
on 100 patients with PE. Those patients were selected from whom
seeking medical advice at the outpatient clinics of Andrology at
2.1 | Statistical analysis
Sohag University Hospital, Sohag, Upper Egypt, between March
2016 and September 2017. An informed consent was obtained from Statistical analysis was carried out using Statistical Analysis
all patients after full explanation of the benefits and possible side Software version 16 (SAS Institute, Inc., Cary, NC, USA). Data
effects from this research. All patients were undergoing preliminary were recorded as a mean ± SD and/or number (percentage) where
assessment included a complete medical and sexual history, fol- appropriate. Independent t test was used for comparison between
lowed by a general and genital examination. the study groups. p-­value of ≤.05 was considered statistically
Patients were considered to have PE if fulfilled the criteria of the significant.
International Society for Sexual Medicine that defined PE as a male
sexual dysfunction characterised by (i) ejaculation which always or
nearly always occurs prior to or within 1 minute of vaginal penetra- 3 | R E S U LT S
tion, either present from the first sexual experience or following a
new bothersome change in ejaculatory latency; (ii) inability to delay The mean age of all patients (n = 100) was 34.59 ± 5.93 years, and
ejaculation on all or nearly all vaginal penetrations; and (iii) negative the mean duration of marriage was 7.05 ± 3.62 years. The mean du-
personal consequences, such as distress, bother, frustration and/ ration of PE of all patients was 5.80 ± 2.97 years, and the mean of
or the avoidance of sexual intimacy (Althof et al., 2014). In addition, IELT was 40.0 ± 9.32 s. The mean frequency of sexual intercourse
other patient inclusion criteria were age ≥20 years old, married and of all patients before treatment was 1.52 ± 0.52 week. No statisti-
in a stable sexual relationship for at least 1 month before enrolment cally significant difference was found on comparing demographic
this study. data of the patients in the placebo and tadalafil groups (p value >.05)
All patients were assessed by the International Index of Erectile (Table 1).
Function 5-­item questionnaires to exclude the patients with erec- This study showed that there were no statistically significant
tile dysfunction (score ≥22) (Rosen, Smith, Lipsky, & Pena, 1999). differences between patients in the placebo and tadalafil groups
Furthermore, patients with a history suggestive of one or more of regarding the mean values of the seven questions and total scores
the following conditions were excluded from this study: (i) diabetes of AIPE questionnaire before the treatment (p value >.05) (Table 2).
mellitus; (ii) chronic prostatitis; (iii) advanced renal or hepatic dis- The mean values of the seven questions and total scores of AIPE
eases; (iv) neurological diseases; and (v) C.N.S. medications. Patients questionnaire in the tadalafil group were significantly higher than
who received medications for PE over the last 3 months prior to en- the placebo group after treatment (p value = .001) (Table 3).
rolment in the study were also excluded. According to AIPE score values, all the patients were had severe
All patients were randomised equally divided into two groups (50 PE before treatment. At the end of 6 weeks of treatment, patients
patients each) and patients were unaware of the nature of the drugs
received. Group 1 was given placebo in the form of oral multivitamin
tablet once a day for 6 weeks. Group 2 was given 5 mg tadalafil once TA B L E 1 Patients’ demographic data
a day for 6 weeks. All patients were instructed to do sexual inter-
Placebo Tadalafil
course 2–3 times per week. (n = 50) (n = 50) p Value
All included patients were instructed to enlist intravaginal ejac-
Age (year) 34.96 ± 5.87 34.22 ± 6.03 .54
ulatory latency time (IELT) using stopwatches before enrolment in
Duration of marriage 7.28 ± 3.61 6.83 ± 3.66 .52
this study after full training about how to measure the ILET (starting (year)
from the time of intromission until ejaculation). Stopwatches were
Duration of PE (year) 5.92 ± 2.98 5.68 ± 2.99 .68
held by the female partners.
Frequency of sexual 1.46 ± 0.54 1.58 ± 0.49 .29
All patients were asked to complete Arabic Index of Premature intercourse (week)
Ejaculation (AIPE) before and after the treatment. The AIPE ques-
IELT (s) 40.90 ± 8.24 39.10 ± 10.28 .35
tionnaire includes seven questions about rate of sexual desire,
PE, premature ejaculation; IELT, intravaginal ejaculatory latency time.
frequency of hard erections, intravaginal ejaculatory latency time
Data were expressed as a mean ± SD. Independent t test was used for
(IELT), ability to prolong ejaculation time, satisfaction for the patient comparison between the study groups.
and his partner, and feel of anxiety, depression or stress owing to p value <.05 was significant.
ABU EL-HAMD | 3 of 5

TA B L E 2 Comparisons of mean (±SD) scores of the 7-­item questionnaires and total scores of AIPE between placebo and tadalafil groups
before treatment

Placebo (n = 50) Tadalafil (n = 50) p Value

Q1 How do you rate your sexual desire? 1.30 ± 0.46 1.28 ± 0.45 .71
Q2 How often do you have hard erections, with sexual stimulation, 1.26 ± 0.44 1.24 ± 0.43 .71
sufficient to complete sexual intercourse?
Q3 How much time does it take from intromission to ejaculation 1.32 ± 0.47 1.30 ± 0.46 .82
(using a stop-­watch)?
Q4 How difficult is it for you to prolong your ejaculation time? 1.26 ± 0.44 1.30 ± 0.46 .56
Q5 How often was sexual intercourse satisfactory for you? 1.30 ± 0.46 1.32 ± 0.47 .78
Q6 How often was sexual intercourse satisfactory for your partner? 1.34 ± 0.47 1.36 ± 0.48 .81
Q7 During sexual intercourse, do you feel anxious, depressed or 1.26 ± 0.44 1.22 ± 0.41 .48
stressed?
Total scores 9.04 ± 3.18 9.02 ± 3.10 .97

AIPE, Arabic Index of Premature Ejaculation; SD, standard deviation.

Data were expressed as a mean ± SD. Independent t test was used for comparison between the study groups.
p value <.05 was significant.

TA B L E 3 Comparisons of mean (±SD) scores of the 7-­item questionnaires and total scores of AIPE between placebo and tadalafil groups
after treatment

Placebo (n = 50) Tadalafil (n = 50) p Value

Q1 How do you rate your sexual desire? 1.34 ± 0.47 4.72 ± 0.45 .001
Q2 How often do you have hard erections, with sexual stimulation, 1.28 ± 0.45 4.78 ± 0.41 .001
sufficient to complete sexual intercourse?
Q3 How much time does it take from intromission to ejaculation (using 1.34 ± 0.47 4.88 ± 0.32 .001
a stop-­watch)?
Q4 How difficult is it for you to prolong your ejaculation time? 1.32 ± 0.47 4.78 ± 0.41 .001
Q5 How often was sexual intercourse satisfactory for you? 1.34 ± 0.47 4.72 ± 0.45 .001
Q6 How often was sexual intercourse satisfactory for your partner? 1.40 ± 0.49 4.60 ± 0.48 .001
Q7 During sexual intercourse, do you feel anxious, depressed or 1.28 ± 0.45 4.50 ± 0.49 .001
stressed?
Total scores 9.70 ± 3.87 32.98 ± 3.5 .001

AIPE, Arabic Index of Premature Ejaculation; SD, standard deviation.

Data were expressed as a mean ± SD. Independent t test was used for comparison between the study groups.
p value <.05 was significant.

in the placebo group showed severe PE (n = 50, 100%) and patients relax smooth muscle in the vas deferens (VD), seminal vesicles (SV),
in the tadalafil group improved to non-­PE (n = 50, 100%) (Table 3). prostate and urethra. Also, PDE5 inhibitors create peripheral anal-
All treatments were well tolerated by all patients. The most ad- gesia, which increase the duration of the erection and decrease the
verse effects in the tadalafil group were headache, back pain, myal- central sympathetic output (Abdel-­Hamid, 2004).
gia, dyspepsia and flushing (Table 4). In addition, it has been found that on-­demand administration
of sildenafil citrate was effective in the improvement of ejacula-
tory latency time control and overall satisfaction in patients with
4 | D I S CU S S I O N PE (Abdel-­Hamid, El Naggar, & El Gilany, 2001). Sildenafil citrate in-
creased self-­confidence, perception of ejaculatory control and over-
PDE5 inhibitors have been approved by US Food and Drug all sexual satisfaction, and decreased the refractory time to achieve
Administration for the treatment of ED (Kandeel, 2013). Several a second erection after ejaculation in men with PE (McMahon et al.,
studies have been found that on-­demand use of PDE5 inhibitors in- 2005).
cluding tadalafil was effective in the treatment of PE (Aversa et al., Several studies reported that once-­daily administration of low-­
2009; Mathers et al., 2009; Mattos et al., 2008). dose tadalafil was effective and well tolerated in the treatment of
There are central and peripheral mechanisms explained the pos- patients with ED compared with on-­demand use. It gives a chance for
sible role PDE5 inhibitors in the treatment of PE. PDE5 inhibitors the patient and his female partner to disconnect its administration
4 of 5 | ABU EL-HAMD

TA B L E 4 Adverse effects among study groups during the This study concluded that the use of 5 mg tadalafil once a day
treatment period for 6 weeks was effective and well tolerated in the treatment of pa-

Tadalafil tients with PE.

Placebo (n = 50) (n = 50)

Headache 0 7 (14%) CONFLIC T OF INTEREST

Back pain 0 6 (12%)
There is no conflict of interest.
Myalgia 0 4 (8%)
Dyspepsia 0 4 (8%)
Flushing 0 3 (6%) ORCID

Data were expressed as n (%). M. Abu El-Hamd http://orcid.org/0000-0002-0100-624X

from sexual activity (Bruzziches, Francomano, Gareri, Lenzi, &

Aversa, 2013; Porst, Hell-­Momeni, & Büttner, 2012). REFERENCES

In a single-­blind placebo-­controlled clinical study, it was evalu- Abdel-Hamid, I. A. (2004). Phosphodiesterase 5 inhibitors in rapid ejac-
ated the efficacy and safety of the once-­daily use of 5 mg tadalafil for ulation: Potential use and possible mechanisms of action. Drugs, 64,
13–26. https://doi.org/10.2165/00003495-200464010-00002
6 weeks in the treatment of patients with PE. This study found that
Abdel-Hamid, I. A., El Naggar, E. A., & El Gilany, A. H. (2001). Assessment
the mean values of the seven questions and total scores of AIPE ques- of as needed use of pharmacotherapy and the pause-­squeeze tech-
tionnaire in the tadalafil group were significantly improved than the nique in premature ejaculation. International Journal of Impotence
placebo group after treatment. In addition, all the patients were had Research, 13, 41–45. https://doi.org/10.1038/sj.ijir.3900630
Althof, S. E., McMahon, C. G., Waldinger, M. D., Serefoglu, E. C., Shindel,
severe PE before treatment, according to AIPE score values, at the end
A. W., Adaikan, P. G., … Torres, L. O. (2014). An Update of the
of 6 weeks of treatment, patients in the placebo group showed severe International Society of Sexual Medicine’s guidelines for the diagno-
PE and patients in tadalafil group improved to non-­PE. sis and treatment of premature ejaculation (PE). The Journal of Sexual
This finding was in agreement with Ozcan et al. (2017), who re- Medicine, 2(2), 60–90. https://doi.org/10.1002/sm2.28
ported that administration of 5 mg tadalafil once daily for 1 month Arafa, M., & Shamloul, R. (2007). Development and evaluation of the Arabic
Index of Premature Ejaculation (AIPE). The Journal of Sexual Medicine,
was effective in the treatment of patients with lifelong PE as it im-
4, 1750–1756. https://doi.org/10.1111/j.1743-6109.2006.00213.x
proved IELT and premature ejaculation profile. Karabakan, Keskin, Aversa, A., Pili, M., Francomano, D., Bruzziches, R., Spera, E., La Pera, G.,
Akdemir, and Bozkurt (2017) found that administration of 5 mg tada- & Spera, G. (2009). Effects of vardenafil administration on intravag-
lafil once daily for 3 months showed a significant increase in IELT inal ejaculatory latency time in men with lifelong premature ejacula-
tion. International Journal of Impotence Research, 21, 221–227. https://
and IIEF-­5 values of patients with ED and PE. Dell’Atti, Galosi, and
doi.org/10.1038/ijir.2009.21
Ippolito (2017) showed that daily administration of 5 mg tadalafil for Bruzziches, R., Francomano, D., Gareri, P., Lenzi, A., & Aversa, A. (2013).
3 months in patients with PE resulted in significant increase in IELT An update on pharmacological treatment of erectile dysfunc-
and sexual satisfaction scores with the best results when combined tion with phosphodiesterase type 5 inhibitors. Expert Opinion on
Pharmacotherapy, 14, 1333–1344. https://doi.org/10.1517/1465656
with the application of lidocaine spray to the glans penis before
6.2013.799665
planned sexual intercourse. Carani, C., Isidori, A. M., Granata, A., Carosa, E., Maggi, M., Lenzi, A.,
Also, this study found that once-­daily administration of 5 mg & Jannini, E. A. (2005). Multicenter study on the prevalence of sex-
tadalafil for 6 weeks was well tolerated in the treatment of patients ual symptoms in male hypo-­and hyperthyroid patients. The Journal
of Clinical Endocrinology & Metabolism, 90, 6472–6479. https://doi.
with PE. The most adverse effects were headache, back pain, myal-
org/10.1210/jc.2005-1135
gia, dyspepsia and flushing. Castiglione, F., Albersen, M., Hedlund, P., Gratzke, C., Salonia, A.,
This finding was in agreement with Ozcan et al. (2017), who & Giuliano, F. (2016). Current pharmacological management
found that administration of 5 mg tadalafil once daily for 1 month of premature ejaculation: A systematic review and metaanaly-
sis. European Urology, 69, 904–916. https://doi.org/10.1016/j.
was safe in the treatment of patients with lifelong PE and the most
eururo.2015.12.028
common side effects were headache, back pain, myalgia, dyspepsia Dell’Atti, L., Galosi, A. B., & Ippolito, C. (2017). A randomized single-­
and gastroesophageal reflux. Dell’Atti et al. (2017) showed that daily center study to compare the efficacy and tolerability of tadalafil
administration of 5 mg tadalafil for 3 months in patients with PE was once daily plus lidocaine anesthetic spray on premature ejacula-
well tolerated. tion. European Review for Medical and Pharmacological Sciences,
21(5), 1036–1040.
The present study has several limitations. Multivitamin tablets
Jannini, E. A., Lombardo, F., & Lenzi, A. (2005). Correlation between
were used as a placebo because these tablets were well established ejaculatory and erectile dysfunction. International Journal of
to be ineffective in the treatment of patients with PE, but it is better Andrology, 28(2), 40–45. https://doi.org/10.1111/j.1365-2605.2005.
to use the tablets of starch as placebo. Further prospective, multi-­ 00593.x
Jern, P., Santtila, P., Johansson, A., Varjonen, M., Witting, K., von der
centre controlled studies on larger sample sizes are needed to estab-
Pahlen, B., & Sandnabba, N. K. (2009). Evidence for a genetic eti-
lish the safety and efficacy of daily use of tadalafil for the treatment ology to ejaculatory dysfunction. International Journal of Impotence
of patients with PE. Research, 21(1), 62–67. https://doi.org/10.1038/ijir.2008.61
ABU EL-HAMD | 5 of 5

Kandeel, F. R. (2013). Treatment of erectile dysfunction in men with heart (PEPA) survey: Prevalence, comorbidities and professional help-­
disease. Male sexual dysfunction: Pathophysiology and treatment (p. seeking. European Urology, 51, 816–824. https://doi.org/10.1016/j.
453). Cleveland, OH: CRC Press. eururo.2006.07.004
Karabakan, M., Bozkurt, A., Hirik, E., Celebi, B., Akdemir, S., Guzel, O., Rosen, R. C., Smith, M. D., Lipsky, J., & Pena, B. M. (1999). Development
& Nuhoglu, B. (2016). The prevalence of premature ejaculation in and evaluation of an abridged, 5-­item version of the International
young Turkish men. Andrologia, 48, 895–899. Index of Erectile Function (IIEF-­5) as a diagnostic tool for erectile
Karabakan, M., Keskin, E., Akdemir, S., & Bozkurt, A. (2017). Effect dysfunction. International Journal of Impotence Research, 11, 319–
of tadalafil 5 mg daily treatment on the ejaculatory times, 326. https://doi.org/10.1038/sj.ijir.3900472
lower urinary tract symptoms and erectile function in pa- Schapiro, B. (1943). Premature ejaculation, a review of 1130 cases.
tients with erectile dysfunction. International Brazilian Journal of Journal of Urology, 50, 374–379. https://doi.org/10.1016/
Urology, 43(2), 317–324. https://doi.org/10.1590/s1677-5538.ibju. S0022-5347(17)70462-4
2016.0376 Screponi, E., Carosa, E., Di Stasi, S. M., Pepe, M., Carruba, G., & Jannini,
Mathers, M. J., Klotz, T., Roth, S., Lummen, G., & Sommer, F. (2009). Safety E. A. (2001). Prevalence of chronic prostatitis in men with prema-
and efficacy of vardenafil versus sertraline in the treatment of premature ture ejaculation. Urology, 58, 198–202. https://doi.org/10.1016/
ejaculation: A randomised, prospective and crossover study. Andrologia, S0090-4295(01)01151-7
41, 169–175. https://doi.org/10.1111/j.1439-0272.2008.00910.x Waldinger, M., Berendsen, H. H., Blok, B. F., Olivier, B., & Holstege, G.
Mattos, R. M., Marmo Lucon, A., & Srougi, M. (2008). Tadalafil and flu- (1998). Premature ejaculation and serotonergic antidepressant s in-
oxetine in premature ejaculation: Prospective, randomized, double-­ duced delayed ejaculation: The involvement of the serotonergic sys-
blind, placebo-­controlled study. Urologia Internationalis, 80, 162–165. tem. Behavioral Brain Research, 92, 111–118. https://doi.org/10.1016/
https://doi.org/10.1159/000112607 S0166-4328(97)00183-6
McMahon, C. G., Stuckey, B. G., Andersen, M., Purvis, K., Koppiker, N., Xin, Z. C., Choi, Y. D., Rha, K. H., & Choi, H. K. (1997). Somatosensory
Haughie, S., & Boolell, M. (2005). Efficacy of sildenafil citrate in men evoked potentials in patients with primary premature ejacula-
with premature ejaculation. The Journal of Sexual Medicine, 2(3), 368– tion. Journal of Urology, 158, 451–455. https://doi.org/10.1016/
375. https://doi.org/10.1111/j.1743-6109.2005.20351.x S0022-5347(01)64499-9
Ozcan, L., Polat, E. C., Onen, E., Kocaaslan, R., Otunctemur, A., Cekmen,
M., … Ozbek, E. (2017). Effects of tadalafil 5 mg dosed once daily in
men with premature ejaculation. Urologia Internationalis, 98(2), 210–
How to cite this article: Abu El-Hamd M. Efficacy and safety
214. https://doi.org/10.1159/000445839
of daily use of tadalafil in treatment of patients with
Porst, H., Hell-Momeni, K., & Büttner, H. (2012). Chronic PDE-­5 inhi-
bition in patients with erectile dysfunction: A treatment approach premature ejaculation: A randomised placebo-­controlled
using tadalafil once-­daily. Expert Opinion on Pharmacotherapy, 13, clinical trial. Andrologia. 2018;e13005.
1481. https://doi.org/10.1517/14656566.2012.693162 https://doi.org/10.1111/and.13005
Porst, H., Montorsi, F., Rosen, R. C., Gaynor, L., Grupe, S., & Alexander,
J. (2007). The premature ejaculation prevalence and attitudes