'Off-Label' Drug Use in Sexual Medicine Treatment

B Fallon


Int J Impot Res. 2008;20(2):127-134. 

In This Article

Premature Ejaculation

All medical treatment for PE is off-label. Drugs used extensively in treatment are principally the selective serotonin reuptake inhibitors (SSRIs), PDE5 inhibitors and clomipramine, a tricyclic antidepressant. Also commonly used are local anesthetic creams, sprays and gels.

Serotonin and 5-hydroxytryptamine are involved in the central control of ejaculation. Rat studies have found that SSRIs block presynaptic membrane 5-hydroxytryptamine transporters, resulting in delayed ejaculation.[6] Increased serotonergic stimulation resulting from SSRIs or clomipramine results in the prominent side effect of delayed ejaculation noted by patients taking these drugs for treatment of depression. The clinical effects of SSRIs in treating PE were first reported in 1994, when eight patients were treated with paroxetine, and compared to nine treated with placebo. The paroxetine dose was 20mgday-1 for week 1 and 40mgday-1 for the next 5 weeks of the trial. Intravaginal ejaculatory latency time (IELT) was felt by patients and partners to be longer with paroxetine.[7] A meta-analysis of 35 SSRI and clomipramine daily dose studies found that only eight studies were conducted according to evidence-based medicine standards.[8] In these eight studies, there was a placebo effect of a 1.4-fold increase in IELT, while paroxetine averaged an 8.8-fold increase in IELT, and clomipramine, sertraline and fluoxetine all increased IELT by approximately four-fold. These drugs appear to be active both for lifelong PE and for acquired PE. Duloxetine, a dual serotonin and epinephrine reuptake inhibitor has also been found to produce approximately a four-fold increase in IELT in a 4-week randomized trial.[9]

Onset of activity with antidepressants used on a daily basis is within 1—2 weeks. Treatment may be continued for a period of several months and a trial of discontinuation may be done. Men who have had acquired PE may permanently maintain their improvement. Unfortunately, in cases of lifelong PE, relapse occurs within 6 months in at least 66% of patients.[10] Treatment can, however, be continued for years, although tachyphylaxis may occur.[8] Typical doses of the antidepressants used in PE treatment are shown in Table 2 .

Side effects of SSRIs. All have similar side effects, with nausea, drowsiness, perspiration and erectile dysfunction, with anejaculation being common on initiating treatment, but lessening within several weeks. Other, less-frequent side effects include abnormal bleeding, hypoglycemia, hyponatremia and movement disorders. There is also a well-recognized SSRI discontinuation syndrome, which may begin within 1—3 days of stopping the drug and lasting for about 7—10 days. The symptoms may consist of nausea, dizziness, headache, anxiety, insomnia and gait instability.

Trials have been conducted of SSRIs taken 1—2h prior to intercourse. Typically, the IELT does not seem to have increased as much as with daily treatment. Also, side effects such as nausea, loose stools and drowsiness may interfere with the pleasure of intercourse. These side effects tend to improve with daily usage.

A new SSRI, dapoxetine, was developed specifically for use as on-demand treatment for PE, and in one study seemed very promising in doses of 30 and 60mg. IELT increased 2.8 and 3.6 times over baseline respectively, while placebo increased IELT 1.8 times.[11] Patient self-ratings of control over ejaculation increased from 2.8% at baseline to 52 and 58% respectively with the 30 and 60mg doses. The drug's half-life is short and the absorption rapid. Peak serum concentration occurs in about 1h and serum levels at 24h are less than 5% of peak levels. Typical SSRI side effects occur—nausea, headache, diarrhea and dizziness, with occasional syncope. Sexual side effects are uncommon as noted in a 9-month open label study, which found an incidence of only 2.6% in 1774 patients with a 60mg dose.[12] Dapoxetine, however, did not receive the expected FDA approval, and is not in general use.

Tramadol HCl is a centrally acting opioid analgesic that exerts its effect through the inhibition of norepinephrine and serotonin reuptake. A recent investigation of its use in PE found that it is effective in a dose of 25mg.[13] Taken 1—2h before sexual activity, it produced an increase in IELT from a mean of 1.17min to a mean of 7.37min (stopwatch observations). Placebo produced a mean IELT of 2.01min in that trial.

Local anesthetics in gel or cream form have historically been used to reduce penile sensitivity and delay ejaculation. They are inexpensive, but may lead to erectile difficulties secondary to glans numbness, and may also reduce vaginal sensation in the partner if a condom is not used. In one double-blind study of 42 patients using a lidocaine/prilocaine cream, IELT increased from 1.5min in the treatment group to 8.5min, while in the placebo group the increase was from 1.67 to 1.95min. Sexual satisfaction scores did not change significantly in either group.[14] Another double-blind, randomized study of a lidocaine/prilocaine spray in 55 patients found an increase in IELT from 1.9 to 4.9min in the treatment group, compared to an increase from 0.9 to 1.6min in the control group.[15] There were also significant improvements in sexual satisfaction scores with the spray. Another study of a lidocaine/prilocaine cream found that EMLA cream produced a 65% improvement or cure rate in PE patients.[16] Unfortunately, the patient numbers were small, IELT was not documented and patient self-assessments were the evaluating tools. Also of note is that placebo cream alone produced a 40% rate of cure or improvement.

None of the studies of topical agents are large and although these agents are frequently used, convincing data about their effectiveness are not available, and patients do not often continue to use them long-term.

There are several studies in the literature regarding the use of PDE5 inhibitors for PE. They suggest that there may be decreased contractile response of the seminal vesicles, vas deferens and urethra due to smooth muscle relaxation. Many of these studies include the concomitant use of antidepressants, local anesthetics or behavioral therapy. For example, in the study of EMLA cream noted above, one of the study groups received sildenafil only, and another received sildenafil plus EMLA cream. The sildenafil groups did not have any statistically significant improvements over the EMLA only group.[16] Another randomized, double-blind crossover study of 31 patients found that sildenafil was superior to SSRIs and the squeeze technique. IELT was measured with a stopwatch, and improved from 1min at baseline to 3 or 4min with SSRIs, and to 15min with sildenafil.[17] Sexual satisfaction scores were higher and anxiety scores lower. Another study noted that although sildenafil did not improve IELT, it did produce increased sexual satisfaction, and increased confidence and decreased post-ejaculatory latency time.[18] A recent review of the literature regarding use of PDE5 inhibitors in PE found 14 such studies between 2001 and 2006.[19] There was large variation in methodology, differences in definition of PE, small numbers of patients, poorly designed studies and inclusion of both acquired and lifelong PE patients. As a result, a meta-analysis could not be performed, and it was felt that the findings and conclusion of 13 of the 14 studies should be regarded as unreliable. Some studies seem to provide evidence of efficacy in men who have coexistent PE and erectile dysfunction, possibly due to increased confidence in the quality of erection producing a lesser anxiety regarding achieving orgasm and ejaculation.


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