Table 1 RCT characteristics, efficacy and safety outcomes, and risk of bias assessment

Alghobary 2010 [15] (Egypt) 6 weeks

DSM-IV-TR All lifelong PE ED, NR

- Tramadol 50 mg 2 to 3 h PC, 17/17 (100%) - Paroxetine 20 mg/d, 18/18 (100%)

IELT (Stopwatch): see Figure 3. Arabic Index of Premature Ejaculation (AIPE): significant improvement in scores at 6 weeks with both tramadol and paroxetine. Difference between groups not significant. Tramadol group had less rigid erections than paroxetine group

The drugs were generally tolerated and no serious side-effects encountered apart from mild headache and gastric upset with paroxetine and mainly gastric upset with tramadol and no withdrawn cases recorded.

Unclear risk - allocation method and blinded outcome assessment not reported

Bar-Or 2012 [18] (11 EU countries) 12 weeks

DSM-IV-TR All lifelong PE ED, excluded

- Tramadol 62 mg, 206/232 (89%) - Tramadol 89 mg, 198/217 (91%) - Placebo, 200/228 (88%) 2 to 8 h PC

IELT (Stopwatch): see Figure 3. Premature Ejaculation Profile (PEP): Mean change for all 4 measures significantly higher in both tramadol groups than placebo Female partner PEP scores: more had improvement (> = 1 category) for tramadol than placebo on all 4 measures

Any adverse event: Tramadol 62 mg: 12% Tramadol 89 mg: 16% Placebo: 7% No difference was observed in the incidence of withdrawal by treatment group (0.0% placebo, 1.0% 62 mg tramadol, 1.6% 89 mg tramadol). There were no serious AEs.

Unclear risk - allocation method and blinded outcome assessment not reported

Eassa 2013[20] (Egypt) 24 weeks

PE def, NR All lifelong PE ED, excluded

- Tramadol 25 mg, 100/100 (100%) - Tramadol 50 mg, 100/100 (100%) - Tramadol 100 mg, 100/100 (100%) 2 to 3 h PC

IELT (Stopwatch): see Figure 3

Tramadol 25 mg - somnolence (100%); pruritus (100%) Tramadol 50 mg - somnolence (100%); pruritus (100%); dizziness (18%); headache (16%); dry mouth (13%) Tramadol 100 mg - somnolence (100%); pruritus (100%); dizziness (38%); headache (30%); dry mouth (20%); nausea (20%); vomiting (17%)

Unclear risk - allocation method and blinded outcome assessment not reported

Gameel 2013 [16] (Egypt) 4 weeks

IELT of <2 min in >75% of episodes All had PE for >1 year ED, excluded

- Tramadol 50 mg 2 h PC + inert lubricating gel 15 min PC, 29/30 (97%) - Sildenafil 50 mg 1 h PC + inert lubricating gel 15 min PC, 30/30 (100%) - Paroxetine 20 mg 4 h PC + inert lubricating gel 15 min PC, 28/30 (93%) - Lidocaine gel 15 min PC + oral multivitamin 1-4 h PC, 30/30 (100%) - Placebo (oral multivitamin 1-4 h PC + inert lubricating gel 15 min PC), 27/30 (90%)

IELT (stopwatch): see Figure 3. Sexual satisfaction (0 to 5 point scale: Tramadol and paroxetine were associated with comparable drug-induced improvements in sexual satisfaction, but tramadol was associated with significantly better sexual satisfaction scores than was the local anaesthetic.

Greater sleep disturbance, dry mouth, nausea, dizziness, fatigue, vomiting, sweating, and headache were reported with tramadol, sildenafil and paroxetine. All side effects were reported as being tolerable.

Unclear risk - allocation method and blinded outcome assessment not reported

Kahn 2013 [21] (India) 8 weeks

DSM-IV TR 41/60 (68%) lifelong PE ED, excluded

- Tramadol 100 mg/d, 4 weeks then 2 or 8 h PC, 4 weeks; 30/30 (100%) - Placebo/d, 4 weeks then 2 or 8 h PC, 4 weeks; 30/30 (100%)

IELT (stopwatch): Week 8 tramadol daily 202.5 s, 2 or 8 h PC, 238.2 s (p < 0.001 vs baseline); placebo daily 94.8 s (p = 0.632 vs baseline) placebo 2 or 8 h PC 96.6 s (p = 0.611 vs baseline). Coital frequency tramadol daily 4.32/week (p = 0.005) tramadol 2 or 8 h PC 4.86/week (p = 0.005). Coital frequency placebo daily 2.88/week (p = 0.875) placebo 2 or 8 h PC 3.23/week (p = 0.752).

The overall AE rate was 9.8% (6.7%, and 12.4% for placebo and 100 mg tramadol respectively) ED occurred in 3.33% of men (n = 1). Vertigo was observed in 3.33% of patients (n = 2); dizziness, headache, drowsiness, and common cold were observed in 6.67% of patients (n = 2 each). There were no serious AEs.

Unclear risk - allocation method and blinded outcome assessment not reported

Kaynar 2012 [17] (Turkey) 8 weeks

IELT ≤2 min during 90% intercourse episodes All lifelong PE ED, excluded

- Tramadol 25 mg, 30/30 (100%) - Placebo, 30/30 (100%) 2 h PC

IELT (stopwatch): see Figure 3. Ability of ejaculation control (AEC): Tramadol: Mean increase 2.0 Placebo: Mean increase 0.57 Tramadol better than placebo (p < 0.001) Sexual satisfaction scores (SSS) Tramadol: Mean increase 1.80 (SD 0.98). Placebo: Mean increase 0.53 (SD 0.92) Tramadol better than placebo (p < 0.001)

Any adverse event: Tramadol: 27% Placebo: 0% Mild nausea/headache: Tramadol: 20% Mild somnolence: Tramadol: (6.5%)

Unclear risk - allocation method and blinded outcome assessment not reported

Safarinejad 2006 [19] (Iran) 8 weeks

IELT ≤2 min during 90% coitus All lifelong PE ED, excluded

- Tramadol 50 mg, 29/32 (91%) - Placebo, 28/32 (88%) 2 h PC

IELT (stopwatch): see Figure 3. IIEF: intercourse satisfaction: Tramadol: mean change 4 Placebo: mean change −1 Between-groups p < 0.05

Any adverse event: Tramadol: 28% Placebo: 16% (mainly nausea)

Unclear risk - blinded outcome assessment not reported

Xiong 2011[22] (China) 12 weeks

IELT ≤2 min All lifelong PE ED, NR

- Tramadol 50 mg 2 h PC with behavioural therapy (not reported which) (n = 36) - Behavioural therapy alone (n = 36);

IELT (stopwatch): see Figure 3. IIEF Tramadol + BT: mean change 4 BT alone: mean change 2 Between-groups p < 0.05

Any adverse event: Tramadol: 28% Placebo: 0% Tramadol: nausea (11.1%), vomiting (2.8%), dry mouth (5.6%), dizziness (8.3%).

Unclear risk - allocation method and blinded outcome assessment not reported (unable to assess fully – body text of article in Chinese)