madman
Super Moderator
Safety and efficacy of botulinum neurotoxin in the treatment of erectile dysfunction refractory to phosphodiesterase inhibitors: Results of a randomized controlled trial (2021)
Islam Fathy Soliman Abdelrahman Amr Abdel Raheem Yaser Elkhiat Abdelrahman A. Aburahma Tarek Abdel-Raheem Hussein Ghanem
Abstract
Background: There has been recent interest in the use of botulinum neurotoxin (BoNT) in the field of Andrology, whereby it has been investigated in the treatment of penile retraction and premature ejaculation.
Objectives: To evaluate the safety and efficacy of intracavernosal BoNT-A injection in the treatment of patients with erectile dysfunction (ED) refractory to oral phosphodiesterase inhibitors (PDE5Is).
Patients and methods: A double-blind randomized placebo-controlled prospective comparative study was conducted at one center and involved 70 patients with ED refractory to PDE5Is. At baseline, the following data were collected: erection hardness score (EHS), peak systolic velocity (PSV), end-diastolic velocity (EDV), sexual health inventory for men (SHIM), and the sexual encounter profile 2&3 (SEP-2&3) questionnaires. The treatment group (n = 35) received a single ICI of 100 units of BoNT-A in 2 ml of saline and the control group (n = 35) received a single ICI of 2 ml of saline. EHS, PSV, and EDV were assessed at 2 weeks post-treatment. SHIM, SEP-2, SEP-3, and global assessment questionnaire (GAQ-Q1&Q2) were completed at 2-, 6-, and 12-weeks post-treatment.
Results: Two weeks post-treatment, the treatment group showed a statistically significant improvement in the mean EHS, PSV, EDV, and GAQ-Q1 positive responders (p < 0.001) compared to the control group. At 6- and 12-weeks post-treatment, the treatment group showed a statistically significant improvement in the SHIM scores, SEP-2, and GAQ-Q1&Q2 positive responders compared to the control group. At 6 weeks, where there was a 5-point improvement in the mean SHIM score of the treatment group (10±5.9 from 5.4±1.7 at baseline) versus no improvement in the placebo group, 18 patients in the treatment group (53%) were able to have an erection hard enough for vaginal penetration versus only one patient in the control group.
Conclusion: BoNT-A is safe and effective as a potential treatment for ED refractory to PDE5I therapy.
INTRODUCTION
Moderate to severe erectile dysfunction (ED) affects 5–20% of men worldwide. It is estimated that by the year 2025, 322 million men will suffer from ED.1,2 ED is treated in a stepwise manner with oral (PDE5Is) being the first-line therapy for ED.3,4 However, despite the fact that PDE5Is have revolutionized ED treatment, they do not work in all cases. Sildenafil Citrate is successful in up to 63% of men with ED and Tadalafil was shown to be successful in up to 52% of ED patients. It is more likely that patients with severe ED will have poor responses to oral PDE5Is.5,6 Second-line therapy includes transurethral alprostadil, intracavernosal injections of vasoactive substances (ICI), and vacuum pump therapy. However, many patients find second-line therapy too invasive and lacking in spontaneity.7–9 Penile implants are used as a last resort when second-line therapy fails or is refused by the patient. Despite having high patient and partner satisfaction rates (exceeding 80%), implant surgery is not free from complications, such as infection, erosion, autoinflation, and mechanical failure, and the surgery is both expensive and invasive.4,10,11 Recent advances in the research for future ED therapies, such as low-intensity shockwave therapy, growth factor injection, gene therapy, stem cell therapy, and tissue engineering, can salvage ED patients from implant surgery as prosthesis surgery partially destroys the normal erection mechanism.4
Botulinum neurotoxin (BoNT) is produced by Clostridium botulinum, an anaerobic, gram-positive bacterium. Poisoning with BoNT can cause botulism, resulting in generalized paralysis, respiratory failure, and death.12,13 There are seven serotypes of BoNT: A, B, C1, D, E, F, and G. BoNT-A is the most commonly used serotype for medical purposes. There are several commercially available forms: Botox (Allergan Pharmaceuticals, Parsippany, NJ, USA) is the most widely used and has the most medical applications.14 Since its first use in 1977 for the treatment of strabismus in children, BoNT-A has since been used in aesthetic medicine and for the treatment of a number of disorders associated with overactive striated muscles, such as strabismus, esotropia, exotropia, focal dystonia, spasticity, and movement disorders.15 BoNT-A has also been used in the management of some smooth-muscle disorders, such as achalasia, oesophageal spasm, ptyalism, hyperhidrosis, intrinsic rhinitis, blepharospasm, muscle spasms, spasticity, axillary hyperhidrosis, and neurogenic detrusor muscle overactivity of the urinary bladder.15–21 It is widely used in aesthetic medicine to treat facial wrinkles in the forehead, lower face, lateral eye, and in between the eyebrows.22–27
BoNT prevents the release of acetylcholine at the presynaptic membrane causing flaccid paralysis for up to 3 months.28,29 BoNT can also inhibit the release of other neurotransmitters, such as noradrenaline, dopamine, glycine, and g-aminobutyrate. BoNT has been used for prostatic smooth-muscle relaxation in the management of lower urinary tract symptoms. It has also been found to inhibit noradrenaline release in the urethra and ano-coccygeus of rats.16,30,31
Erection depends on adequate cavernosal smooth muscle relaxation. PDE5Is and ICIs of vasoactive substances exert their effect by inducing corporal smooth muscle relaxation.32 Since BoNT-A is a strong inducer of smooth muscle relaxation, it may be effective in the treatment of ED refractory to PDE5Is.33
There has been recent interest in the use of BoNT in the field of Andrology, whereby it has been investigated in the treatment of penile retraction and premature ejaculation.34,35 The use of BoNT in the treatment of ED was first studied in 2016 by Ghanem et al., who performed an animal study followed by a human pilot study and showed promising results.33,36–38
*This study investigated the safety and efficacy of BoNT in the treatment of ED refractory to oral PDE5Is with the aim of salvaging those patients from second-and third-line ED therapies by downgrading the level of their ED.
2 PATIENTS AND METHODS
This is a double-blind randomized placebo-controlled prospective comparative study. Both the patients and the investigator were not aware of the active drug or the placebo that was injected. It was registered at NIH ClinicalTrials.gov (Home - ClinicalTrials.gov), number NCT03102762. The study protocol was approved by the local ethics committee.
2.1 Study design
Seventy consecutive patients from a single high-volume Andrology unit presenting with ED, not responding to on-demand PDE5Is, were recruited and randomly assigned to treatment group (n = 35) and control group (n = 35) using computer-generated randomization sequence. The sample size was calculated based upon the previous pilot study36 with the difference between the two groups was 3 ± 5 in SHIM score. Using power 85% and 5% significance level, 51 patients were required. That number was increased to 59 to adjust for nonparametric usage and increased again to 70 to compensate for possible losses during follow-up (20% more than calculated). The sample size was calculated using PS: Power & Sample Size Calculation Software Version 3.1.2 (Vanderbilt University, Nashville, TN, USA). A nonresponse to PDE5Is was defined as an erection not sufficient enough for penetration of the vagina or loss of the erection before completion of intercourse, after trying the highest dose of Sildenafil and Tadalafil on four separate occasions for each PDE5I. All the patients included in the study were PDE5Is failures, they were already on the highest dose of on-demand Sildenafil or tadalafil and were unable to achieve an erection sufficient for penetrative intercourse, this was also demonstrated in their baseline questionnaires. After treatment, in order to avoid any bias, each patient was asked to use the same dose (highest) of the same PDE5I that he was using before the injection.
4 METHODS
At baseline, all patients signed an informed consent form and had history taking as well as general and genital examination. Penile duplex with a trimix solution (20 µg alprostadil + 1 mg phentolamine + 30 mg papaverine) was also performed to assess the erection hardness score (EHS) and penile hemodynamics according to Standard Operating Procedures for Duplex Ultrasound: Standardization of Vascular Assessment of Erectile Dysfunction in order to achieve maximal cavernosal smooth muscle relaxation and possibly full erectile response.39 The latter was done by measuring the peak systolic (PSV) and the end-diastolic (EDV) velocities in the right and left cavernosal arteries and calculating the mean PSV and mean EDV. No cases of priapism needed intervention occurred. The patients also completed the validated Arabic translated version of sexual health inventory for men (SHIM), which consist of a 5-point questionnaire consisting of five questions assessing the erectile function, and it gives a full picture of the capability of the male for initiation and maintenance of erection sufficient for successful intercourse.40 They also completed sexual encounter profile 2&3 (SEP2&3) questionnaires.
The patients were then randomized into a treatment group (n = 35) and a control group (n = 35). Patients in the treatment group received a single ICI of 100 units of onabotulinumtoxinA BoNT-A (Botox™; Allergan Pharmaceuticals, Parsippany, NJ, USA) diluted in 2 ml of normal saline. A tourniquet was applied at the base of the penis, the treatment dose was distributed along 4 points, right and left distal and proximal shaft using a 23G insulin syringe (the tourniquet was removed after 20 min). Patients in the control group received a single ICI of 2 ml of IV saline administered in the same manner as the treatment group. Patients in both groups were asked to resume sexual activity 1 week after treatment with the help of on-demand PDE5Is trying the highest dose of Sildenafil and Tadalafil. ICI test, penile duplex, SHIM, SEP2 & SEP-3, and global assessment questions 1&2 (GAQ-Q1&Q2) were done at 2 weeks post-treatment. We used penile duplex to compare the hemodynamics of the penile arteries before and after injection. SHIM, SEP-2&SEP-3, and GAQ-Q1&Q2 were completed at 6- and 12-weeks post-treatment, respectively.
Statistical analysis was done using SPSS software (statistical package for the social sciences, version 21, SPSS Inc, Chicago, IL, USA). Frequency tables with percentages were used for categorical variables and descriptive statistics (median of minimum and maximum values) were used for numerical variables. Mann–Whitney test was used to compare quantitative variables, and the Chi-square test was used to analyze categorical variables. A p-value of < 0.05 was considered statistically significant.
6 DISCUSSION
The present study showed that (53%) of the patients in the treatment group (n = 18) were able to have an erection hard enough for vaginal penetration. Twenty-two (64.7%) patients in the treatment group reported improvement in their erections and 14 (41.2%) patients reported that the treatment improved their ability to engage in sexual activity versus none of the patients in the control group. Also, 2 weeks post-treatment, the treatment group showed a statistically significant improvement in the penile hemodynamics in the form of the mean EHS, PSV, and EDV (p < 0.001) compared to the control group. Finally, at 6- and 12-weeks post-treatment, there was a statistically significant difference between both groups in the SHIM score, SEP-2, GAQ-Q1, and GAQ-Q2 positive responders favoring the treatment group.
*The first human pilot study involved 24 men with severe vasculogenic ED refractory to PDE5Is; the patients were randomized to treatment and control groups (1:1). The treatment group received a single ICI of Botox 50 Units and the control group received a single ICI of 0.9% normal saline 1 ml. There was a statistically significant improvement in the mean PSV, SHIM score, and EHS in the treatment group. And 58% of the patients in the treatment group were able to engage in penetrative sex with their partners with the help of PDE5Is. There were no episodes of priapism or systemic toxicity from BoNT-A encountered in the treatment group.36 These results are comparable to the results obtained from the present study as (64.7%) patients in the treatment group reported improvement in their erections and 14 (41.2%) patients reported that the treatment improved their ability to engage in sexual activity.
7 CONCLUSION AND RECOMMENDATION
This study has demonstrated that ICIs of 100 units of BoNT-A is a safe and effective potential treatment modality for ED refractory to PDE5Is. BoNT-A may thus have a role in the ED management protocol by downgrading the level of ED and reducing the number of patients requiring second-line or third-line therapy. Further multicenter randomized controlled trials with longer follow-up periods are warranted in order to further explore the therapeutic efficacy and clinical safety of BoNT-A in the treatment of different subsets and severity levels of ED. Unfortunately, we did not look into whether or not some of the patients would be able to function without using PDE5Is because we asked all the patients to use the same dose of the same PDE5I that they were using before treatment. However, this is something that can be investigated in future studies.
Islam Fathy Soliman Abdelrahman Amr Abdel Raheem Yaser Elkhiat Abdelrahman A. Aburahma Tarek Abdel-Raheem Hussein Ghanem
Abstract
Background: There has been recent interest in the use of botulinum neurotoxin (BoNT) in the field of Andrology, whereby it has been investigated in the treatment of penile retraction and premature ejaculation.
Objectives: To evaluate the safety and efficacy of intracavernosal BoNT-A injection in the treatment of patients with erectile dysfunction (ED) refractory to oral phosphodiesterase inhibitors (PDE5Is).
Patients and methods: A double-blind randomized placebo-controlled prospective comparative study was conducted at one center and involved 70 patients with ED refractory to PDE5Is. At baseline, the following data were collected: erection hardness score (EHS), peak systolic velocity (PSV), end-diastolic velocity (EDV), sexual health inventory for men (SHIM), and the sexual encounter profile 2&3 (SEP-2&3) questionnaires. The treatment group (n = 35) received a single ICI of 100 units of BoNT-A in 2 ml of saline and the control group (n = 35) received a single ICI of 2 ml of saline. EHS, PSV, and EDV were assessed at 2 weeks post-treatment. SHIM, SEP-2, SEP-3, and global assessment questionnaire (GAQ-Q1&Q2) were completed at 2-, 6-, and 12-weeks post-treatment.
Results: Two weeks post-treatment, the treatment group showed a statistically significant improvement in the mean EHS, PSV, EDV, and GAQ-Q1 positive responders (p < 0.001) compared to the control group. At 6- and 12-weeks post-treatment, the treatment group showed a statistically significant improvement in the SHIM scores, SEP-2, and GAQ-Q1&Q2 positive responders compared to the control group. At 6 weeks, where there was a 5-point improvement in the mean SHIM score of the treatment group (10±5.9 from 5.4±1.7 at baseline) versus no improvement in the placebo group, 18 patients in the treatment group (53%) were able to have an erection hard enough for vaginal penetration versus only one patient in the control group.
Conclusion: BoNT-A is safe and effective as a potential treatment for ED refractory to PDE5I therapy.
INTRODUCTION
Moderate to severe erectile dysfunction (ED) affects 5–20% of men worldwide. It is estimated that by the year 2025, 322 million men will suffer from ED.1,2 ED is treated in a stepwise manner with oral (PDE5Is) being the first-line therapy for ED.3,4 However, despite the fact that PDE5Is have revolutionized ED treatment, they do not work in all cases. Sildenafil Citrate is successful in up to 63% of men with ED and Tadalafil was shown to be successful in up to 52% of ED patients. It is more likely that patients with severe ED will have poor responses to oral PDE5Is.5,6 Second-line therapy includes transurethral alprostadil, intracavernosal injections of vasoactive substances (ICI), and vacuum pump therapy. However, many patients find second-line therapy too invasive and lacking in spontaneity.7–9 Penile implants are used as a last resort when second-line therapy fails or is refused by the patient. Despite having high patient and partner satisfaction rates (exceeding 80%), implant surgery is not free from complications, such as infection, erosion, autoinflation, and mechanical failure, and the surgery is both expensive and invasive.4,10,11 Recent advances in the research for future ED therapies, such as low-intensity shockwave therapy, growth factor injection, gene therapy, stem cell therapy, and tissue engineering, can salvage ED patients from implant surgery as prosthesis surgery partially destroys the normal erection mechanism.4
Botulinum neurotoxin (BoNT) is produced by Clostridium botulinum, an anaerobic, gram-positive bacterium. Poisoning with BoNT can cause botulism, resulting in generalized paralysis, respiratory failure, and death.12,13 There are seven serotypes of BoNT: A, B, C1, D, E, F, and G. BoNT-A is the most commonly used serotype for medical purposes. There are several commercially available forms: Botox (Allergan Pharmaceuticals, Parsippany, NJ, USA) is the most widely used and has the most medical applications.14 Since its first use in 1977 for the treatment of strabismus in children, BoNT-A has since been used in aesthetic medicine and for the treatment of a number of disorders associated with overactive striated muscles, such as strabismus, esotropia, exotropia, focal dystonia, spasticity, and movement disorders.15 BoNT-A has also been used in the management of some smooth-muscle disorders, such as achalasia, oesophageal spasm, ptyalism, hyperhidrosis, intrinsic rhinitis, blepharospasm, muscle spasms, spasticity, axillary hyperhidrosis, and neurogenic detrusor muscle overactivity of the urinary bladder.15–21 It is widely used in aesthetic medicine to treat facial wrinkles in the forehead, lower face, lateral eye, and in between the eyebrows.22–27
BoNT prevents the release of acetylcholine at the presynaptic membrane causing flaccid paralysis for up to 3 months.28,29 BoNT can also inhibit the release of other neurotransmitters, such as noradrenaline, dopamine, glycine, and g-aminobutyrate. BoNT has been used for prostatic smooth-muscle relaxation in the management of lower urinary tract symptoms. It has also been found to inhibit noradrenaline release in the urethra and ano-coccygeus of rats.16,30,31
Erection depends on adequate cavernosal smooth muscle relaxation. PDE5Is and ICIs of vasoactive substances exert their effect by inducing corporal smooth muscle relaxation.32 Since BoNT-A is a strong inducer of smooth muscle relaxation, it may be effective in the treatment of ED refractory to PDE5Is.33
There has been recent interest in the use of BoNT in the field of Andrology, whereby it has been investigated in the treatment of penile retraction and premature ejaculation.34,35 The use of BoNT in the treatment of ED was first studied in 2016 by Ghanem et al., who performed an animal study followed by a human pilot study and showed promising results.33,36–38
*This study investigated the safety and efficacy of BoNT in the treatment of ED refractory to oral PDE5Is with the aim of salvaging those patients from second-and third-line ED therapies by downgrading the level of their ED.
2 PATIENTS AND METHODS
This is a double-blind randomized placebo-controlled prospective comparative study. Both the patients and the investigator were not aware of the active drug or the placebo that was injected. It was registered at NIH ClinicalTrials.gov (Home - ClinicalTrials.gov), number NCT03102762. The study protocol was approved by the local ethics committee.
2.1 Study design
Seventy consecutive patients from a single high-volume Andrology unit presenting with ED, not responding to on-demand PDE5Is, were recruited and randomly assigned to treatment group (n = 35) and control group (n = 35) using computer-generated randomization sequence. The sample size was calculated based upon the previous pilot study36 with the difference between the two groups was 3 ± 5 in SHIM score. Using power 85% and 5% significance level, 51 patients were required. That number was increased to 59 to adjust for nonparametric usage and increased again to 70 to compensate for possible losses during follow-up (20% more than calculated). The sample size was calculated using PS: Power & Sample Size Calculation Software Version 3.1.2 (Vanderbilt University, Nashville, TN, USA). A nonresponse to PDE5Is was defined as an erection not sufficient enough for penetration of the vagina or loss of the erection before completion of intercourse, after trying the highest dose of Sildenafil and Tadalafil on four separate occasions for each PDE5I. All the patients included in the study were PDE5Is failures, they were already on the highest dose of on-demand Sildenafil or tadalafil and were unable to achieve an erection sufficient for penetrative intercourse, this was also demonstrated in their baseline questionnaires. After treatment, in order to avoid any bias, each patient was asked to use the same dose (highest) of the same PDE5I that he was using before the injection.
4 METHODS
At baseline, all patients signed an informed consent form and had history taking as well as general and genital examination. Penile duplex with a trimix solution (20 µg alprostadil + 1 mg phentolamine + 30 mg papaverine) was also performed to assess the erection hardness score (EHS) and penile hemodynamics according to Standard Operating Procedures for Duplex Ultrasound: Standardization of Vascular Assessment of Erectile Dysfunction in order to achieve maximal cavernosal smooth muscle relaxation and possibly full erectile response.39 The latter was done by measuring the peak systolic (PSV) and the end-diastolic (EDV) velocities in the right and left cavernosal arteries and calculating the mean PSV and mean EDV. No cases of priapism needed intervention occurred. The patients also completed the validated Arabic translated version of sexual health inventory for men (SHIM), which consist of a 5-point questionnaire consisting of five questions assessing the erectile function, and it gives a full picture of the capability of the male for initiation and maintenance of erection sufficient for successful intercourse.40 They also completed sexual encounter profile 2&3 (SEP2&3) questionnaires.
The patients were then randomized into a treatment group (n = 35) and a control group (n = 35). Patients in the treatment group received a single ICI of 100 units of onabotulinumtoxinA BoNT-A (Botox™; Allergan Pharmaceuticals, Parsippany, NJ, USA) diluted in 2 ml of normal saline. A tourniquet was applied at the base of the penis, the treatment dose was distributed along 4 points, right and left distal and proximal shaft using a 23G insulin syringe (the tourniquet was removed after 20 min). Patients in the control group received a single ICI of 2 ml of IV saline administered in the same manner as the treatment group. Patients in both groups were asked to resume sexual activity 1 week after treatment with the help of on-demand PDE5Is trying the highest dose of Sildenafil and Tadalafil. ICI test, penile duplex, SHIM, SEP2 & SEP-3, and global assessment questions 1&2 (GAQ-Q1&Q2) were done at 2 weeks post-treatment. We used penile duplex to compare the hemodynamics of the penile arteries before and after injection. SHIM, SEP-2&SEP-3, and GAQ-Q1&Q2 were completed at 6- and 12-weeks post-treatment, respectively.
Statistical analysis was done using SPSS software (statistical package for the social sciences, version 21, SPSS Inc, Chicago, IL, USA). Frequency tables with percentages were used for categorical variables and descriptive statistics (median of minimum and maximum values) were used for numerical variables. Mann–Whitney test was used to compare quantitative variables, and the Chi-square test was used to analyze categorical variables. A p-value of < 0.05 was considered statistically significant.
6 DISCUSSION
The present study showed that (53%) of the patients in the treatment group (n = 18) were able to have an erection hard enough for vaginal penetration. Twenty-two (64.7%) patients in the treatment group reported improvement in their erections and 14 (41.2%) patients reported that the treatment improved their ability to engage in sexual activity versus none of the patients in the control group. Also, 2 weeks post-treatment, the treatment group showed a statistically significant improvement in the penile hemodynamics in the form of the mean EHS, PSV, and EDV (p < 0.001) compared to the control group. Finally, at 6- and 12-weeks post-treatment, there was a statistically significant difference between both groups in the SHIM score, SEP-2, GAQ-Q1, and GAQ-Q2 positive responders favoring the treatment group.
*The first human pilot study involved 24 men with severe vasculogenic ED refractory to PDE5Is; the patients were randomized to treatment and control groups (1:1). The treatment group received a single ICI of Botox 50 Units and the control group received a single ICI of 0.9% normal saline 1 ml. There was a statistically significant improvement in the mean PSV, SHIM score, and EHS in the treatment group. And 58% of the patients in the treatment group were able to engage in penetrative sex with their partners with the help of PDE5Is. There were no episodes of priapism or systemic toxicity from BoNT-A encountered in the treatment group.36 These results are comparable to the results obtained from the present study as (64.7%) patients in the treatment group reported improvement in their erections and 14 (41.2%) patients reported that the treatment improved their ability to engage in sexual activity.
7 CONCLUSION AND RECOMMENDATION
This study has demonstrated that ICIs of 100 units of BoNT-A is a safe and effective potential treatment modality for ED refractory to PDE5Is. BoNT-A may thus have a role in the ED management protocol by downgrading the level of ED and reducing the number of patients requiring second-line or third-line therapy. Further multicenter randomized controlled trials with longer follow-up periods are warranted in order to further explore the therapeutic efficacy and clinical safety of BoNT-A in the treatment of different subsets and severity levels of ED. Unfortunately, we did not look into whether or not some of the patients would be able to function without using PDE5Is because we asked all the patients to use the same dose of the same PDE5I that they were using before treatment. However, this is something that can be investigated in future studies.
