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Alkalization Does Not Alleviate Penile Pain Induced By Intracavernous Injection of Prostaglandin E1
0022-534719611563-0999$03.0010
THE JOLIKNAL OF UROLOGY Copyright 0 1996 by AMERICAN UROLOCICAL ASSOCIATION,INC.
Vol. 156,999-1000, September 1996 Printed in U.S.A.
ALKALIZATION DOES NOT ALLEVIATE PENILE PAIN INDUCED BY INTRACAVERNOUS INJECTION OF PROSTAGLANDIN E l MICHAEL GODSCHALK, DAVID GHEORGHIU, P. GARY KATZ AND THOMAS MULLIGAN From the Divisions
of
Geriatric Medicine and Urology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Richmond, Virginia
ABSTRACT
Purpose: A prospective, randomized, double-blind study was done to determine whether alkalization of prostaglandin E l decreases pain associated with intracavernous injection. Materials and Methods: Ten subjects with a history of pain following at least 70% of injections of prostaglandin E l received 2 injections of prostaglandin E l , 1 with and 1 without sodium bicarbonate. Patients reported the duration and intensity of pain following each injection. Results: Comparing injections of prostaglandin E l with and without bicarbonate, there were no significant differences in number of subjects reporting pain, or duration and intensity of pain. Conclusions: Addition of sodium bicarbonate does not alleviate penile pain associated with injection of prostaglandin El. KEY WORDS:prostaglandins E, alprostadil, pain, impotence The most frequent side effect (and reason for discontinuation of therapy) associated with intracavernous injection of prostaglandin E l is pain, which has been reported in 11.5 to 80% of patients who inject prostaglandin El.’-6 The etiology of pain following injection of prostaglandin E l is not well understood. A possible explanation is that pain is due to acidity or ionization of the prostaglandin E l solution.7 To determine whether alkalization of prostaglandin E l decreases penile pain with injection, we performed a prospective, randomized, double-blind study of subjects who had experienced penile pain with at least 70% of prior prostaglandin E l injections performed at home. MATERIALS AND METHODS
reconstitute the prostaglandin E l as described. The pH of the prostaglandin E l solution was 3.5 to 6.0 without sodium bicarbonate and greater than 7 after sodium bicarbonate was added. All injections were performed by the same investigator (M. G.). Following each intracavernous injection, subjects completed a questionnaire asking whether they experienced any pain after injection and its duration. Subjects also rated the severity of pain on a 10-point Likert scale from 1-no penile pain to lO-“worst penile pain I ever had.” RESULTS
Of 13 subjects screened for this study 2 were excluded because they did not report pain with at least 70% of injections of prostaglandin E l a t home and 1was excluded due to persistently elevated serum glucose concentrations. The remaining 10 subjects completed the study. After prostaglandin E l injections without bicarbonate, 8 of 10 subjects reported mild penile pain (mean pain intensity plus or minus standard deviation 2.7 t 1.9)lasting approximately 57 minutes. Seven of the 10 prostaglandin E l injections with bicarbonate also produced penile pain (mean pain intensity 3.4 2 2.9) for an average duration of 51 minutes. Six subjects had pain with both injections. There was no statistically significant difference in reported pain when comparing prostaglandin E l injections with or without bicarbonate (see table).
We recruited from the outpatient clinics of our Veterans Affairs medical center and from the community subjects 18 to 75 years old with erectile dysfunction who had experienced penile pain after at least 70% of intracavernous prostaglandin E l self-injections at home. After informed consent was obtained, the initial evaluation included medical history, physical examination, electrocardiogram, complete blood count, serum chemistry studies and urinalysis. Exclusion criteria were a recent major illness, uncontrolled hypertension or diabetes, a history of priapism, Peyronie’s plaques or laboratory abnormalities greater than 25% above or below accepted normal ranges. Subjects were not permitted to use analgesics, such as aspirin, acetaminophen or ibuprofen, durDISCUSSION ing the study. Subjects received 2 injections (at least 1 day apart) of the Although pain following injection of prostaglandin E l is a same dose of prostaglandin E l that they were using at home, common reason for discontinuation of therapy, its etiology is 1 with and 1 without sodium bicarbonate. The sequence of unknown. Attempts t o eliminate pain have included combininjections (alkaline versus acidic injection) was determined ing prostaglandin E l with a local anesthetic, such as lidoby the research pharmacist using a randomization list, and the subject and investigator were blinded as to which formulation the patient received. Prostaglandin E l was provided Degree and duration of penile pain when prostaglandin E l is as a sterile powder that was reconstituted with 1 ml. bacinjected with and without bicarbonate teriostatic water for injection with benzyl alcohol, resulting in a solution containing 20 pg./ml. prostaglandin E l . For the Mean ? SD ( p value) injections containing sodium bicarbonate, 0.1 ml. of a 4.2% Added Sodium Bicarbonate Duration (mins.) Degree of Pain’ (42 mg./ml.) sodium bicarbonate solution was added to a 20 56.9 i 59.5 (0.37) No 2.7 ? 1.9 (0.27) ml. vial of bacteriostatic water, and this mixture was used to Yes
Accepted for publication February 16,1996. Supported in part by the Upjohn Company.
3.4 t- 2.9 50.9 2 45.3 10-point Likert scale from 1-no penile pain to 10“worst penile pain I ever had.”
* Measured using a
999
1000
ALKALIZATION DOES NOT RELIEVE PAIN DUE TO INTRACAVERNOUS PROSTAGLANDIN E l
caine8 or procaine,g or altering the pH of the injected solution glandin E l does not alleviate penile pain associated with with sodium b i ~ a r b o n a t eIn . ~a double-blind study Moriel and injection of this agent. Rajfer added sodium bicarbonate to a combination of papaverine, phentolamine and prostaglandin E l (increasing pH to REFERENCES 7.05L7 Subjects received injections with or without sodium 1. Waldhauser, M. and Schramek, P.: Efficiencyand side effects of bicarbonate, without crossover. Of the subjects receiving inprostaglandin E l in the treatment of erectile dysfunction. jections without sodium bicarbonate 58%reported pain verJ. Urol., 140: 525, 1988. sus 5% of men who received bicarbonate. We attempted to 2. Kattan, S., Collins, J. P. and Mohr, D.: Double-blind, cross-over clarify the relationship of prostaglandin E l , pH and pain by study comparing prostaglandin E l and papaverine in patients injecting solely prostaglandin E 1with and without bicarbonwith vasculogenic impotence. Urology, 37: 516, 1991. ate using a double-blind crossover design in men with a 3. Gerber, G. S. and Levine, L. A.: Pharmacological erection program using prostaglandin E l . J. Urol., 146: 786, 1991. history of penile pain after prostaglandin E l injections. 4. Lakin, M. M., Montague, D. K., VanderBrug Medendorp, S., Unexpectedly, we found no significant difference in reTesar, L. and Schover, L. R.: Intracavernous injection therapy: ported frequency of pain between injections of prostaglandin analysis of results and complications.J. Urol., 1 4 3 1138,1990. E l with and without sodium bicarbonate. Although fre5. Mahmoud, K Z., El Dakhli, M. R., Fahmi, I. M. and Abdel-Aziz, quency of pain was slightly decreased in the bicarbonate A. A.: Comparative value of prostaglandin E l and papaverine as was duration (51 versus 57 mingroup (70 versus 800/0), in treatment of erectile failure: double-blind crossover study utes), severity of pain was increased (scale 3.4 versus 2.7). among Egyptian patients. J. Urol., 147: 623, 1992. The disparity between our results and those of Moriel and 6. Chen, J., Godschalk, M. F., Katz, P. G. and Mulligan, T.: InciRajfer7 may be due to the type of solution used, for example dence of penile pain after injection of a new formulation of prostaglandin El. J. Urol., 154: 77, 1995. prostaglandin E l in combination with papaverine and phen7. Moriel, E. Z. and Rajfer, J.: Sodium bicarbonate alleviates penile tolamine versus prostaglandin E l alone, or because ours was pain induced by intracavernous injections for erectile dysfunca prospective double-blind randomized study in which men tion. J. Urol., part 2, 1 4 9 1299, 1993. with a history of penile pain following prostaglandin E l 8. Schoumann, M., Lacroix, P. and Amer, M.: Suppression of prosinjection served as their own controls. Of note is the difficulty taglandin El-induced pain by dilution of the drug with lidowe encountered in recruiting subjects for this study. Alcaine before intracavernous injection. Letter to the Editor. though patients may report pain with occasional injections,6 J. Urol., 148: 1266, 1992. in our experience it is unusual for patients to have pain with 9. Schramek, P., Plas, E. G., Hubner, W. A. and Pfluger, H.: Intramost or all injections. cavernous injection of prostaglandin E l plus procaine in the treatment of erectile dysfunction. J. Urol., 152: 1108, 1994. In conclusion, addition of sodium bicarbonate to prosta-
THE JOLIKNAL OF UROLOGY Copyright 0 1996 by AMERICAN UROLOCICAL ASSOCIATION,INC.
Vol. 156,999-1000, September 1996 Printed in U.S.A.
ALKALIZATION DOES NOT ALLEVIATE PENILE PAIN INDUCED BY INTRACAVERNOUS INJECTION OF PROSTAGLANDIN E l MICHAEL GODSCHALK, DAVID GHEORGHIU, P. GARY KATZ AND THOMAS MULLIGAN From the Divisions
of
Geriatric Medicine and Urology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Richmond, Virginia
ABSTRACT
Purpose: A prospective, randomized, double-blind study was done to determine whether alkalization of prostaglandin E l decreases pain associated with intracavernous injection. Materials and Methods: Ten subjects with a history of pain following at least 70% of injections of prostaglandin E l received 2 injections of prostaglandin E l , 1 with and 1 without sodium bicarbonate. Patients reported the duration and intensity of pain following each injection. Results: Comparing injections of prostaglandin E l with and without bicarbonate, there were no significant differences in number of subjects reporting pain, or duration and intensity of pain. Conclusions: Addition of sodium bicarbonate does not alleviate penile pain associated with injection of prostaglandin El. KEY WORDS:prostaglandins E, alprostadil, pain, impotence The most frequent side effect (and reason for discontinuation of therapy) associated with intracavernous injection of prostaglandin E l is pain, which has been reported in 11.5 to 80% of patients who inject prostaglandin El.’-6 The etiology of pain following injection of prostaglandin E l is not well understood. A possible explanation is that pain is due to acidity or ionization of the prostaglandin E l solution.7 To determine whether alkalization of prostaglandin E l decreases penile pain with injection, we performed a prospective, randomized, double-blind study of subjects who had experienced penile pain with at least 70% of prior prostaglandin E l injections performed at home. MATERIALS AND METHODS
reconstitute the prostaglandin E l as described. The pH of the prostaglandin E l solution was 3.5 to 6.0 without sodium bicarbonate and greater than 7 after sodium bicarbonate was added. All injections were performed by the same investigator (M. G.). Following each intracavernous injection, subjects completed a questionnaire asking whether they experienced any pain after injection and its duration. Subjects also rated the severity of pain on a 10-point Likert scale from 1-no penile pain to lO-“worst penile pain I ever had.” RESULTS
Of 13 subjects screened for this study 2 were excluded because they did not report pain with at least 70% of injections of prostaglandin E l a t home and 1was excluded due to persistently elevated serum glucose concentrations. The remaining 10 subjects completed the study. After prostaglandin E l injections without bicarbonate, 8 of 10 subjects reported mild penile pain (mean pain intensity plus or minus standard deviation 2.7 t 1.9)lasting approximately 57 minutes. Seven of the 10 prostaglandin E l injections with bicarbonate also produced penile pain (mean pain intensity 3.4 2 2.9) for an average duration of 51 minutes. Six subjects had pain with both injections. There was no statistically significant difference in reported pain when comparing prostaglandin E l injections with or without bicarbonate (see table).
We recruited from the outpatient clinics of our Veterans Affairs medical center and from the community subjects 18 to 75 years old with erectile dysfunction who had experienced penile pain after at least 70% of intracavernous prostaglandin E l self-injections at home. After informed consent was obtained, the initial evaluation included medical history, physical examination, electrocardiogram, complete blood count, serum chemistry studies and urinalysis. Exclusion criteria were a recent major illness, uncontrolled hypertension or diabetes, a history of priapism, Peyronie’s plaques or laboratory abnormalities greater than 25% above or below accepted normal ranges. Subjects were not permitted to use analgesics, such as aspirin, acetaminophen or ibuprofen, durDISCUSSION ing the study. Subjects received 2 injections (at least 1 day apart) of the Although pain following injection of prostaglandin E l is a same dose of prostaglandin E l that they were using at home, common reason for discontinuation of therapy, its etiology is 1 with and 1 without sodium bicarbonate. The sequence of unknown. Attempts t o eliminate pain have included combininjections (alkaline versus acidic injection) was determined ing prostaglandin E l with a local anesthetic, such as lidoby the research pharmacist using a randomization list, and the subject and investigator were blinded as to which formulation the patient received. Prostaglandin E l was provided Degree and duration of penile pain when prostaglandin E l is as a sterile powder that was reconstituted with 1 ml. bacinjected with and without bicarbonate teriostatic water for injection with benzyl alcohol, resulting in a solution containing 20 pg./ml. prostaglandin E l . For the Mean ? SD ( p value) injections containing sodium bicarbonate, 0.1 ml. of a 4.2% Added Sodium Bicarbonate Duration (mins.) Degree of Pain’ (42 mg./ml.) sodium bicarbonate solution was added to a 20 56.9 i 59.5 (0.37) No 2.7 ? 1.9 (0.27) ml. vial of bacteriostatic water, and this mixture was used to Yes
Accepted for publication February 16,1996. Supported in part by the Upjohn Company.
3.4 t- 2.9 50.9 2 45.3 10-point Likert scale from 1-no penile pain to 10“worst penile pain I ever had.”
* Measured using a
999
1000
ALKALIZATION DOES NOT RELIEVE PAIN DUE TO INTRACAVERNOUS PROSTAGLANDIN E l
caine8 or procaine,g or altering the pH of the injected solution glandin E l does not alleviate penile pain associated with with sodium b i ~ a r b o n a t eIn . ~a double-blind study Moriel and injection of this agent. Rajfer added sodium bicarbonate to a combination of papaverine, phentolamine and prostaglandin E l (increasing pH to REFERENCES 7.05L7 Subjects received injections with or without sodium 1. Waldhauser, M. and Schramek, P.: Efficiencyand side effects of bicarbonate, without crossover. Of the subjects receiving inprostaglandin E l in the treatment of erectile dysfunction. jections without sodium bicarbonate 58%reported pain verJ. Urol., 140: 525, 1988. sus 5% of men who received bicarbonate. We attempted to 2. Kattan, S., Collins, J. P. and Mohr, D.: Double-blind, cross-over clarify the relationship of prostaglandin E l , pH and pain by study comparing prostaglandin E l and papaverine in patients injecting solely prostaglandin E 1with and without bicarbonwith vasculogenic impotence. Urology, 37: 516, 1991. ate using a double-blind crossover design in men with a 3. Gerber, G. S. and Levine, L. A.: Pharmacological erection program using prostaglandin E l . J. Urol., 146: 786, 1991. history of penile pain after prostaglandin E l injections. 4. Lakin, M. M., Montague, D. K., VanderBrug Medendorp, S., Unexpectedly, we found no significant difference in reTesar, L. and Schover, L. R.: Intracavernous injection therapy: ported frequency of pain between injections of prostaglandin analysis of results and complications.J. Urol., 1 4 3 1138,1990. E l with and without sodium bicarbonate. Although fre5. Mahmoud, K Z., El Dakhli, M. R., Fahmi, I. M. and Abdel-Aziz, quency of pain was slightly decreased in the bicarbonate A. A.: Comparative value of prostaglandin E l and papaverine as was duration (51 versus 57 mingroup (70 versus 800/0), in treatment of erectile failure: double-blind crossover study utes), severity of pain was increased (scale 3.4 versus 2.7). among Egyptian patients. J. Urol., 147: 623, 1992. The disparity between our results and those of Moriel and 6. Chen, J., Godschalk, M. F., Katz, P. G. and Mulligan, T.: InciRajfer7 may be due to the type of solution used, for example dence of penile pain after injection of a new formulation of prostaglandin El. J. Urol., 154: 77, 1995. prostaglandin E l in combination with papaverine and phen7. Moriel, E. Z. and Rajfer, J.: Sodium bicarbonate alleviates penile tolamine versus prostaglandin E l alone, or because ours was pain induced by intracavernous injections for erectile dysfunca prospective double-blind randomized study in which men tion. J. Urol., part 2, 1 4 9 1299, 1993. with a history of penile pain following prostaglandin E l 8. Schoumann, M., Lacroix, P. and Amer, M.: Suppression of prosinjection served as their own controls. Of note is the difficulty taglandin El-induced pain by dilution of the drug with lidowe encountered in recruiting subjects for this study. Alcaine before intracavernous injection. Letter to the Editor. though patients may report pain with occasional injections,6 J. Urol., 148: 1266, 1992. in our experience it is unusual for patients to have pain with 9. Schramek, P., Plas, E. G., Hubner, W. A. and Pfluger, H.: Intramost or all injections. cavernous injection of prostaglandin E l plus procaine in the treatment of erectile dysfunction. J. Urol., 152: 1108, 1994. In conclusion, addition of sodium bicarbonate to prosta-