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ORIGINAL RESEARCH—ED PHARMACOTHERAPY: Patient-Reported Pain with Initial Intracavernosal Injection
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ORIGINAL RESEARCH—ED PHARMACOTHERAPY Patient-Reported Pain with Initial Intracavernosal Injection Jeffrey Albaugh, PhD (cand), APRN, CUCNS,* and Carol Estwing Ferrans, PhD, RN, FAAN† *Department of Sexual Health Program, Northwestern Memorial Wellness Institute and Jesse Brown VA Medical Center, Chicago, IL, USA; †College of Nursing, University of Illinois at Chicago, Chicago, IL, USA DOI: 10.1111/j.1743-6109.2008.01037.x
ABSTRACT
Introduction. Despite the efficacy of intracavernosal injections, one of the greatest impediments to injection therapy is the negative reaction of men to the thought of a needle inserted into the penis. Aim. To determine the severity of pain associated with the initial intracavernosal self-injections for erectile dysfunction (both pain associated with the needle insertion and the medications). Methods. This is a descriptive study of self-reported pain associated with intracavernosal self-injections in 65 men with erectile dysfunction. Pain was assessed immediately after needle insertion and again approximately 10–20 minutes postinjection, utilizing a verbal 0–10 pain scale. Main Outcome Measures. A verbal 0–10 pain rating scale was used to assess pain both for injection pain and medication pain. Results. For needle insertion, the mean pain rating was 0.80 (standard deviation [SD] = 0.81), with 40% reporting no pain at all. Of the 39 patients who reported pain, the mean pain rating was 1.33 (SD = 0.61). For the medication itself, the mean pain rating was 0.92 (SD = 1.5), with more than half (64.6%) reporting no pain. For those experiencing pain from the medication (N = 23), the mean pain rating was 2.6 (SD = 1.27, range 0.5–5.0). Significantly more patients with radical prostatectomy experienced pain from the medication than other men (51.9% vs. 23.7%, P = 0.02). Conclusion. The majority of patients experienced little or no pain from either the needle insertion or the medication. Even for men who experienced pain, the severity was relatively low. This study provides information to help diminish fears about injection pain for patients considering penile injections. In addition, this study suggests that medication pain is more common in men postradical prostatectomy, so that it may be advisable to start with lower dosages of prostaglandin alone or in combination with other vasoactive medications for these patients. Albaugh J, and Ferrans CE. Patient-reported pain with initial intracavernosal injection. J Sex Med 2009;6:513–519. Key Words. Erectile Dysfunction; Intracavernosal Injections; Pain
Introduction
E
rectile dysfunction (ED) is a common problem for men in the United States, affecting almost 1 in 5 men over the age of 20, with greater prevalence in older men (60 years and over) [1]. Although oral phosphodiesterase type 5 (PDE5) inhibitors are typically preferred as a first option for the treatment of ED, the failure rate for these agents in men with ED has been reported to be approximately 32% [2]. In men after radical prostatectomy,
© 2008 International Society for Sexual Medicine
the failure rates of oral agents are even greater and have been reported as high as 69–80% [3–5]. When oral treatments fail, intracavernosal injections are the most efficacious medical treatment option [3]. Intracavernosal injections have been utilized for ED since their introduction in 1982 [6]. Penile injections of vasoactive agents have been shown to be effective in as high as 87–93% of men utilizing this treatment [7,8]. Intracavernosal injections are used throughout the world as monotherapy or in combination with other vasoactive medications. J Sex Med 2009;6:513–519
514 Alprostadil (prostaglandin E1 [PGE1]) is a commonly used monotherapy and is available from two pharmaceutical companies as alprostadil alfadex (Edex or Viridal, Schwarz Pharma, Monheim, Germany) and alprostadil for injection (Caverject or Caverject Impulse, Pfizer, New York, NY, USA). Other vasoactive drugs that may be used in combinations are papaverine, phentolamine, and PGE1. One of the most commonly used combinations of injectable agents for ED is trimix, which typically contains papaverine, phentolamine, and prostaglandin [9–11]. Trimix may be used instead of prostaglandin monotherapy related to lack of efficacy of monotherapy, pain related to prostaglandin, and/or cost factors [12]. Despite the efficacy of intracavernosal injections, one of the largest impediments to injection therapy is the negative reaction of most men to the thought of a needle inserted into the penis. In the clinic, patients frequently comment on how surprisingly little pain is felt with the needle insertion during injection, yet there is little research documenting the pain actually experienced. Pain with injections can occur related to the needle insertion and/or from the medication itself. Regarding pain with the needle insertion, there is only one previous study that prospectively assessed this at the time of the needle insertion [13]. This study examined pain ratings using a 0–10 visual analog scale with needle insertion by either a nurse or the patient. The average pain rating for the injection was 1.93 ⫾ 1.76 for the 59 participants. The majority of the injections in the study was performed by a nurse (N = 42) and not the patient (N = 17). In addition, this study only measured pain with needle insertion and did not assess pain associated with the action of the medication. Another study retrospectively evaluated long-term satisfaction with intracavernosal injections [14]. Recognizing the limitations of a retrospective analysis, the authors recommended that a subsequent study should assess patients at the time of initiation of therapy. The most common side effect of alprostadil (PGE1) is pain [15,16]. Pain has been reported in up to 50% of the patients using intracavernosal injections of prostaglandin products, such as alprostadil, and pain also increases with higher dosages of alprostadil [7,8,10]. Although the pain was primarily mild, some of the men (6%) using these injections found it distressing enough to withdraw from therapy. No studies were found that prospectively assessed pain from both the needle insertion at the time of the injection as well as the injectable medications themselves. J Sex Med 2009;6:513–519
Albaugh and Ferrans Aims
The purpose of this study was to determine the severity of pain associated with intracavernosal injections for ED (both the pain associated with the needle insertion and the medications), in a cohort of patients who either failed to respond to oral PDE5 inhibitor treatments or were unable to utilize PDE5 inhibitors because of contraindication with other medications. Methods
Study Design This prospective, descriptive study involved collecting information on pain at the time it was experienced during the educational clinical visit for the initial intracavernosal self-injection, in men who never had previous penile injections. Self-reported pain was measured twice using the verbal 0–10 pain rating scale: immediately after the needle insertion and again after the medication began to take effect (approximately 10–20 minutes postinjection). The type and amount of medication was recorded along with the responses to pain and the erectile response. All measures were administered during the clinic appointment by the clinician and were immediately recorded. Demographic information was also gathered from the patients and was recorded. In addition, the participants were asked who initiated the discussion about their ED. The study received institutional review board approval, and all participants provided written informed consent prior to participation. Sample The participants were men (N = 65) who selfselected penile injections and came to the clinic of the principal investigator between August 2006 and April 2008 to learn how to perform penile self-injections for ED. The inclusion criteria were as follows: (i) adult men 21 years or older diagnosed with ED; (ii) were attending the clinic to obtain intracavernosal injection treatments for ED; and (iii) the injection associated with the study must have been the patient’s first self-injection. Measures A verbal 0–10 pain rating scale was used to assess pain for both injection pain and medication pain. The verbal pain rating scale was selected for use in this study because it provides a valid measurement of pain and is the most commonly used for pain assessment in clinical practice [17]. The verbal
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Pain with Self-Injection pain rating scale and visual analogue scale have been found to be highly correlated (r = 0.95, 95% confidence interval [CI] 0.94–0.96) [17]. Immediately following the self-injection, the patients were asked to rate the pain with the needle insertion on a scale of 0–10 with 0 being no pain at all and 10 being the worse possible pain the participants could imagine. Approximately 10–20 minutes after injection, as the penis began to respond to the medication with increased fullness, the patients were again asked to rate any pain on the same 0–10 verbal pain rating scale. After each pain rating, the patients were asked if the amount of pain they just experienced would be likely to discourage them from giving themselves the injections at home. The possible response choices were (i) no—not at all, (ii) yes—a little, (iii) yes—somewhat, and (iv) yes—a great deal.
Procedure All patients recruited for the study were attending the clinic to learn to perform self-injections into the penis to treat ED. If the patient met the inclusion criteria, he was asked to participate in the study. If a patient chose to perform injection therapy, the clinician would discuss the pros and cons of each vasoactive injectable agent option available, and the clinician and the patient would choose which injectable agent the patient would utilize for the initial injection. Factors that may affect a patient’s choice of agents are cost, insurance coverage of the medication, concerns or fears about pain from the medication (specifically from prostaglandin/ alprostadil), previous pain experienced with alprostadil urethral suppository (if the patient had previously used a urethral suppository), and patient or provider preferences. Starting doses of alprostadil used in the clinic typically range from 5 to 20 mcg, while starting doses of trimix or bimix typically may range from 0.1 to 0.5 mL depending on the patients’ history, age, previous failed treatment with other ED treatment options (such as alprostadil urethral suppository or the vacuum constriction device), and how long they have had ED. Intracavernosal injection therapy used for the patients who participated in this study included commonly utilized vasoactive agents (prostaglandin, phentolamine, and papaverine) as monotherapy (prostaglandin/alprostadil) or combined therapy. The trimix (papaverine 30 mg/ phentolamine 1 mg/PGE1 10 mcg/1 mL), bimix (papaverine 30 mg/phentolamine 1.5 mg/1 mL), or prostaglandin E1 (20 mcg/mL) was self-injected using a 0.5–1 mL insulin syringe with a 0.5-in.
length, 29-gauge needle. The same needle was used to draw up and administer the medication. No automatic injector device was used by the patients in this study. The most commonly used alprostadil preparation in the clinic was Edex/Viridal (Alprostadil-Alfadex, Schwarz Pharma). Edex is supplied in a single-dose, dual chamber cartridge with a 0.5-in., 29-gauge needle. All patients were taught to self-perform intracavernosal injections by the same advanced practice urology clinical nurse specialist (J.A.). Each patient who used Edex watched the Edex patient instruction video prior to injecting. All patients read through the written instruction for injecting their particular vasoactive medication. The patients were than given explicit instruction on the medication, side effects, and what to do if problems occur (including pain, priapism, and/or Peyronie’s). The patients were shown how to prepare the medication and selfinject the medication (using an anatomical model for demonstration.) If the patient had no further questions or concerns, the first self-injection was performed. Results
Sixty-five patients, ranging in age from 37 to 82 years (mean = 60.9, SD = 9.57), participated in the study. Demographic and clinical information is presented in Table 1. The education level of the participants ranged from high school graduates to doctorally prepared men with 67.7% having at least Table 1
Clinical and demographic characteristics Mean (SD) or frequency
Characteristic Age in years Comorbidities (%)* Hypertension Prostatectomy Hyperlipidemia Cardiovascular disease Diabetes Ethnicity (%) Caucasian African American Latino Educational level (%) High school Some college or associates degree Bachelor’s degree Master’s degree Doctorate Who Raised the Issue of ED? (%) Patient Health care clinician
60.9 (SD = 9.57) 50.8 41.5 43.1 32.3 23.1 78.5 16.9 4.6 10.8 21.5 27.7 26.2 13.8 80 20
*Participants had more than one comorbidity. SD = standard deviation; ED = erectile dysfunction.
J Sex Med 2009;6:513–519
516 a bachelor’s degree. The majority was Caucasian (78.5%), 16.9% was African American, and 4.6% was Latino. The comorbidities associated with ED were greatly varied and included, but were not limited to hypertension, hyperlipidemia, cardiovascular disease, diabetes, postradical prostatectomy, or a combination of any of these factors. For this study, the majority (N = 51) of participants used monotherapy with a prostaglandin injection, while others (N = 13) used trimix (papaverine 30 mg/ phentolamine 1 mg/prostaglandin 10 mcg/1 mL), and the remaining patient (N = 1) used bimix (phentolamine and papaverine). The initial dosages of prostaglandin ranged from 5 to 20 mcg with 94% of the patients (N = 48 out of the total 51 men who used monotherapy of prostaglandin) using the lower initial doses of 5–10 mcg. The dosages of trimix (papaverine 30 mg/phentolamine 1 mg/ prostaglandin 10 mcg/1 mL) used in the clinic for the participants in this study ranged from 0.1 mL (papaverine 3 mg/phentolamine 0.1 mg/prostaglandin 1 mcg) through 0.5 mL (papaverine 15 mg/ phentolamine 0.5 mg/prostaglandin 5 mcg), and the dose of bimix for the one patient who used bimix (papaverine 30 mg and phentolamine 1.5 mg/mL) was 0.20 mL (Papaverine 6 mg and phentolamine 0.3 mg). All the men, except for two men who could not use a PDE5 inhibitor related to a contraindication with other medications, had previously tried PDE5 inhibitors multiple times without achieving satisfactory results.
Number of Patients Reporting Pain
Pain with Needle Insertion The pain ratings for needle insertion pain are presented in Figure 1. Of the 65 patients in the study, 40% (N = 26) reported no pain at all with the needle insertion. The mean pain rating for the needle insertion process for all 65 participants was very slight at 0.80 (SD = 0.81) out of 10. Of those 30
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Figure 1 Needle insertion pain with injections.
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Albaugh and Ferrans 45
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Figure 2 Medication pain from the side effects of injectable medications.
patients who reported any pain at all (N = 39) with the needle insertion, the mean pain rating was 1.33 (SD = 0.63), with a range of 0.5–3.0 out of a possible 10 pain score. In response to the question “Would the amount of pain you just experienced with the injection be likely to discourage you from giving yourself the injections at home?”, all 65 patients responded “no, not at all.”
Pain from the Medication The pain related to medication was assessed 10–20 minutes after the initial injection, to coincide with the evaluation of the erectile response from the medication. The pain ratings for medication pain are presented in Figure 2. The mean pain rating for the entire group was 0.92 (SD = 1.5). More than half (65%, N = 42) of the patients did not report any pain from the medication itself. For those who did experience pain, the mean pain rating was 2.6 (SD = 1.27) out of 10 with reports of pain ranging from 0.5 to 5. Medication pain occurred in 35% (N = 23) of the men and occurred only in those who utilized the prostaglandin products of monotherapy or trimix, because no pain was reported by the one patient who used bimix (which does not contain prostaglandin). In response to the question “Would the amount of pain you just experienced with the injection be likely to discourage you from giving yourself the injections at home?”, only 4 of the 26 patients (15.4%) who had medication pain said the pain would discourage them from using the medication again at home. The average pain rating for the men using a monotherapy with prostaglandin (N = 51) was 0.83 (SD = 1.4), and the average pain rating for the men using trimix (papaverine 30 mg/ phentolamine 1 mg/prostaglandin 10 mcg/1 mL; N = 13) was 1.3 (SD = 1.7). A comparison of men who had radical prostatectomy (N = 27) with those who had not (N = 38)
Pain with Self-Injection revealed that a significantly larger proportion of postradical prostatectomy men experienced pain from the medication (51.9% vs. 23.7%) (c2(1,N=65) = 5.5, P = 0.02). Examination of the data showed that pain was experienced by men regardless of the time since radical prostatectomy, ranging from 8 weeks to 33 months.
Who Raised the Issue of Sexual Dysfunction Of the 65 participants, 80% of the patients (N = 52) stated that they had initiated the conversation about sexual dysfunction with their healthcare provider, rather than the healthcare provider asking about the issue. Discussion
This study is unique in that pain from both needle insertion and medication for intracavernosal therapy was evaluated prospectively during the initial in-clinic self-injection of intracavernosal vasoactive medications. Although it is not possible to generalize from this sample, this study provides evidence that needle insertion for intracavernosal injections is not necessarily painful. Another published study reporting pain with needle insertions, most of which were performed by a nurse rather than the patient himself, used a visual analog pain rating scale from 0 to 10 and reported low levels of pain also, although not as low as those in this sample [13]. In addition, Lane et al. did not report the proportion of men experiencing no pain. In our study, there was a surprisingly high percentage who reported feeling no pain with needle insertion (40%). Although men typically anticipate the injection to be painful, the needles used for intracavernosal injections are very fine (29 gauge) and are only inserted into the lower part of the shaft of the penis. In a study comparing preference for intraurethral alprostadil vs. injectable alprostadil, despite the perceived fear of needle insertion, men who tried both the urethral suppository and injectable preparations of alprostadil preferred the intracavernosal injections, which also lends support to the premise that needle insertion pain is not significant [18]. In terms of medication pain, men who had a history of radical prostatectomy reported the side effect of pain with the use of prostaglandins more often than men who had not undergone a radical prostatectomy. Intracavernosal injections may be prescribed after radical prostatectomy for treatment of ED and/or for penile rehabilitation, and a recent study revealed that injections are the most
517 common first-line treatment after radical prostatectomy of urologists in France [19]. The complaint of pain in the penis and groin area after prostaglandin injections is not completely understood. Montorsi et al. provides several theories for the local corporeal pain occurring with injection of prostaglandin, including activation of pain receptors via the prostaglandin [10]. Prostaglandins produce a hyperalgesic affect by elevating sensitivity to pain receptors and increasing painful input to the central nervous system through direct cellular action on the membrane of the organ, which in this case is the penis [20]. It is important to note that pain in the penis and groin area from the injected medication was experienced by some participants even as many as 33 months after radical prostatectomy surgery. These findings indicate that it may be appropriate to start with lower dosages of prostaglandin alone or in combination with other vasoactive medications for postradical prostatectomy patients and other patients who experience medication pain after injection. Prostaglandin may even need to be eliminated as a vasoactive injectable in patients who continue to have pain with these agents at lower doses. These patients may do better with a bimix solution of either papaverine and phentolamine as used in this study. When pain occurs from the prostaglandin, switching to a trimix (papaverine/phentolamine/ PGE1) or even a bimix (papaverine/phentolamine) combination has been associated with lower incidence of pain (2.9% for trimix and 0% for bimix) in a previous study [21]. Another injectable agent currently under investigation in the United States uses a combination of vasoactive intestinal polypeptide (VIP) and phentolamine (Invicorp is currently undergoing phase III clinical trials in the United States sponsored by Plethora Solutions PLC, under license from Senetek PLC, Nasdaq, SNTKY), and has been shown to be an effective treatment for ED with less incidence of pain and priapism [22–24]. This study provides evidence that although patients may be nervous about the first injection into the penis, patients do not find the needle insertion to be painful, and the majority of patients does not have significant pain from the medication with initial dosing. A previous study examining long-term treatment with intracavernosal injections utilized a questionnaire to have patients rate their pain with injections since beginning injections (patients had to have been injecting themselves for a minimum of 3 months) and found pain scores to be low (2.09/10 from the injection, and J Sex Med 2009;6:513–519
518 2.15/10 with the erection) with self-injections [14]. This previous retrospective study, coupled with the current prospective study, provides important information for clinicians and patients about the minimal amount of pain involved in selfinjections. To guide practice, an algorithm for medications to use to diminish or eliminate pain with intracavernosal therapy has been developed [25]. If men do have pain from the medication, alternative vasoactive medications (such as phentolamine and/or papaverine or combinations of VIP and phentolamine) can be utilized effectively while minimizing pain [21,24]. The majority of participants stated that they initiated the discussion of ED with their health care provider. Because ED is a common problem in men of all ages, especially older men, this issue is important to address during the normal clinical visit. There are validated reliable tools such as the Sexual Health Inventory for Men (five-item) to help clinicians easily evaluate the presence and severity of ED during a normal health history [26]. If a patient has ED, the health care provider can provide information about the various treatment options for ED including intracavernosal injections. Conclusion
Although based on a convenience sample of men from one clinic, this was the first prospective study to show that participants experienced little or no pain with needle insertion or from injected vasoactive medications during initial self-injection. This research, in conjunction with previous studies that have shown little or no pain with injections, provides important information for clinicians and patients [13,14]. Knowing that the injections are not associated with significant pain can remove a crucial barrier to utilizing this efficacious treatment option. This study provides information that may be helpful to patients in diminishing fears about injection pain when considering penile injections. In addition, this study suggests that medication pain is more common in men postradical prostatectomy, and that it may be advisable to start with lower dosages of prostaglandin alone, use lower doses of prostaglandin in combination with other vasoactive medications, or use other vasoactive injectable medications that do not contain prostaglandins for these patients. Acknowledgements
The authors would like to thank Kevin T. McVary, MD and Laura Szalacha, EdD for their expert advice and for J Sex Med 2009;6:513–519
Albaugh and Ferrans review of preliminary drafts of this manuscript. The authors would also like to thank the Northwestern Wellness Institute for support of this research. Corresponding Author: Jeffrey Albaugh, PhD (cand), APRN, CUCNS, Northwestern Memorial Wellness Institute, 150 E. Huron, Suite 1100, Chicago, IL 60611, USA. Tel: 312-926-4032; Fax: 312-926-1986; E-mail: [email protected] Conflict of Interest: None declared.
Statement of Authorship
Category 1 (a) Conception and Design Jeffrey Albaugh; Carol Estwing Ferrans (b) Acquisition of Data Jeffrey Albaugh (c) Analysis and Interpretation of Data Jeffrey Albaugh; Carol Estwing Ferrans
Category 2 (a) Drafting the Article Jeffrey Albaugh; Carol Estwing Ferrans (b) Revising It for Intellectual Content Jeffrey Albaugh; Carol Estwing Ferrans
Category 3 (a) Final Approval of the Completed Article Jeffrey Albaugh; Carol Estwing Ferrans
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J Sex Med 2009;6:513–519
ORIGINAL RESEARCH—ED PHARMACOTHERAPY Patient-Reported Pain with Initial Intracavernosal Injection Jeffrey Albaugh, PhD (cand), APRN, CUCNS,* and Carol Estwing Ferrans, PhD, RN, FAAN† *Department of Sexual Health Program, Northwestern Memorial Wellness Institute and Jesse Brown VA Medical Center, Chicago, IL, USA; †College of Nursing, University of Illinois at Chicago, Chicago, IL, USA DOI: 10.1111/j.1743-6109.2008.01037.x
ABSTRACT
Introduction. Despite the efficacy of intracavernosal injections, one of the greatest impediments to injection therapy is the negative reaction of men to the thought of a needle inserted into the penis. Aim. To determine the severity of pain associated with the initial intracavernosal self-injections for erectile dysfunction (both pain associated with the needle insertion and the medications). Methods. This is a descriptive study of self-reported pain associated with intracavernosal self-injections in 65 men with erectile dysfunction. Pain was assessed immediately after needle insertion and again approximately 10–20 minutes postinjection, utilizing a verbal 0–10 pain scale. Main Outcome Measures. A verbal 0–10 pain rating scale was used to assess pain both for injection pain and medication pain. Results. For needle insertion, the mean pain rating was 0.80 (standard deviation [SD] = 0.81), with 40% reporting no pain at all. Of the 39 patients who reported pain, the mean pain rating was 1.33 (SD = 0.61). For the medication itself, the mean pain rating was 0.92 (SD = 1.5), with more than half (64.6%) reporting no pain. For those experiencing pain from the medication (N = 23), the mean pain rating was 2.6 (SD = 1.27, range 0.5–5.0). Significantly more patients with radical prostatectomy experienced pain from the medication than other men (51.9% vs. 23.7%, P = 0.02). Conclusion. The majority of patients experienced little or no pain from either the needle insertion or the medication. Even for men who experienced pain, the severity was relatively low. This study provides information to help diminish fears about injection pain for patients considering penile injections. In addition, this study suggests that medication pain is more common in men postradical prostatectomy, so that it may be advisable to start with lower dosages of prostaglandin alone or in combination with other vasoactive medications for these patients. Albaugh J, and Ferrans CE. Patient-reported pain with initial intracavernosal injection. J Sex Med 2009;6:513–519. Key Words. Erectile Dysfunction; Intracavernosal Injections; Pain
Introduction
E
rectile dysfunction (ED) is a common problem for men in the United States, affecting almost 1 in 5 men over the age of 20, with greater prevalence in older men (60 years and over) [1]. Although oral phosphodiesterase type 5 (PDE5) inhibitors are typically preferred as a first option for the treatment of ED, the failure rate for these agents in men with ED has been reported to be approximately 32% [2]. In men after radical prostatectomy,
© 2008 International Society for Sexual Medicine
the failure rates of oral agents are even greater and have been reported as high as 69–80% [3–5]. When oral treatments fail, intracavernosal injections are the most efficacious medical treatment option [3]. Intracavernosal injections have been utilized for ED since their introduction in 1982 [6]. Penile injections of vasoactive agents have been shown to be effective in as high as 87–93% of men utilizing this treatment [7,8]. Intracavernosal injections are used throughout the world as monotherapy or in combination with other vasoactive medications. J Sex Med 2009;6:513–519
514 Alprostadil (prostaglandin E1 [PGE1]) is a commonly used monotherapy and is available from two pharmaceutical companies as alprostadil alfadex (Edex or Viridal, Schwarz Pharma, Monheim, Germany) and alprostadil for injection (Caverject or Caverject Impulse, Pfizer, New York, NY, USA). Other vasoactive drugs that may be used in combinations are papaverine, phentolamine, and PGE1. One of the most commonly used combinations of injectable agents for ED is trimix, which typically contains papaverine, phentolamine, and prostaglandin [9–11]. Trimix may be used instead of prostaglandin monotherapy related to lack of efficacy of monotherapy, pain related to prostaglandin, and/or cost factors [12]. Despite the efficacy of intracavernosal injections, one of the largest impediments to injection therapy is the negative reaction of most men to the thought of a needle inserted into the penis. In the clinic, patients frequently comment on how surprisingly little pain is felt with the needle insertion during injection, yet there is little research documenting the pain actually experienced. Pain with injections can occur related to the needle insertion and/or from the medication itself. Regarding pain with the needle insertion, there is only one previous study that prospectively assessed this at the time of the needle insertion [13]. This study examined pain ratings using a 0–10 visual analog scale with needle insertion by either a nurse or the patient. The average pain rating for the injection was 1.93 ⫾ 1.76 for the 59 participants. The majority of the injections in the study was performed by a nurse (N = 42) and not the patient (N = 17). In addition, this study only measured pain with needle insertion and did not assess pain associated with the action of the medication. Another study retrospectively evaluated long-term satisfaction with intracavernosal injections [14]. Recognizing the limitations of a retrospective analysis, the authors recommended that a subsequent study should assess patients at the time of initiation of therapy. The most common side effect of alprostadil (PGE1) is pain [15,16]. Pain has been reported in up to 50% of the patients using intracavernosal injections of prostaglandin products, such as alprostadil, and pain also increases with higher dosages of alprostadil [7,8,10]. Although the pain was primarily mild, some of the men (6%) using these injections found it distressing enough to withdraw from therapy. No studies were found that prospectively assessed pain from both the needle insertion at the time of the injection as well as the injectable medications themselves. J Sex Med 2009;6:513–519
Albaugh and Ferrans Aims
The purpose of this study was to determine the severity of pain associated with intracavernosal injections for ED (both the pain associated with the needle insertion and the medications), in a cohort of patients who either failed to respond to oral PDE5 inhibitor treatments or were unable to utilize PDE5 inhibitors because of contraindication with other medications. Methods
Study Design This prospective, descriptive study involved collecting information on pain at the time it was experienced during the educational clinical visit for the initial intracavernosal self-injection, in men who never had previous penile injections. Self-reported pain was measured twice using the verbal 0–10 pain rating scale: immediately after the needle insertion and again after the medication began to take effect (approximately 10–20 minutes postinjection). The type and amount of medication was recorded along with the responses to pain and the erectile response. All measures were administered during the clinic appointment by the clinician and were immediately recorded. Demographic information was also gathered from the patients and was recorded. In addition, the participants were asked who initiated the discussion about their ED. The study received institutional review board approval, and all participants provided written informed consent prior to participation. Sample The participants were men (N = 65) who selfselected penile injections and came to the clinic of the principal investigator between August 2006 and April 2008 to learn how to perform penile self-injections for ED. The inclusion criteria were as follows: (i) adult men 21 years or older diagnosed with ED; (ii) were attending the clinic to obtain intracavernosal injection treatments for ED; and (iii) the injection associated with the study must have been the patient’s first self-injection. Measures A verbal 0–10 pain rating scale was used to assess pain for both injection pain and medication pain. The verbal pain rating scale was selected for use in this study because it provides a valid measurement of pain and is the most commonly used for pain assessment in clinical practice [17]. The verbal
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Pain with Self-Injection pain rating scale and visual analogue scale have been found to be highly correlated (r = 0.95, 95% confidence interval [CI] 0.94–0.96) [17]. Immediately following the self-injection, the patients were asked to rate the pain with the needle insertion on a scale of 0–10 with 0 being no pain at all and 10 being the worse possible pain the participants could imagine. Approximately 10–20 minutes after injection, as the penis began to respond to the medication with increased fullness, the patients were again asked to rate any pain on the same 0–10 verbal pain rating scale. After each pain rating, the patients were asked if the amount of pain they just experienced would be likely to discourage them from giving themselves the injections at home. The possible response choices were (i) no—not at all, (ii) yes—a little, (iii) yes—somewhat, and (iv) yes—a great deal.
Procedure All patients recruited for the study were attending the clinic to learn to perform self-injections into the penis to treat ED. If the patient met the inclusion criteria, he was asked to participate in the study. If a patient chose to perform injection therapy, the clinician would discuss the pros and cons of each vasoactive injectable agent option available, and the clinician and the patient would choose which injectable agent the patient would utilize for the initial injection. Factors that may affect a patient’s choice of agents are cost, insurance coverage of the medication, concerns or fears about pain from the medication (specifically from prostaglandin/ alprostadil), previous pain experienced with alprostadil urethral suppository (if the patient had previously used a urethral suppository), and patient or provider preferences. Starting doses of alprostadil used in the clinic typically range from 5 to 20 mcg, while starting doses of trimix or bimix typically may range from 0.1 to 0.5 mL depending on the patients’ history, age, previous failed treatment with other ED treatment options (such as alprostadil urethral suppository or the vacuum constriction device), and how long they have had ED. Intracavernosal injection therapy used for the patients who participated in this study included commonly utilized vasoactive agents (prostaglandin, phentolamine, and papaverine) as monotherapy (prostaglandin/alprostadil) or combined therapy. The trimix (papaverine 30 mg/ phentolamine 1 mg/PGE1 10 mcg/1 mL), bimix (papaverine 30 mg/phentolamine 1.5 mg/1 mL), or prostaglandin E1 (20 mcg/mL) was self-injected using a 0.5–1 mL insulin syringe with a 0.5-in.
length, 29-gauge needle. The same needle was used to draw up and administer the medication. No automatic injector device was used by the patients in this study. The most commonly used alprostadil preparation in the clinic was Edex/Viridal (Alprostadil-Alfadex, Schwarz Pharma). Edex is supplied in a single-dose, dual chamber cartridge with a 0.5-in., 29-gauge needle. All patients were taught to self-perform intracavernosal injections by the same advanced practice urology clinical nurse specialist (J.A.). Each patient who used Edex watched the Edex patient instruction video prior to injecting. All patients read through the written instruction for injecting their particular vasoactive medication. The patients were than given explicit instruction on the medication, side effects, and what to do if problems occur (including pain, priapism, and/or Peyronie’s). The patients were shown how to prepare the medication and selfinject the medication (using an anatomical model for demonstration.) If the patient had no further questions or concerns, the first self-injection was performed. Results
Sixty-five patients, ranging in age from 37 to 82 years (mean = 60.9, SD = 9.57), participated in the study. Demographic and clinical information is presented in Table 1. The education level of the participants ranged from high school graduates to doctorally prepared men with 67.7% having at least Table 1
Clinical and demographic characteristics Mean (SD) or frequency
Characteristic Age in years Comorbidities (%)* Hypertension Prostatectomy Hyperlipidemia Cardiovascular disease Diabetes Ethnicity (%) Caucasian African American Latino Educational level (%) High school Some college or associates degree Bachelor’s degree Master’s degree Doctorate Who Raised the Issue of ED? (%) Patient Health care clinician
60.9 (SD = 9.57) 50.8 41.5 43.1 32.3 23.1 78.5 16.9 4.6 10.8 21.5 27.7 26.2 13.8 80 20
*Participants had more than one comorbidity. SD = standard deviation; ED = erectile dysfunction.
J Sex Med 2009;6:513–519
516 a bachelor’s degree. The majority was Caucasian (78.5%), 16.9% was African American, and 4.6% was Latino. The comorbidities associated with ED were greatly varied and included, but were not limited to hypertension, hyperlipidemia, cardiovascular disease, diabetes, postradical prostatectomy, or a combination of any of these factors. For this study, the majority (N = 51) of participants used monotherapy with a prostaglandin injection, while others (N = 13) used trimix (papaverine 30 mg/ phentolamine 1 mg/prostaglandin 10 mcg/1 mL), and the remaining patient (N = 1) used bimix (phentolamine and papaverine). The initial dosages of prostaglandin ranged from 5 to 20 mcg with 94% of the patients (N = 48 out of the total 51 men who used monotherapy of prostaglandin) using the lower initial doses of 5–10 mcg. The dosages of trimix (papaverine 30 mg/phentolamine 1 mg/ prostaglandin 10 mcg/1 mL) used in the clinic for the participants in this study ranged from 0.1 mL (papaverine 3 mg/phentolamine 0.1 mg/prostaglandin 1 mcg) through 0.5 mL (papaverine 15 mg/ phentolamine 0.5 mg/prostaglandin 5 mcg), and the dose of bimix for the one patient who used bimix (papaverine 30 mg and phentolamine 1.5 mg/mL) was 0.20 mL (Papaverine 6 mg and phentolamine 0.3 mg). All the men, except for two men who could not use a PDE5 inhibitor related to a contraindication with other medications, had previously tried PDE5 inhibitors multiple times without achieving satisfactory results.
Number of Patients Reporting Pain
Pain with Needle Insertion The pain ratings for needle insertion pain are presented in Figure 1. Of the 65 patients in the study, 40% (N = 26) reported no pain at all with the needle insertion. The mean pain rating for the needle insertion process for all 65 participants was very slight at 0.80 (SD = 0.81) out of 10. Of those 30
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Figure 1 Needle insertion pain with injections.
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Number of Patients Reporting Pain
Albaugh and Ferrans 45
42
40 35 30 25 20 15 8
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Figure 2 Medication pain from the side effects of injectable medications.
patients who reported any pain at all (N = 39) with the needle insertion, the mean pain rating was 1.33 (SD = 0.63), with a range of 0.5–3.0 out of a possible 10 pain score. In response to the question “Would the amount of pain you just experienced with the injection be likely to discourage you from giving yourself the injections at home?”, all 65 patients responded “no, not at all.”
Pain from the Medication The pain related to medication was assessed 10–20 minutes after the initial injection, to coincide with the evaluation of the erectile response from the medication. The pain ratings for medication pain are presented in Figure 2. The mean pain rating for the entire group was 0.92 (SD = 1.5). More than half (65%, N = 42) of the patients did not report any pain from the medication itself. For those who did experience pain, the mean pain rating was 2.6 (SD = 1.27) out of 10 with reports of pain ranging from 0.5 to 5. Medication pain occurred in 35% (N = 23) of the men and occurred only in those who utilized the prostaglandin products of monotherapy or trimix, because no pain was reported by the one patient who used bimix (which does not contain prostaglandin). In response to the question “Would the amount of pain you just experienced with the injection be likely to discourage you from giving yourself the injections at home?”, only 4 of the 26 patients (15.4%) who had medication pain said the pain would discourage them from using the medication again at home. The average pain rating for the men using a monotherapy with prostaglandin (N = 51) was 0.83 (SD = 1.4), and the average pain rating for the men using trimix (papaverine 30 mg/ phentolamine 1 mg/prostaglandin 10 mcg/1 mL; N = 13) was 1.3 (SD = 1.7). A comparison of men who had radical prostatectomy (N = 27) with those who had not (N = 38)
Pain with Self-Injection revealed that a significantly larger proportion of postradical prostatectomy men experienced pain from the medication (51.9% vs. 23.7%) (c2(1,N=65) = 5.5, P = 0.02). Examination of the data showed that pain was experienced by men regardless of the time since radical prostatectomy, ranging from 8 weeks to 33 months.
Who Raised the Issue of Sexual Dysfunction Of the 65 participants, 80% of the patients (N = 52) stated that they had initiated the conversation about sexual dysfunction with their healthcare provider, rather than the healthcare provider asking about the issue. Discussion
This study is unique in that pain from both needle insertion and medication for intracavernosal therapy was evaluated prospectively during the initial in-clinic self-injection of intracavernosal vasoactive medications. Although it is not possible to generalize from this sample, this study provides evidence that needle insertion for intracavernosal injections is not necessarily painful. Another published study reporting pain with needle insertions, most of which were performed by a nurse rather than the patient himself, used a visual analog pain rating scale from 0 to 10 and reported low levels of pain also, although not as low as those in this sample [13]. In addition, Lane et al. did not report the proportion of men experiencing no pain. In our study, there was a surprisingly high percentage who reported feeling no pain with needle insertion (40%). Although men typically anticipate the injection to be painful, the needles used for intracavernosal injections are very fine (29 gauge) and are only inserted into the lower part of the shaft of the penis. In a study comparing preference for intraurethral alprostadil vs. injectable alprostadil, despite the perceived fear of needle insertion, men who tried both the urethral suppository and injectable preparations of alprostadil preferred the intracavernosal injections, which also lends support to the premise that needle insertion pain is not significant [18]. In terms of medication pain, men who had a history of radical prostatectomy reported the side effect of pain with the use of prostaglandins more often than men who had not undergone a radical prostatectomy. Intracavernosal injections may be prescribed after radical prostatectomy for treatment of ED and/or for penile rehabilitation, and a recent study revealed that injections are the most
517 common first-line treatment after radical prostatectomy of urologists in France [19]. The complaint of pain in the penis and groin area after prostaglandin injections is not completely understood. Montorsi et al. provides several theories for the local corporeal pain occurring with injection of prostaglandin, including activation of pain receptors via the prostaglandin [10]. Prostaglandins produce a hyperalgesic affect by elevating sensitivity to pain receptors and increasing painful input to the central nervous system through direct cellular action on the membrane of the organ, which in this case is the penis [20]. It is important to note that pain in the penis and groin area from the injected medication was experienced by some participants even as many as 33 months after radical prostatectomy surgery. These findings indicate that it may be appropriate to start with lower dosages of prostaglandin alone or in combination with other vasoactive medications for postradical prostatectomy patients and other patients who experience medication pain after injection. Prostaglandin may even need to be eliminated as a vasoactive injectable in patients who continue to have pain with these agents at lower doses. These patients may do better with a bimix solution of either papaverine and phentolamine as used in this study. When pain occurs from the prostaglandin, switching to a trimix (papaverine/phentolamine/ PGE1) or even a bimix (papaverine/phentolamine) combination has been associated with lower incidence of pain (2.9% for trimix and 0% for bimix) in a previous study [21]. Another injectable agent currently under investigation in the United States uses a combination of vasoactive intestinal polypeptide (VIP) and phentolamine (Invicorp is currently undergoing phase III clinical trials in the United States sponsored by Plethora Solutions PLC, under license from Senetek PLC, Nasdaq, SNTKY), and has been shown to be an effective treatment for ED with less incidence of pain and priapism [22–24]. This study provides evidence that although patients may be nervous about the first injection into the penis, patients do not find the needle insertion to be painful, and the majority of patients does not have significant pain from the medication with initial dosing. A previous study examining long-term treatment with intracavernosal injections utilized a questionnaire to have patients rate their pain with injections since beginning injections (patients had to have been injecting themselves for a minimum of 3 months) and found pain scores to be low (2.09/10 from the injection, and J Sex Med 2009;6:513–519
518 2.15/10 with the erection) with self-injections [14]. This previous retrospective study, coupled with the current prospective study, provides important information for clinicians and patients about the minimal amount of pain involved in selfinjections. To guide practice, an algorithm for medications to use to diminish or eliminate pain with intracavernosal therapy has been developed [25]. If men do have pain from the medication, alternative vasoactive medications (such as phentolamine and/or papaverine or combinations of VIP and phentolamine) can be utilized effectively while minimizing pain [21,24]. The majority of participants stated that they initiated the discussion of ED with their health care provider. Because ED is a common problem in men of all ages, especially older men, this issue is important to address during the normal clinical visit. There are validated reliable tools such as the Sexual Health Inventory for Men (five-item) to help clinicians easily evaluate the presence and severity of ED during a normal health history [26]. If a patient has ED, the health care provider can provide information about the various treatment options for ED including intracavernosal injections. Conclusion
Although based on a convenience sample of men from one clinic, this was the first prospective study to show that participants experienced little or no pain with needle insertion or from injected vasoactive medications during initial self-injection. This research, in conjunction with previous studies that have shown little or no pain with injections, provides important information for clinicians and patients [13,14]. Knowing that the injections are not associated with significant pain can remove a crucial barrier to utilizing this efficacious treatment option. This study provides information that may be helpful to patients in diminishing fears about injection pain when considering penile injections. In addition, this study suggests that medication pain is more common in men postradical prostatectomy, and that it may be advisable to start with lower dosages of prostaglandin alone, use lower doses of prostaglandin in combination with other vasoactive medications, or use other vasoactive injectable medications that do not contain prostaglandins for these patients. Acknowledgements
The authors would like to thank Kevin T. McVary, MD and Laura Szalacha, EdD for their expert advice and for J Sex Med 2009;6:513–519
Albaugh and Ferrans review of preliminary drafts of this manuscript. The authors would also like to thank the Northwestern Wellness Institute for support of this research. Corresponding Author: Jeffrey Albaugh, PhD (cand), APRN, CUCNS, Northwestern Memorial Wellness Institute, 150 E. Huron, Suite 1100, Chicago, IL 60611, USA. Tel: 312-926-4032; Fax: 312-926-1986; E-mail: [email protected] Conflict of Interest: None declared.
Statement of Authorship
Category 1 (a) Conception and Design Jeffrey Albaugh; Carol Estwing Ferrans (b) Acquisition of Data Jeffrey Albaugh (c) Analysis and Interpretation of Data Jeffrey Albaugh; Carol Estwing Ferrans
Category 2 (a) Drafting the Article Jeffrey Albaugh; Carol Estwing Ferrans (b) Revising It for Intellectual Content Jeffrey Albaugh; Carol Estwing Ferrans
Category 3 (a) Final Approval of the Completed Article Jeffrey Albaugh; Carol Estwing Ferrans
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