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Prevention of Recurrent Ischemic Priapism with Ketoconazole: Evolution of a Treatment Protocol and Patient Outcomes
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Prevention of Recurrent Ischemic Priapism with Ketoconazole: Evolution of a Treatment Protocol and Patient Outcomes Michael P. Hoeh, MD and Laurence A. Levine, MD Department of Urology, Rush University Medical Center, Chicago, IL, USA DOI: 10.1111/jsm.12359
ABSTRACT
Introduction. The management of recurrent ischemic priapism (RIP) is not clearly defined. Ketoconazole (KTZ) is used to treat RIP and produces a temporary hypogonadal state to suppress sleep-related erections (SREs), which often evolve into episodes of ischemic priapism in this population. Aim. We review our experience to prevent RIP using KTZ and present our outcomes using a decreased dose regimen. Methods. A retrospective chart review and phone survey of 17 patients with RIP was performed. KTZ inhibits adrenal and gonadal testosterone production with a half-life of 8 hours. By suppressing testosterone levels, SREs are interrupted. We compared our previous protocol of three times daily (TID) KTZ dosing with prednisone for 6 months with our current regimen of initiating KTZ 200 mg TID with prednisone 5 mg daily for 2 weeks and then tapering to KTZ 200 mg nightly for 6 months. Main Outcome Measures. The primary outcome was the prevention of RIP using KTZ. Secondary outcomes included side effects secondary to KTZ use and patient satisfaction. Results. All men experienced daily or almost daily episodes of prolonged, painful erections prior to starting KTZ. The mean number of emergency room (ER) visits per patient prior to starting KTZ was 6.5. No patient required an ER visit for RIP while on KTZ. Sixteen of 17 patients (94%) had complete resolution of priapism while on KTZ with effects noted immediately after starting therapy and no reported sexual side effects attributed to KTZ. One man stopped therapy after 4 days because of nausea/vomiting. Fourteen of 16 men eventually discontinued KTZ after a median duration of 7 months. Twenty-nine percent reported no recurrent priapic episodes after discontinuing. A total of 78.6% had partial or complete resolution of symptoms persisting after KTZ was discontinued with a mean post-treatment follow-up of 36.7 months. Conclusion. No reliable effective preventative therapy has been identified for RIP. In our relatively sizable singlecenter experience, KTZ appears to be a reasonably effective, safe, and inexpensive treatment to prevent RIP while preserving sexual function. We now recommend our tapered dose regimen listed above. After 6 months, we recommend stopping the medication as we have found a majority of patients will not need to resume nightly KTZ. Hoeh MP and Levine LA. Prevention of recurrent ischemic priapism with ketoconazole: Evolution of a treatment protocol and patient outcomes. J Sex Med 2014;11:197–204. Key Words. Recurrent Ischemic Priapism; Stuttering Priapism; Ketoconazole; Sleep-Related Erections; Priapism; Induced Hypogonadal State and Recurrent Priapism
Introduction
P
riapism is defined as a prolonged penile erection lasting greater than 4 hours which may or may not be triggered by sexual stimulation or desire. Priapism is divided into three main categories: ischemic, nonischemic, and recurrent priapism. Recurrent ischemic priapism (RIP), also
© 2013 International Society for Sexual Medicine
known as stuttering priapism, is an uncommon form of ischemic priapism. Patients with RIP typically present with episodes of prolonged sleeprelated erections (SREs) or “brief transitory attacks” of priapism. These SRE, although painful, usually last less than 3–4 hours. However, this disorder is known to progress to major episodes of ischemic priapism in 28% of cases necessitating J Sex Med 2014;11:197–204
198 emergent intervention [1]. Likewise, any man who has suffered from an acute ischemic priapic event is at risk for developing RIP. Left untreated, this disease process may lead to irreversible corporal fibrosis and erectile dysfunction (ED) [1–5]. Elegant animal model studies have suggested that the pathophysiology of RIP may be based on dysregulation of nitric oxide (NO) and phosphodiesterase type 5 (PDE5) inhibitors in corporal smooth muscle [6]. Hematologic disorders such as sickle cell disease (SCD) and glucose 6-phosphate dehydrogenase deficiency (G6PDD) are more commonly present in children with RIP, whereas the disease is often idiopathic in adult-onset RIP. Those with SCD are affected with ischemic and recurrent priapism at a much greater frequency. Men diagnosed with SCD have an estimated lifetime probability for the development of clinically significant priapism as high as 42% and the rate of subsequent ED up to 30% [7–11]. G6PDD may also lead to an increased frequency of RIP, possibly secondary to hemolytic anemia and subsequent oxidative stress to the penis, affecting NO and PDE5 response [12]. SREs occur naturally during REM sleep in healthy men, and their purpose is believed to provide engorgement of the corpora cavernosa, which in turn leads to increased tissue oxygenation and prevention of cavernous fibrosis, the histopathological etiology for corporeal venooclusive ED [13]. Various human and animal studies have shown that androgens appear to play a key role in the regulation of SRE, in contrast to the erectile response to tactile and/or visual erotic stimuli during waking hours, which predominantly involves an androgen-independent system [13– 15]. All men without physiologic ED experience SRE approximately three to seven times during sleep. These erections resolve spontaneously and typically do not cause pain [14]. SREs in men with RIP, however, may be prolonged and are characteristically painful and may eventually lead to episodes of priapism. The first-line therapy for men experiencing episodes of acute ischemic priapism secondary to RIP remains the same as for any ischemic priapism: aspiration/irrigation in combination with intracavernous α-agonist injection therapy [2]. There are multiple pharmacologic treatments proposed for the management and prevention of RIP, including hormonal agents such as ketoconazole (KTZ) [16]. KTZ is an orally active antifungal drug known to inhibit androgen production in both the testicle J Sex Med 2014;11:197–204
Hoeh and Levine and adrenal gland. As a result, high-dose KTZ (400 mg orally three times a day) is a standard treatment option for hormone-refractory prostate cancer and is typically given with 5 mg prednisone to prevent adrenal insufficiency which is known to occur with continuous 24-hour dosing of KTZ. Adverse effects of KTZ tend to be dose dependent and include nausea and vomiting in up to one-half of patients on high-dose regimens, skin rash in 10%, weakness/fatigue, nail dystrophy, and gynecomastia. Gastrointestinal side effects typically improve or resolve with dose modification. Hepatotoxicity is a rare (<1%) but potentially lifethreatening adverse reaction. The FDA recommends that all patients undergoing KTZ therapy have liver function tests (LFTs) performed prior to initiation, at weeks 2 and 4 following initiation, and monthly thereafter until the medication is discontinued. If LFTs increase greater than three times the upper limit of normal or if patients develop clinical signs/symptoms of hepatotoxicity, the treatment should be discontinued [17–19]. KTZ typically has rapid absorption in fasting men, with peak serum concentrations achieved within 2 hours after administration. The mean elimination half-life values are 7.5–8 hours [20]. Santen et al. found that after administration of low dose KTZ (200 mg KTZ daily), total and free plasma testosterone levels fall to levels 60% below baseline levels within 4–8 hours before returning to basal values within 24 hours [21]. In 2009, we reported our initial positive experience with the management of RIP using KTZ in eight patients with an average follow-up of approximately 1.5 years. We have revised our protocol in this report. Material and Methods
Seventeen patients were referred to our center with RIP for management who were ultimately treated with our revised KTZ protocol. In 2009, our treatment protocol was KTZ 200 mg three times daily (TID) with prednisone 5 mg daily for 6 months [16]. These 17 new patients were treated with a revised protocol of 2 weeks KTZ 200 mg TID with prednisone 5 mg once daily. If there were no breakthrough priapisms, the protocol was adjusted to KTZ 200 mg nightly without prednisone for a total of 6 months. The average follow-up was approximately 3 years. LFTs were obtained prior to initiation, at weeks 2 and 4, and monthly following initiation. A chart review and subsequent phone survey were obtained for each patient. All patients were
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Prevention of Recurrent Ischemic Priapism with Ketoconazole Table 1
Patient demographics and pre-KTZ treatment
Pt
Age KTZ started (years)
Etiology
ER visits/treatments before KTZ
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
17 25 37 42 25 37 23 22 18 26 22 30 19 45 22 21 31
SCD Id Id Id Id Id SCD Id Id Id Id Id SCD Id SCD SCD Id
ER × 3, I × 1 ER/I × 5–10 ER/I × 5–10 ER × 5, shunt ER/I × >10 ER/I, shunt ER, shunt × 2 ER/I × 2 ER/I × 4 ER/I × 5–10 ER/I × 3–4 ER/I × 3 ER/I × ∼50 ER/I × 1 ER/I × 3–4, shunt ER/I × 3 ER/I × 2
ED = erectile dysfunction; ER = emergency room; I = irrigation and aspiration and/or intracavernosal injection; Id = idiopathic; KTZ = ketoconazole; SCD = sickle cell disease
fully consented on the off-label administration of this medication and for the use of their clinical data for this report. Each patient was interviewed either during a recent clinic visit or over the phone. Questions asked included how many recurrences of painful nocturnal erections or episodes of priapism did they have while on KTZ therapy and after discontinuation. We also inquired if they experienced any sexual side effects as described in the International Index of Erectile Function (IIEF) Questionnaire including changes in ability to initiate or maintain an erection, confidence in
Table 2
the ability to initiate or maintain an erection, penile rigidity, libido, sexual satisfaction, or problems with orgasm or ejaculation. Unfortunately, the IIEF questionnaire was not routinely offered before initiating treatment as KTZ was started acutely during an emergency room visit for RIP. Therefore, subsequent interviews were structured using the IIEF questions. They were also asked to rate their overall experience on this protocol on a scale from 1 to 10 with 1 being completely dissatisfied and 10 being completely satisfied. For patients who did not score 10 out of 10, we asked them to comment specifically why they were not completely satisfied with the treatment protocol. Results
Tables 1 and 2 summarize patient demographics, chart review, and patient questionnaire findings. Twelve men had idiopathic RIP, and five patients had sickle cell anemia. All patients had a hematologic workup including hemoglobin electrophoresis to evaluate for potential underlying hematologic disorders. All of these men had a history of prolonged, painful SRE occurring nightly or almost nightly since puberty. Every patient had experienced at least one episode of ischemic priapism (>4 hours) requiring emergent intervention which included at least one intracavernosal (IC) injection of phenylephrine and/or corporal body irrigation and aspiration. Four men (patients 4, 6, 7, 15) underwent at least
Summary of chart review and questionnaire
KTZ duration (mo)
Recurrence on KTZ
Recurrence after discontinuation
Rating
6 24 6 12 24 61 1 8 14 9 0.25 6
0 0 0 0 0 0 0 0 0 0 0 1
0 4 self injection 2 self injection 0 15–20 self injection 1 ER visit 0 0 Takes prn KTZ Prn self injection ER × 2 with I Takes prn phenylephrine
10 10 10 10 6 10 10 10 10 10 1 8
7
0
N/A
1 5 16 5
0 0 0 0
0 Takes oral pseudoephedrine 10 episodes when he stopped 1 ED visit with I
7 10 10 7 10
Reason for low rating/side effects
Did not like frequency of medication
GI upset—nausea and vomiting Rare occurrences of prolonged SRE while on KTZ. Stopped taking KTZ and still requires prn phenylephrine. Prolonged SREs after stopping KTZ, much less painful/frequent, last <2 hours, resolve spontaneously
Did not like frequency of medication
ED = erectile dysfunction; ER = emergency room; GI = gastrointestinal; KTZ = ketoconazole; SRE = sleep-related erections
J Sex Med 2014;11:197–204
200
Hoeh and Levine Monthly follow-up visit*:
2007
2012
200 mg KTZ three Ɵmes daily (TID) + 5 mg prednisone daily
Suppression of recurrent ischemic priapism (RIP)
Persistence of RIP
Plan: ConƟnue current regimen x ~ 6 months. Re-evaluate monthly. DisconƟnue aŌer 6 months.
Increase to 400 mg KTZ TID x ~ 6 months, then disconƟnue. ConƟnue prednisone 5 mg daily. Re-evaluate monthly. Titrate down to 200 mg TID or up to 400 mg TID
2 week f/u visit*:
Plan:
Suppression of RIP
Switch to 200 mg KTZ nightly without prednisone. ConƟnue for ~ 6 months, then disconƟnue.
Persistence of RIP
Increase to 400 mg KTZ TID + 5 mg prednisone daily x ~ 6 months. Re-evaluate monthly and decrease dose if possible. DisconƟnue aŌer 6 months.
200 mg KTZ TID + 5 mg prednisone daily x 2 weeks
Figure 1 Evolution of ketoconazole (KTZ) treatment protocol. * Current Recommendations: obtain total testosterone and LFTs prior to initiating KTZ, at weeks 2 and 4, and monthly until KTZ is discontinued.
one shunt procedure prior to starting KTZ. The mean number of emergency room visits prior to initiating KTZ treatment was 6.5 (range one to over 50). The average patient age was 27 when KTZ was initiated (range 17–42). The mean duration of therapy was 11.8 months with a median duration of 7 months (range 1–61 months). The average follow-up period after KTZ was discontinued was 36.7 months. Consistent with our earlier protocol, all men were started on an initial regimen of 200 mg KTZ TID with 5 mg prednisone daily for at least 2 weeks. If there were no breakthrough episodes of priapism, the dose was dropped to 200 mg KTZ nightly without prednisone. After approximately 6 months of nightly KTZ, the therapy was discontinued (Figure 1). No patient required an ER visit for RIP while on KTZ. Patient 12 reported infrequent recurrences of painful morning erections while taking KTZ, though episodes were much less painful and went away with oral pseudoephedrine. The remaining 16 men reported no recurrences in painful erections while taking KTZ. Importantly, all men reported that these effects were noted immediately after starting therapy. All men who J Sex Med 2014;11:197–204
did not have a shunt procedure reported normal erections for coitus while on therapy. There were no reported changes in ability to initiate or maintain an erection, confidence in the ability to initiate or maintain an erection, penile rigidity, libido, sexual satisfaction, or problems with orgasm or ejaculation. Patient 11 reported that although KTZ successfully resolved prolonged SRE, he had to stop the medication after 4 days because of nausea and vomiting. He has since returned to the ER twice over the past 12 months with priapism requiring phenylephrine injections. He subsequently learned to perform self-injection with phenylephrine. Of the 15 men who eventually did stop therapy, five patients reported complete lasting resolution of symptoms after stopping therapy. Seven reported that although their symptoms had greatly improved, they experienced infrequent recurrence of prolonged erections (lasting less than 2 hours), which resolved at home with phenylephrine self injection (five), oral pseudoephedrine (one), or KTZ (one) as needed. Twelve of 15 or 80% of patients did not need to resume nightly KTZ after discontinuing as they experienced lasting resolu-
Prevention of Recurrent Ischemic Priapism with Ketoconazole tion or significant improvement in symptoms for an average follow-up duration of 36.7 months (range 1–95 months). We attempted to obtain a pretreatment baseline total testosterone (TT) in all patients, but in this cohort, many men began the KTZ protocol while in the ER during acute treatment of RIP without obtaining a TT. For the 10 patients in whom we have both pretreatment and post-treatment TT, the mean pretreatment TT was 434 (range 115– 1,187), and post-treatment TT was 384 (range 250–679) with an average decrease of 25 ng/dL which was not statistically significant (P = 0.77). On a scale from 1 to 10 with 1 being very dissatisfied and 10 being extremely satisfied with KTZ therapy to prevent RIP, the average score was 8.8. Reasons for not scoring 10 included one report of nausea/vomiting, displeasure with taking a daily medication, and one patient was unhappy that although he experienced complete resolution of prolonged SRE while on KTZ, when the therapy was discontinued after 7 months, the prolonged SRE resumed, though at a decreased frequency and intensity. Discussion
The management of RIP has not been clearly delineated. According to the American Urological Association Guidelines, the goal of the management of stuttering priapism is the prevention of future episodes, whereas the management of each episode should follow the specific treatment recommendations for ischemic priapism [1]. Current medical options for prevention of RIP include hormonal agents such as KTZ, 5-α-reductase inhibitors, antiandrogens, estrogen, gonadotropin-releasing hormone agonists, and other oral agents including PDE5 inhibitors, terbutaline, digoxin, gabapentin, and baclofen. To date, all of these therapies are only supported with level three or four evidence with small case series and case-control studies [1–4]. As this is an uncommon problem, ultimately a randomized multicenter study will be needed to identify the best treatment. Finasteride has been shown to decrease the frequency of recurrent priapism. Rachid-Filho et al. found that after 4 months of finasteride therapy in 35 men with RIP secondary to SCD, only 16 (42%) experienced zero episodes of priapism per month, another 16 men experienced 1–15 recurrences per month, and the remaining men with over 15 recurrences [22]. Barroso et al. also found that finasteride can decrease the frequency and
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severity of priapic episodes in children and adolescents with recurrent priapism [23]. Advantages of this therapy include the potential for fewer side effects, with disadvantages being that recurrent priapic episodes are not uncommon in a substantial number of men, especially within the first few months after initiating therapy. There are also reported sexual side effects including decreased libido and ED [24]. The major concern for hormonal therapy is producing a hypogonadal state, which may have many adverse outcomes. Caution is strongly advised in using hormonal treatments for prepubertal or adolescent men who have not reached sexual maturation or in those desiring children, as side effects may include growth impairment and infertility [2]. Other concerns for prolonged hormonal treatment include decreased bone density, gynecomastia, and potential sexual side effects, including decreased libido, ED, and inability to achieve orgasm or ejaculation. Given our current understanding of SRE and its relationship to RIP, it would appear that an ideal antiandrogen therapy would suppress SRE and subsequent RIP without producing a hypogonadal state. Bedtime administration of KTZ appears to satisfy these criteria, as it creates only a temporary hypogonadal state to suppress SRE. Several studies suggest that long-term, lowdose PDE5 inhibitor therapy may be useful as a preventative strategy for recurrent priapism, likely by achieving a normative, albeit reversible, resetting of PDE5 expression in penile tissue, which in turn controls the excessive cyclic guanosine monophosphate signaling associated with priapism [25–29]. One drawback from this therapy is the potential for PDE5 inhibitor use to trigger or exacerbate episodes of prolonged morning erections and/or priapism, especially if used incorrectly. The authors of these studies advocate that long-acting PDE5 inhibitors be used only in the morning and never in the evening or with sexual stimulation in this patient population [25,30]. PDE5 inhibitors are also quite costly, which has deterred adoption of this approach for most of our patient population. Another option includes IC self-injection of sympathomimetic agents for episodes of priapism or prolonged, painful morning erections. Studies suggest that this approach may be safely indicated in select cases [31–36]. One concern with IC selfinjection for long-term management is that it does not address prevention of episodes of priapism but rather treats episodes once they occur. One benefit J Sex Med 2014;11:197–204
202 is the avoidance of hormonal therapy and its attendant side effects. Experience in our clinic indicates that the majority of patients are almost uniformly resistant to initiating a self-injection approach as first-line treatment. To our knowledge, this is the largest published study examining the short- and long-term effects of KTZ for the management of RIP. Together with our 2009 report, we have examined the results of KTZ in 25 patients with RIP. In our current cohort, all men reported daily or almost daily episodes of prolonged, painful erections prior to initiating KTZ. One man discontinued the medication after 4 days because of nausea and had recurrence of symptoms. There were no ER visits necessary while on treatment, and 16 of 17 men reported complete resolution of daily episodes of prolonged erections after starting therapy. Fifteen of 16 men eventually discontinued scheduled KTZ after a median duration of 7 months (range 1–24 months). Five of those 15 patients (33%) reported no recurrent priapic episodes. Another seven men reported that after stopping KTZ, the frequency and intensity of prolonged erections were significantly less problematic, and episodes were easily managed with oral pseudoephedrine (30–60 mg), self-injection of IC phenylephrine, or oral KTZ (200 mg) taken as needed. Twelve of 15 patients (80%) did not need to resume a nightly KTZ regimen. Three men (20%) did have recurrence of RIP after discontinuation and elected to resume a nightly KTZ regimen (patients 6, 16, and 17). In our previous study, all eight patients reported no RIP episodes following completion of the 6-month course of KTZ TID with daily prednisone [16]. Between 2006 and 2009, Flum found that the average cost of one emergency room visit for priapism in the United States was $1,778 if patients were discharged home. Costs jumped to $41,909 per encounter if a hospital stay was involved [37]. On the other hand, a 1 month prescription for 30 tablets of 200 mg generic KTZ costs between $12 and $24. Low-dose KTZ taken at bedtime appears to be particularly advantageous to this patient population given its rapid onset of action and subsequent elimination resulting in minimal, if any, reported sexual side effects while suppressing SRE, which in this population can progress to a full-blown priapism. Diminished number, duration, and amplitude of nocturnal erections were demonstrated by plethysmography in our 2009 trial [16]. KTZ did not appear to have a signifiJ Sex Med 2014;11:197–204
Hoeh and Levine cant impact on long-term testosterone values after discontinuation in our cohort, though larger, longer term studies are necessary to prove this finding. Once the acute episode has resolved in men with RIP, we recommend starting the prevention treatment protocol with KTZ 200 mg TID and prednisone 5 mg daily for approximately 2 weeks. If there are no breakthrough priapic erections, we reduce the KTZ dose to 200 mg nightly without prednisone to suppress SRE. If side effects secondary to KTZ are encountered such as nausea and vomiting, we recommend decreasing the total daily dose to 200 mg at bedtime as this common side effect is known to be dose dependent. After approximately 6 months of nightly KTZ therapy, we recommend discontinuing the medication as we have observed a majority of patients will not need to resume a nightly KTZ regimen. We elected to revise our previous 2009 protocol which caused continuous prolonged suppression of testosterone levels. This revision allowed us to reduce the KTZ dosing to bedtime only to suppress serum testosterone for 6–8 hours during sleep. This presumably will reduce the risk of side effects associated with KTZ and prolonged hormonal suppression as well as reduce the cost of therapy. We acknowledge that our study size is small, and given the uncommon nature of this problem, a multicenter trial would be necessary to achieve a larger group to evaluate with a randomized trial possibly comparing a PDE5 inhibitor with KTZ treatment. This study has also shown that some patients may only have partial response to KTZ therapy, though all patients reported an immediate significant improvement in symptoms. The mean follow-up for our study was approximately 3 years; clearly, a longer duration of follow-up is in order to determine the safety of long-term KTZ use. We also recognize the limitation of our sexual function assessment which was not standardized for all patients. We recommend using KTZ cautiously in the pediatric or adolescent population and do not recommend KTZ use beyond 6 months in these populations, given the concern for alternations in bone mineralization and fertility in spite of the limited suppression of androgen production. Patients who are still taking KTZ therapy are undergoing LFT and testosterone testing; as of this time, no patient has shown a significant sustained decline in testosterone values or rise in LFTs. Until larger scale randomized trials can be performed, KTZ treatment should be considered a potential treatment option as it appears to be a
Prevention of Recurrent Ischemic Priapism with Ketoconazole reasonably effective, safe, cost-effective treatment to prevent RIP while preserving sexual function. As we learned from this cohort analysis, there was almost an immediate resolution of priapism episodes once KTZ was initiated. Corresponding Author: Laurence A. Levine, MD, Department of Urology, Rush University Medical Center, Chicago, IL 60661, USA. Tel: 3125635000; Fax: 312-563-5007; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Michael P. Hoeh; Laurence A. Levine (b) Acquisition of Data Michael P. Hoeh; Laurence A. Levine (c) Analysis and Interpretation of Data Michael P. Hoeh; Laurence A. Levine
Category 2 (a) Drafting the Article Michael P. Hoeh; Laurence A. Levine (b) Revising It for Intellectual Content Michael P. Hoeh; Laurence A. Levine
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Prevention of Recurrent Ischemic Priapism with Ketoconazole: Evolution of a Treatment Protocol and Patient Outcomes Michael P. Hoeh, MD and Laurence A. Levine, MD Department of Urology, Rush University Medical Center, Chicago, IL, USA DOI: 10.1111/jsm.12359
ABSTRACT
Introduction. The management of recurrent ischemic priapism (RIP) is not clearly defined. Ketoconazole (KTZ) is used to treat RIP and produces a temporary hypogonadal state to suppress sleep-related erections (SREs), which often evolve into episodes of ischemic priapism in this population. Aim. We review our experience to prevent RIP using KTZ and present our outcomes using a decreased dose regimen. Methods. A retrospective chart review and phone survey of 17 patients with RIP was performed. KTZ inhibits adrenal and gonadal testosterone production with a half-life of 8 hours. By suppressing testosterone levels, SREs are interrupted. We compared our previous protocol of three times daily (TID) KTZ dosing with prednisone for 6 months with our current regimen of initiating KTZ 200 mg TID with prednisone 5 mg daily for 2 weeks and then tapering to KTZ 200 mg nightly for 6 months. Main Outcome Measures. The primary outcome was the prevention of RIP using KTZ. Secondary outcomes included side effects secondary to KTZ use and patient satisfaction. Results. All men experienced daily or almost daily episodes of prolonged, painful erections prior to starting KTZ. The mean number of emergency room (ER) visits per patient prior to starting KTZ was 6.5. No patient required an ER visit for RIP while on KTZ. Sixteen of 17 patients (94%) had complete resolution of priapism while on KTZ with effects noted immediately after starting therapy and no reported sexual side effects attributed to KTZ. One man stopped therapy after 4 days because of nausea/vomiting. Fourteen of 16 men eventually discontinued KTZ after a median duration of 7 months. Twenty-nine percent reported no recurrent priapic episodes after discontinuing. A total of 78.6% had partial or complete resolution of symptoms persisting after KTZ was discontinued with a mean post-treatment follow-up of 36.7 months. Conclusion. No reliable effective preventative therapy has been identified for RIP. In our relatively sizable singlecenter experience, KTZ appears to be a reasonably effective, safe, and inexpensive treatment to prevent RIP while preserving sexual function. We now recommend our tapered dose regimen listed above. After 6 months, we recommend stopping the medication as we have found a majority of patients will not need to resume nightly KTZ. Hoeh MP and Levine LA. Prevention of recurrent ischemic priapism with ketoconazole: Evolution of a treatment protocol and patient outcomes. J Sex Med 2014;11:197–204. Key Words. Recurrent Ischemic Priapism; Stuttering Priapism; Ketoconazole; Sleep-Related Erections; Priapism; Induced Hypogonadal State and Recurrent Priapism
Introduction
P
riapism is defined as a prolonged penile erection lasting greater than 4 hours which may or may not be triggered by sexual stimulation or desire. Priapism is divided into three main categories: ischemic, nonischemic, and recurrent priapism. Recurrent ischemic priapism (RIP), also
© 2013 International Society for Sexual Medicine
known as stuttering priapism, is an uncommon form of ischemic priapism. Patients with RIP typically present with episodes of prolonged sleeprelated erections (SREs) or “brief transitory attacks” of priapism. These SRE, although painful, usually last less than 3–4 hours. However, this disorder is known to progress to major episodes of ischemic priapism in 28% of cases necessitating J Sex Med 2014;11:197–204
198 emergent intervention [1]. Likewise, any man who has suffered from an acute ischemic priapic event is at risk for developing RIP. Left untreated, this disease process may lead to irreversible corporal fibrosis and erectile dysfunction (ED) [1–5]. Elegant animal model studies have suggested that the pathophysiology of RIP may be based on dysregulation of nitric oxide (NO) and phosphodiesterase type 5 (PDE5) inhibitors in corporal smooth muscle [6]. Hematologic disorders such as sickle cell disease (SCD) and glucose 6-phosphate dehydrogenase deficiency (G6PDD) are more commonly present in children with RIP, whereas the disease is often idiopathic in adult-onset RIP. Those with SCD are affected with ischemic and recurrent priapism at a much greater frequency. Men diagnosed with SCD have an estimated lifetime probability for the development of clinically significant priapism as high as 42% and the rate of subsequent ED up to 30% [7–11]. G6PDD may also lead to an increased frequency of RIP, possibly secondary to hemolytic anemia and subsequent oxidative stress to the penis, affecting NO and PDE5 response [12]. SREs occur naturally during REM sleep in healthy men, and their purpose is believed to provide engorgement of the corpora cavernosa, which in turn leads to increased tissue oxygenation and prevention of cavernous fibrosis, the histopathological etiology for corporeal venooclusive ED [13]. Various human and animal studies have shown that androgens appear to play a key role in the regulation of SRE, in contrast to the erectile response to tactile and/or visual erotic stimuli during waking hours, which predominantly involves an androgen-independent system [13– 15]. All men without physiologic ED experience SRE approximately three to seven times during sleep. These erections resolve spontaneously and typically do not cause pain [14]. SREs in men with RIP, however, may be prolonged and are characteristically painful and may eventually lead to episodes of priapism. The first-line therapy for men experiencing episodes of acute ischemic priapism secondary to RIP remains the same as for any ischemic priapism: aspiration/irrigation in combination with intracavernous α-agonist injection therapy [2]. There are multiple pharmacologic treatments proposed for the management and prevention of RIP, including hormonal agents such as ketoconazole (KTZ) [16]. KTZ is an orally active antifungal drug known to inhibit androgen production in both the testicle J Sex Med 2014;11:197–204
Hoeh and Levine and adrenal gland. As a result, high-dose KTZ (400 mg orally three times a day) is a standard treatment option for hormone-refractory prostate cancer and is typically given with 5 mg prednisone to prevent adrenal insufficiency which is known to occur with continuous 24-hour dosing of KTZ. Adverse effects of KTZ tend to be dose dependent and include nausea and vomiting in up to one-half of patients on high-dose regimens, skin rash in 10%, weakness/fatigue, nail dystrophy, and gynecomastia. Gastrointestinal side effects typically improve or resolve with dose modification. Hepatotoxicity is a rare (<1%) but potentially lifethreatening adverse reaction. The FDA recommends that all patients undergoing KTZ therapy have liver function tests (LFTs) performed prior to initiation, at weeks 2 and 4 following initiation, and monthly thereafter until the medication is discontinued. If LFTs increase greater than three times the upper limit of normal or if patients develop clinical signs/symptoms of hepatotoxicity, the treatment should be discontinued [17–19]. KTZ typically has rapid absorption in fasting men, with peak serum concentrations achieved within 2 hours after administration. The mean elimination half-life values are 7.5–8 hours [20]. Santen et al. found that after administration of low dose KTZ (200 mg KTZ daily), total and free plasma testosterone levels fall to levels 60% below baseline levels within 4–8 hours before returning to basal values within 24 hours [21]. In 2009, we reported our initial positive experience with the management of RIP using KTZ in eight patients with an average follow-up of approximately 1.5 years. We have revised our protocol in this report. Material and Methods
Seventeen patients were referred to our center with RIP for management who were ultimately treated with our revised KTZ protocol. In 2009, our treatment protocol was KTZ 200 mg three times daily (TID) with prednisone 5 mg daily for 6 months [16]. These 17 new patients were treated with a revised protocol of 2 weeks KTZ 200 mg TID with prednisone 5 mg once daily. If there were no breakthrough priapisms, the protocol was adjusted to KTZ 200 mg nightly without prednisone for a total of 6 months. The average follow-up was approximately 3 years. LFTs were obtained prior to initiation, at weeks 2 and 4, and monthly following initiation. A chart review and subsequent phone survey were obtained for each patient. All patients were
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Prevention of Recurrent Ischemic Priapism with Ketoconazole Table 1
Patient demographics and pre-KTZ treatment
Pt
Age KTZ started (years)
Etiology
ER visits/treatments before KTZ
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
17 25 37 42 25 37 23 22 18 26 22 30 19 45 22 21 31
SCD Id Id Id Id Id SCD Id Id Id Id Id SCD Id SCD SCD Id
ER × 3, I × 1 ER/I × 5–10 ER/I × 5–10 ER × 5, shunt ER/I × >10 ER/I, shunt ER, shunt × 2 ER/I × 2 ER/I × 4 ER/I × 5–10 ER/I × 3–4 ER/I × 3 ER/I × ∼50 ER/I × 1 ER/I × 3–4, shunt ER/I × 3 ER/I × 2
ED = erectile dysfunction; ER = emergency room; I = irrigation and aspiration and/or intracavernosal injection; Id = idiopathic; KTZ = ketoconazole; SCD = sickle cell disease
fully consented on the off-label administration of this medication and for the use of their clinical data for this report. Each patient was interviewed either during a recent clinic visit or over the phone. Questions asked included how many recurrences of painful nocturnal erections or episodes of priapism did they have while on KTZ therapy and after discontinuation. We also inquired if they experienced any sexual side effects as described in the International Index of Erectile Function (IIEF) Questionnaire including changes in ability to initiate or maintain an erection, confidence in
Table 2
the ability to initiate or maintain an erection, penile rigidity, libido, sexual satisfaction, or problems with orgasm or ejaculation. Unfortunately, the IIEF questionnaire was not routinely offered before initiating treatment as KTZ was started acutely during an emergency room visit for RIP. Therefore, subsequent interviews were structured using the IIEF questions. They were also asked to rate their overall experience on this protocol on a scale from 1 to 10 with 1 being completely dissatisfied and 10 being completely satisfied. For patients who did not score 10 out of 10, we asked them to comment specifically why they were not completely satisfied with the treatment protocol. Results
Tables 1 and 2 summarize patient demographics, chart review, and patient questionnaire findings. Twelve men had idiopathic RIP, and five patients had sickle cell anemia. All patients had a hematologic workup including hemoglobin electrophoresis to evaluate for potential underlying hematologic disorders. All of these men had a history of prolonged, painful SRE occurring nightly or almost nightly since puberty. Every patient had experienced at least one episode of ischemic priapism (>4 hours) requiring emergent intervention which included at least one intracavernosal (IC) injection of phenylephrine and/or corporal body irrigation and aspiration. Four men (patients 4, 6, 7, 15) underwent at least
Summary of chart review and questionnaire
KTZ duration (mo)
Recurrence on KTZ
Recurrence after discontinuation
Rating
6 24 6 12 24 61 1 8 14 9 0.25 6
0 0 0 0 0 0 0 0 0 0 0 1
0 4 self injection 2 self injection 0 15–20 self injection 1 ER visit 0 0 Takes prn KTZ Prn self injection ER × 2 with I Takes prn phenylephrine
10 10 10 10 6 10 10 10 10 10 1 8
7
0
N/A
1 5 16 5
0 0 0 0
0 Takes oral pseudoephedrine 10 episodes when he stopped 1 ED visit with I
7 10 10 7 10
Reason for low rating/side effects
Did not like frequency of medication
GI upset—nausea and vomiting Rare occurrences of prolonged SRE while on KTZ. Stopped taking KTZ and still requires prn phenylephrine. Prolonged SREs after stopping KTZ, much less painful/frequent, last <2 hours, resolve spontaneously
Did not like frequency of medication
ED = erectile dysfunction; ER = emergency room; GI = gastrointestinal; KTZ = ketoconazole; SRE = sleep-related erections
J Sex Med 2014;11:197–204
200
Hoeh and Levine Monthly follow-up visit*:
2007
2012
200 mg KTZ three Ɵmes daily (TID) + 5 mg prednisone daily
Suppression of recurrent ischemic priapism (RIP)
Persistence of RIP
Plan: ConƟnue current regimen x ~ 6 months. Re-evaluate monthly. DisconƟnue aŌer 6 months.
Increase to 400 mg KTZ TID x ~ 6 months, then disconƟnue. ConƟnue prednisone 5 mg daily. Re-evaluate monthly. Titrate down to 200 mg TID or up to 400 mg TID
2 week f/u visit*:
Plan:
Suppression of RIP
Switch to 200 mg KTZ nightly without prednisone. ConƟnue for ~ 6 months, then disconƟnue.
Persistence of RIP
Increase to 400 mg KTZ TID + 5 mg prednisone daily x ~ 6 months. Re-evaluate monthly and decrease dose if possible. DisconƟnue aŌer 6 months.
200 mg KTZ TID + 5 mg prednisone daily x 2 weeks
Figure 1 Evolution of ketoconazole (KTZ) treatment protocol. * Current Recommendations: obtain total testosterone and LFTs prior to initiating KTZ, at weeks 2 and 4, and monthly until KTZ is discontinued.
one shunt procedure prior to starting KTZ. The mean number of emergency room visits prior to initiating KTZ treatment was 6.5 (range one to over 50). The average patient age was 27 when KTZ was initiated (range 17–42). The mean duration of therapy was 11.8 months with a median duration of 7 months (range 1–61 months). The average follow-up period after KTZ was discontinued was 36.7 months. Consistent with our earlier protocol, all men were started on an initial regimen of 200 mg KTZ TID with 5 mg prednisone daily for at least 2 weeks. If there were no breakthrough episodes of priapism, the dose was dropped to 200 mg KTZ nightly without prednisone. After approximately 6 months of nightly KTZ, the therapy was discontinued (Figure 1). No patient required an ER visit for RIP while on KTZ. Patient 12 reported infrequent recurrences of painful morning erections while taking KTZ, though episodes were much less painful and went away with oral pseudoephedrine. The remaining 16 men reported no recurrences in painful erections while taking KTZ. Importantly, all men reported that these effects were noted immediately after starting therapy. All men who J Sex Med 2014;11:197–204
did not have a shunt procedure reported normal erections for coitus while on therapy. There were no reported changes in ability to initiate or maintain an erection, confidence in the ability to initiate or maintain an erection, penile rigidity, libido, sexual satisfaction, or problems with orgasm or ejaculation. Patient 11 reported that although KTZ successfully resolved prolonged SRE, he had to stop the medication after 4 days because of nausea and vomiting. He has since returned to the ER twice over the past 12 months with priapism requiring phenylephrine injections. He subsequently learned to perform self-injection with phenylephrine. Of the 15 men who eventually did stop therapy, five patients reported complete lasting resolution of symptoms after stopping therapy. Seven reported that although their symptoms had greatly improved, they experienced infrequent recurrence of prolonged erections (lasting less than 2 hours), which resolved at home with phenylephrine self injection (five), oral pseudoephedrine (one), or KTZ (one) as needed. Twelve of 15 or 80% of patients did not need to resume nightly KTZ after discontinuing as they experienced lasting resolu-
Prevention of Recurrent Ischemic Priapism with Ketoconazole tion or significant improvement in symptoms for an average follow-up duration of 36.7 months (range 1–95 months). We attempted to obtain a pretreatment baseline total testosterone (TT) in all patients, but in this cohort, many men began the KTZ protocol while in the ER during acute treatment of RIP without obtaining a TT. For the 10 patients in whom we have both pretreatment and post-treatment TT, the mean pretreatment TT was 434 (range 115– 1,187), and post-treatment TT was 384 (range 250–679) with an average decrease of 25 ng/dL which was not statistically significant (P = 0.77). On a scale from 1 to 10 with 1 being very dissatisfied and 10 being extremely satisfied with KTZ therapy to prevent RIP, the average score was 8.8. Reasons for not scoring 10 included one report of nausea/vomiting, displeasure with taking a daily medication, and one patient was unhappy that although he experienced complete resolution of prolonged SRE while on KTZ, when the therapy was discontinued after 7 months, the prolonged SRE resumed, though at a decreased frequency and intensity. Discussion
The management of RIP has not been clearly delineated. According to the American Urological Association Guidelines, the goal of the management of stuttering priapism is the prevention of future episodes, whereas the management of each episode should follow the specific treatment recommendations for ischemic priapism [1]. Current medical options for prevention of RIP include hormonal agents such as KTZ, 5-α-reductase inhibitors, antiandrogens, estrogen, gonadotropin-releasing hormone agonists, and other oral agents including PDE5 inhibitors, terbutaline, digoxin, gabapentin, and baclofen. To date, all of these therapies are only supported with level three or four evidence with small case series and case-control studies [1–4]. As this is an uncommon problem, ultimately a randomized multicenter study will be needed to identify the best treatment. Finasteride has been shown to decrease the frequency of recurrent priapism. Rachid-Filho et al. found that after 4 months of finasteride therapy in 35 men with RIP secondary to SCD, only 16 (42%) experienced zero episodes of priapism per month, another 16 men experienced 1–15 recurrences per month, and the remaining men with over 15 recurrences [22]. Barroso et al. also found that finasteride can decrease the frequency and
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severity of priapic episodes in children and adolescents with recurrent priapism [23]. Advantages of this therapy include the potential for fewer side effects, with disadvantages being that recurrent priapic episodes are not uncommon in a substantial number of men, especially within the first few months after initiating therapy. There are also reported sexual side effects including decreased libido and ED [24]. The major concern for hormonal therapy is producing a hypogonadal state, which may have many adverse outcomes. Caution is strongly advised in using hormonal treatments for prepubertal or adolescent men who have not reached sexual maturation or in those desiring children, as side effects may include growth impairment and infertility [2]. Other concerns for prolonged hormonal treatment include decreased bone density, gynecomastia, and potential sexual side effects, including decreased libido, ED, and inability to achieve orgasm or ejaculation. Given our current understanding of SRE and its relationship to RIP, it would appear that an ideal antiandrogen therapy would suppress SRE and subsequent RIP without producing a hypogonadal state. Bedtime administration of KTZ appears to satisfy these criteria, as it creates only a temporary hypogonadal state to suppress SRE. Several studies suggest that long-term, lowdose PDE5 inhibitor therapy may be useful as a preventative strategy for recurrent priapism, likely by achieving a normative, albeit reversible, resetting of PDE5 expression in penile tissue, which in turn controls the excessive cyclic guanosine monophosphate signaling associated with priapism [25–29]. One drawback from this therapy is the potential for PDE5 inhibitor use to trigger or exacerbate episodes of prolonged morning erections and/or priapism, especially if used incorrectly. The authors of these studies advocate that long-acting PDE5 inhibitors be used only in the morning and never in the evening or with sexual stimulation in this patient population [25,30]. PDE5 inhibitors are also quite costly, which has deterred adoption of this approach for most of our patient population. Another option includes IC self-injection of sympathomimetic agents for episodes of priapism or prolonged, painful morning erections. Studies suggest that this approach may be safely indicated in select cases [31–36]. One concern with IC selfinjection for long-term management is that it does not address prevention of episodes of priapism but rather treats episodes once they occur. One benefit J Sex Med 2014;11:197–204
202 is the avoidance of hormonal therapy and its attendant side effects. Experience in our clinic indicates that the majority of patients are almost uniformly resistant to initiating a self-injection approach as first-line treatment. To our knowledge, this is the largest published study examining the short- and long-term effects of KTZ for the management of RIP. Together with our 2009 report, we have examined the results of KTZ in 25 patients with RIP. In our current cohort, all men reported daily or almost daily episodes of prolonged, painful erections prior to initiating KTZ. One man discontinued the medication after 4 days because of nausea and had recurrence of symptoms. There were no ER visits necessary while on treatment, and 16 of 17 men reported complete resolution of daily episodes of prolonged erections after starting therapy. Fifteen of 16 men eventually discontinued scheduled KTZ after a median duration of 7 months (range 1–24 months). Five of those 15 patients (33%) reported no recurrent priapic episodes. Another seven men reported that after stopping KTZ, the frequency and intensity of prolonged erections were significantly less problematic, and episodes were easily managed with oral pseudoephedrine (30–60 mg), self-injection of IC phenylephrine, or oral KTZ (200 mg) taken as needed. Twelve of 15 patients (80%) did not need to resume a nightly KTZ regimen. Three men (20%) did have recurrence of RIP after discontinuation and elected to resume a nightly KTZ regimen (patients 6, 16, and 17). In our previous study, all eight patients reported no RIP episodes following completion of the 6-month course of KTZ TID with daily prednisone [16]. Between 2006 and 2009, Flum found that the average cost of one emergency room visit for priapism in the United States was $1,778 if patients were discharged home. Costs jumped to $41,909 per encounter if a hospital stay was involved [37]. On the other hand, a 1 month prescription for 30 tablets of 200 mg generic KTZ costs between $12 and $24. Low-dose KTZ taken at bedtime appears to be particularly advantageous to this patient population given its rapid onset of action and subsequent elimination resulting in minimal, if any, reported sexual side effects while suppressing SRE, which in this population can progress to a full-blown priapism. Diminished number, duration, and amplitude of nocturnal erections were demonstrated by plethysmography in our 2009 trial [16]. KTZ did not appear to have a signifiJ Sex Med 2014;11:197–204
Hoeh and Levine cant impact on long-term testosterone values after discontinuation in our cohort, though larger, longer term studies are necessary to prove this finding. Once the acute episode has resolved in men with RIP, we recommend starting the prevention treatment protocol with KTZ 200 mg TID and prednisone 5 mg daily for approximately 2 weeks. If there are no breakthrough priapic erections, we reduce the KTZ dose to 200 mg nightly without prednisone to suppress SRE. If side effects secondary to KTZ are encountered such as nausea and vomiting, we recommend decreasing the total daily dose to 200 mg at bedtime as this common side effect is known to be dose dependent. After approximately 6 months of nightly KTZ therapy, we recommend discontinuing the medication as we have observed a majority of patients will not need to resume a nightly KTZ regimen. We elected to revise our previous 2009 protocol which caused continuous prolonged suppression of testosterone levels. This revision allowed us to reduce the KTZ dosing to bedtime only to suppress serum testosterone for 6–8 hours during sleep. This presumably will reduce the risk of side effects associated with KTZ and prolonged hormonal suppression as well as reduce the cost of therapy. We acknowledge that our study size is small, and given the uncommon nature of this problem, a multicenter trial would be necessary to achieve a larger group to evaluate with a randomized trial possibly comparing a PDE5 inhibitor with KTZ treatment. This study has also shown that some patients may only have partial response to KTZ therapy, though all patients reported an immediate significant improvement in symptoms. The mean follow-up for our study was approximately 3 years; clearly, a longer duration of follow-up is in order to determine the safety of long-term KTZ use. We also recognize the limitation of our sexual function assessment which was not standardized for all patients. We recommend using KTZ cautiously in the pediatric or adolescent population and do not recommend KTZ use beyond 6 months in these populations, given the concern for alternations in bone mineralization and fertility in spite of the limited suppression of androgen production. Patients who are still taking KTZ therapy are undergoing LFT and testosterone testing; as of this time, no patient has shown a significant sustained decline in testosterone values or rise in LFTs. Until larger scale randomized trials can be performed, KTZ treatment should be considered a potential treatment option as it appears to be a
Prevention of Recurrent Ischemic Priapism with Ketoconazole reasonably effective, safe, cost-effective treatment to prevent RIP while preserving sexual function. As we learned from this cohort analysis, there was almost an immediate resolution of priapism episodes once KTZ was initiated. Corresponding Author: Laurence A. Levine, MD, Department of Urology, Rush University Medical Center, Chicago, IL 60661, USA. Tel: 3125635000; Fax: 312-563-5007; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Michael P. Hoeh; Laurence A. Levine (b) Acquisition of Data Michael P. Hoeh; Laurence A. Levine (c) Analysis and Interpretation of Data Michael P. Hoeh; Laurence A. Levine
Category 2 (a) Drafting the Article Michael P. Hoeh; Laurence A. Levine (b) Revising It for Intellectual Content Michael P. Hoeh; Laurence A. Levine
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