Alcohol and Alcoholism Advance Access published online on May 30, 2007
Alcohol and Alcoholism, doi:10.1093/alcalc/agm041
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The Author 2007. Published by Oxford University Press on behalf of the Medical Council on Alcohol.
Sildenafil citrate in the treatment of sexual dysfunction and its effect on quality of life in alcohol dependent men: preliminary findings
1 Mental Health Services, Ministry of Health, Jerusalem, Israel
2 Tirat Carmel Mental Health Center, Ministry of Health, Tirat Carmel, Israel
3 Department of Substance Dependence Treatment, Ministry of Health, Jerusalem, Israel and
4 Geha Mental Health Center and Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Petakh Tikva, Sackler Faculty of Medicine, Tel Aviv University, Israel
* Author to whom correspondence should be addressed at: Mental Health Services, Ministry of Health, 2 Ben Tabai St., 93591 Jerusalem, Israel. Tel: 972 2 6727794; Fax: 972 2 6719007; E-mail: alexander.ponizovsky{at}moh.health.gov.il
Received 28 December 2006; first review notified 10 April 2007; in revised form 11 April 2007; accepted 12 April 2007
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ABSTRACT |
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Background: Alcohol-dependent men commonly suffer from erectile dysfunction (ED) and men with ED are frequently chronic alcohol addicts. Sildenafil is used for treatment of ED caused by diverse factors. The aim of this study was to examine (i) the effect of sildenafil citrate (VIAGRA) on ED in alcohol dependent men, and (ii) whether the effective treatment of ED with sildenafil improves the patient's QoL and related emotional distress. Methods: Fifty-four men with an ICD-10 diagnosis of alcohol dependence (AD) and concomitant ED agreed to enter an open-label trial, in which they were assigned to take 50 mg of sildenafil as add-on to a standard treatment for AD for 12 weeks. Fifty patients (92.3%) completed all baseline and endpoint assessments. Efficacy was evaluated using the International Index of Erectile Function (IIEF), Quality of Life Enjoyment and Satisfaction Questionnaire and General Health Questionnaire. Results: At endpoint, total IIEF scores had improved significantly (
= 16.9), reflecting a 42% improvement (P < 0.0001). A significant increase in the mean scores of each sexual function domain was also noted among all subjects. Sildenafil's positive effect was accompanied by a significant improvement (P < 0.001) in satisfaction with overall QoL and specific life-domains, as well as a significant reduction in emotional distress scores (P < 0.001).Conclusion: The sildenafil add-on evaluated in this trial had a marked beneficial effect on ED and QoL, and was associated with a significant reduction in emotional distress among men with AD. The information obtained is valuable for both clinicians and policymakers in developing innovative therapeutic strategies for men with AD. |
INTRODUCTION |
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Alcohol dependence (AD) is defined as repeated alcohol-related difficulties in at least three of seven areas of functioning, clustered together over any 12-month period (DSM-IV, American Psychiatric Association, 1994
). The lifetime risk for male AD in most western countries is about 10–15%. Alcohol-dependent men commonly suffer from erectile dysfunction (ED) (Fahrner, 1987; Van Steenbergen, 1993; O'Farrell et al., 1998; Wetterling et al.,1999) and men with ED are frequently chronic alcohol addicts (Jeffcoate, 1991; McCambridge et al., 2006). Former addicts, after forcible withdrawal from alcohol, particularly complain about impotence and report it as a ‘cause’ for relapse. The findings of previous studies show that modest ethanol doses (e.g. at blood alcohol concentrations of 
100 mg/dL) can both increase sexual drive and decrease erectile capacity in men (Caspari et al., 1999). In turn, the effect of ethanol in boosting sexual desire may lead to greater alcohol consumption in an attempt at ‘self-treatment’. In this way, a vicious circle of ED and heavy alcohol consumption develops.
Sildenafil citrate (VIAGRA) is reportedly an effective and safe medication indicated for the treatment of ED (Cheitlin et al., 1999; Benchekroun et al., 2003). It is a competitive inhibitor of cGMP-specfic phosphodiesterase type 5. The medication amplifies the effect of sexual stimulation by retarding the degradation of this enzyme. Sildenafil has been found effective in several subpopulations of men with ED, including sufferers from diabetes (Basu and Ryder, 2004), hypertension (Feldman et al., 1999), spinal cord injuries (Hultling et al., 2000; Deforge et al., 2006), multiple sclerosis (Fowler et al., 2005), depression (Seidman et al., 2001; Rosen et al., 2004; Tignol et al., 2004; Fava et al., 2006), PTSD (Orr et al., 2006), and schizophrenia (Aviv et al., 2004; Gopalakrishnan et al., 2006), men after resection of the prostate or radical prostatectomy (Nandipati et al., 2006), after renal transplant (Sharma et al., 2006), men on dialysis (Dachille et al., 2006), and men aged 65 years and older (Wagner et al., 2001; Carson, 2004). To our knowledge, there has been no investigation of the effects of sildenafil on ED in men with AD.
The impact of disease on health-related quality of life (QoL) is now accepted, as is the importance of health-related QoL as a measure of treatment efficacy (NIH Consensus Development Panel on Impotence, 1993; Donovan et al., 2005). Health-related QoL is severely impaired in alcohol dependants (Feeney et al., 2004; Fisher et al., 2005), and one of the causes is the distress associated with ED, since sexual health is an important component of QoL (Donovan et al., 2005). Newly introduced compounds, such as acamprosate, naltrexone and topiramate, used as an add-on treatment for alcoholism, by promoting abstinence, have been shown to improve QoL profiles to levels comparable to those of healthy individuals (Johnson et al., 2004; Morgan et al., 2004; UKATT Research Team,2005). An analogous effect may be achieved with innovative social behavior and network therapy for alcohol problems (UKATT Research Team, 2005), with a cognitive behaviour treatment program (Feeney et al., 2004) and with medication compliance enhancement treatment (Johnson et al., 2004). Because sexual health is an important component of QoL, ED that caused significant distress can diminish the QoL (NIH Consensus Development Panel on Impotence, 1993).
The goal of the study reported here was to attempt to break the vicious circle of ED and heavy alcohol consumption by using VIAGRA to treat impotence in subjects with AD. Specifically, we sought to examine (i) the effect of VIAGRA on ED in alcohol-dependent men, (ii) whether the effective treatment of ED with VIAGRA improves the patient's QoL, and (iii) reduced emotional distress.
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Methods |
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Study design
This paper reports preliminary results of a 12-week, open-label trial was conducted from January 1, 2005 to June 31, 2006 simultaneously at 11 outpatient medical centres for alcohol abuse across Israel. All the centres belong to the Ministry of Health and are audited by its Department for the Treatment of Addictions. The Ministry of Health's institutional review board approved the study protocol, and all patients gave their written informed consent before enrollment in the study.
The patients
Male patients were eligible if they met the following criteria: (i) aged 18–50 years, (ii) had an ICD-10 diagnosis of AD (F10.2), (iii) had sought treatment to stop alcohol consumption, (iv) had completed a detoxification program not later than 1 month before study enrolment, (v) had complained of ED for at least the 12 weeks preceding the study, and (vi) had a regular female partner during the research period.
AD was diagnosed according to International Classification of Diseases, Tenth Edition (ICD-10) criteria (World Health Organization, 1993). The subjects’ alcohol history was described by the following parameters: (i) age at first alcohol consumption, (2) age at first binge, (3) duration of harmful alcohol consumption, (4) number of inpatient or outpatient detoxifications, (5) average alcohol intake in last 6 months (grams alcohol/drinking day), and (6) number of drinking days during last month. AD severity was rated on ICD-10 criteria into one of three categories, according to frequency of drinking (during the previous 6 months) and amount of alcohol intake. The three categories were: (1) continuous drinkers = (almost) daily alcohol consumption without binges, (2) frequent heavy drinkers = frequent alcohol consumption (more than 3 days/week) with frequent intoxication (more than one/week), and (3) episodic drinkers = less frequent, irregular alcohol consumption with longer (> 5 days) sober periods, and some binges (less than one/week).
Alcohol-associated sexual dysfunction (AASD) was defined by DSM-IV criteria for substance-induced sexual dysfunction (American Psychiatric Association, 1994). The criteria include impaired desire, arousal (ED), orgasm, and sexual pain. Trial subjects had to have substantially impaired sexual function, as defined by at least one of the following criteria, and which was causing significant distress: ED, defined as persistent or recurrent inability to retain an adequate erection until completion of sexual activity; inability to reach orgasm; ejaculatory delay of at least 10 min in masturbation or intercourse.
Patients were not enrolled if they had anatomical penile deformities (e.g. Peyronie's disease), a primary or prior diagnosis of a sexual disorder other than AASD, or had serious co-morbid medical illnesses (hepatic, renal, neurological, cardiovascular, hematological, diabetes mellitus); if they were evaluated as a suicide risk; if they suffered from acute psychosis, severe depression, or organic brain syndromes; or if they were currently using psychoactive substances, drugs or therapies other than alcohol, such as benzodiazipines, sedatives, antidepressants, barbiturates, and antipsychotics.
Study protocol
Patients were recruited from outpatient settings and referrals. All patients were evaluated for eligibility at screening and all consenting patients (N = 54) completed the International Index of Erectile Function (IIEF) (Rosen et al., 2002) to establish their ability to self-evaluate sexual dysfunction. All patients received a physical examination covering blood pressure, electrocardiogram, and standard biochemistry and hematological laboratory tests.
A total of 54 patients were assigned to VIAGRA as an add-on to a standard outpatient program for AD treatment. This program consisted of education and therapy, addressing problems contributing to or resulting from alcoholism, and learning skills to manage alcoholism over time. At the baseline, eligible patients assigned to receive sildenafil were instructed to take 1 tablet approximately 1 h before anticipated sexual activity but not more than once a day. They also were instructed to make at least two attempts at sexual activity each week. The dose of the drug could be adjusted from 1 to 2 tablets (VIAGRA, was provided by Pfizer Pharmaceuticals Israel Ltd, Herzliya Pituakh, Israel).
Drug accountability, and self-rated and physician-rated assessment were performed at baseline and after 12 weeks. Throughout the study, the investigators monitored for spontaneous reports of adverse events and evaluated their severity and relationship to the study medication.
Outcome measures
Efficacy was evaluated using a battery of validated measurements. The primary outcome measure was the IIEF (Rosen et al., 2002), supplemented by two global efficacy questions: (a) Did treatment improve your erections? and (b) Did treatment improve your ability to perform sexual intercourse? The questions were asked at baseline and at weeks 4, 8, and 12. Secondary outcome measures used were the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (Endicott et al., 1993) and the General Health Questionnaire (GHQ) (Goldberg and Williams, 1988). Time frame for the measures was the 10 days preceding the assessment.
The IIEF is a self-rated 15-item instrument for assessing sexual function across five functional domains: erection, orgasm, desire, intercourse satisfaction and overall satisfaction. Questions are answered on a 6-point scale, where 1 = ‘almost never/never’ and 5 = ‘almost always/always’. A score of 0 means ‘no attempt at sexual intercourse’. The possible total score ranges from a minimum of 5 to a maximum of 75. The changes in the IIEF scores quantified the magnitude of the response to the treatment. A score of 21 is the cut-off point to roughly distinguish respondents with a degree of ED (score = 21 or less) from those who have no ED (score > 21).
The Q-LES-Q is a valid, reliable, time-sensitive self-report instrument for assessing satisfaction with QoL and five specific life-domains (physical health, subjective feelings, leisure-time activities, social relationships and general activities). Each domain score and an average of the subscale scores (QoL Index) was calculated. Responses were scored on a 5-point scale (from ‘not at all/never’ to ‘frequently/all the time’), with higher scores indicating more enjoyment and satisfaction with particular life-domains and QoL as a whole.
The GHQ-12 has been used extensively worldwide as a valid and reliable measure of non-specific psychological distress or demoralisation (Ustun and Sartorius, 1993). The questionnaire asks whether the respondent has experienced a particular symptom or behavior recently. Responses are rated on a 4-point Likert frequency scale, ranging from ‘much less than usual’ (weighted as 0) to ‘much more than usual’ (weighted as 3). Total scores range from 0–36. Though scores vary by study population, scores of about 11–12 are typical, and a score higher than 20 suggests severe problems and psychological distress.
Internal consistency reliability, as measured by Cronbach's 
coefficient, was satisfactory for all instruments used, specifically: 0.96 for the QoL Index (from 0.91 for physical health to 0.94 for the general activities domain) and 0.71 for the GHQ.
Statistical analysis
We computed frequency distribution and mean scores for the subjects’ sociodemographic characteristics and mean scores and standard deviations (SDs) were computed for the outcome measures. Pearson product moment correlations were calculated to measure relationships between sexual function, QoL, and emotional distress. The statistical significance of the change from baseline to week 12 () was calculated by paired two-tailed t-tests. All the men who completed two treatment efficacy assessments were classified as either responsive or non-responsive to the treatment. For all analyses, the level of statistical significance was set at P < 0.05. Analyses were performed with SAS version 9.1 (SAS Institute Inc, Cary, NC).
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Results |
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Patients’ characteristics
Of the 54 men who consented to participate in the study, 50 (94.4%) completed all baseline and endpoint (week 12) assessments. The four subjects who withdrew did not show significantly different baseline demographic and clinical characteristics compared to those who completed the study. Table 1 presents demographic and selected clinical characteristics for the completers. Sixty two percent of the sample were Jews; mean age was 44 years (SD = 8.7); most patients were married (62%), 26% were divorced, separated or widowed and 12% were single. Mean length of schooling was 11.1 years (SD = 4.5); 68% were unemployed and 54% had immigrated to Israel from the former Soviet Union, with a mean time since immigration of 16.4 years (SD = 13.3).
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The subjects’ alcohol history was characterized by an early age of onset. Mean age at first-in-life alcohol consumption was 17.2 years (SD = 3.4) and age at first alcohol binge was 20.5 years (SD = 6.4). The mean duration of harmful alcohol consumption was 14.8 years (SD = 9.7). Most patients (60%) had no prior inpatient detoxification, 26% had one and 14%, more than two. Average alcohol intake in the last 6 months was 700 g per drinking day (SD = 648.8), and the mean number of drinking days in the last month was 8.6 (SD = 10.8).
Correlation between measures
Table 2 presents the correlations between baseline scores for sexual function, quality of life domains, and emotional distress. As can be seen, the IIEF total score is moderately and positively associated with the Q-LES-Q Index score and moderately but negatively with the GHQ total score (P < 0.001). Significant correlations similar in magnitude and direction were also found between sexual function and QoL specific life-domain scores and emotional distress scores. The results suggest that sexual function, quality of life, and emotional distress are distinctly separate constructs.
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Sexual function
At baseline, patients reported the following extensive sexual dysfunction symptoms: 85.5% erectile dysfunction, 70.3% libido problem, 61.3% premature ejaculation or delay in ejaculation, 25% weak or absent orgasm, and 5.5% lack of pleasure or pain. Table 3 presents changes in the IIEF total score and five domain scores over 12 weeks of treatment. At the endpoint, total IIEF scores had significantly improved (
= 16.8), reflecting 42% improvement in the scores (P < 0.0001). A statistically significant increase was noted also in the mean scores for each sexual function domain. The largest improvement (61.7%) came in the overall satisfaction domain score, followed by, in descending order: Erectile Function (45.9%), Intercourse Satisfaction (45.1%), Orgasmic Function (34.4%), and Sexual Desire (21.7%). In addition, at the end of week 4 and at week 12, 94 and 98% of patients, respectively, gave affirmative responses to the global efficacy questions on treatment-related improvement in (a) erectile function, and (b) ability to perform sexual intercourse. Using the IIEF cut-off score of 21, 37 patients (74%) responded positively to the 12-week sildenafil treatment, and 13 (26%) were non-responders.
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Quality of life
Table 4 presents changes in the Q-LES-Q Index and specific life-domain mean scores over the trial. A significant improvement in satisfaction with overall QoL and all specific life-domains was found (P < 0.0001). The improvements ranged from 10.3% for the Social Relationships domain to 17.2% for the Physical Health domain. QoL measures improved particularly among the sildenafil-responsive patients (N = 37), compared to those whose ED did not respond to this treatment (N = 13): at endpoint, the responders scored significantly higher than the non-responders on the Q-LES-Q Index (3.5 ± 0.5 vs 2.9 ± 0.4, t = 3.84, P < 0.001).
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Emotional distress
Baseline levels of emotional distress were generally unrelated to efficacy or treatment satisfaction. Over the course of the trial the subjects demonstrated a statistically significant reduction in GHQ distress scores (P < 0.0001). From baseline to the week 12 endpoint, the percentage of distressed persons, defined as those with a GHQ score higher than 20, decreased from 68 to 22%.
Side effects
Sildenafil was well tolerated. The most common side effect was headache, reported by 32% of sildenafil-treated patients (N = 16). Only one patient reported dyspepsia (2%). All these adverse effects were transient and mild in nature. No serious adverse events related to the study drug were reported.
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Discussion |
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This is the first study showing the effects of sildenafil on men with both ED and AD and to measure the effect of their consequent improved erectile function on QoL and related emotional distress. Our results indicate that sildenafil, as an adjunct drug to a standard treatment for men with alcoholism, significantly improved erectile function and other components of sexual function and also significantly raised satisfaction with QoL and all specific life-domains. Finally, this intervention markedly reduced psychological distress.
The improvements observed in this study were comparable to those observed in other clinical trials of sildenafil for ED in depressive disorder (Fava et al., 2006), schizophrenia (Gopalakrishnan et al., 2006), PTSD (Orr et al., 2006), as well as in medical diseases and treatments such as diabetes (Basu and Ryder, 2004), hypertension (Hultling et al., 2000), heart failure (Freitas et al., 2006), spinal cord injuries (Deforge et al., 2006), renal transplant (Sharma et al., 2006), dialytic treatment (Dachille et al., 2006), and radical prostatectomy (Nandipati et al., 2006). The study treatment entailed little risk, as adverse effects were limited to headache (N = 16) and dyspepsia (N = 1). Given that discontinuation rates are a powerful indicator of medication effectiveness, the low dropout rate (6%) in this study may be considered as additional evidence of the intervention's clinical benefit.
ED is a complex condition, deriving from many physical, emotional, societal, and relationship factors (Althof et al., 2006; O'Leary et al., 2006), and which has a serious impact on the satisfaction with QoL of an affected male and his partner (Benchekroun et al., 2003; Donovan et al., 2005). In their recent qualitative study, Tomlinson and Wright (2004) described the impact of ED on the subjective feelings of 40 men, their expectations of sildenafil, and the self-reported impact of the treatment on the subjects and their relationships. ED caused serious distress and sildenafil, when it worked, brought about a great improvement in well-being. However, when the treatment was ineffective, the distress worsened. In line with these findings and those from a few other earlier studies (Althof et al., 2006; Montorsi et al., 2006; Steidle et al., 2006; Cappelleri et al., 2006), we found that sildenafil treatment meaningfully reduced the symptoms of emotional distress.
We agree with Rosen et al.’s conclusion (Rosen et al., 2006) that the changes in QoL associated with ED therapy may be mediated by changes in sexual function, mood, and family relationships and/or, as we observed, by a reduction in psychological distress. Stopping alcohol consumption while undergoing treatment may also be a reason for an improved QoL, although abstinence that is only temporary may not be able to change behaviour and underlying psychosocial features. One can suggest that the well studied stress reduction effect of alcohol that is a major motivation for drinking (Hall, 1995) may be replaced here by the analogous tension-reduction effect of sildenafil. Whatever, the precise mechanisms by which the beneficial effects of sildenafil on ED translate into a positive QoL response require further research.
The obvious limitation of our study is the lack of a control group without additional or with alternative treatment for ED or with a placebo. Thus, a non-specific, placebo effect on ED cannot be ruled out. This effect, however, is unlikely, given the significant improvements not only in sexual function but also in QoL and distress scores achieved over a relatively short trial. The positive effects of sildenafil on emotional well-being, self-esteem, confidence and relationship satisfaction of men with ED revealed in several recent double-blind, placebo controlled studies, support our findings (Cappelleri et al., 2006; O'Leary et al., 2006; Steidle et al., 2006). Unlike a double blind clinical trial, an open label design is susceptible to the clinician's subjective bias during data collection and the evaluation of study parameters, usually in favor of the efficacy of the experimental compound over a comparative compound, or vice versa. However, this bias would mostly show itself on the clinician's clinical impressions and symptom assessment. On self-administered questionnaires the clinician's impact on outcomes is practically excluded. A potential bias deriving from the participating physicians’ differential levels of expertise is also precluded because, to our knowledge, the clinicians in all participating centres were equivalently trained and experienced.
Another potential limitation is not the diagnosis specific nature of the tool we used to assess QoL in patients with AD. Although the Q-LES-Q was initially developed to assess QoL in depressed patients, it has been used for evaluating health-related QoL outcomes in various clinical populations (Schwartz et al., 1998; Phillips et al., 2005; Grant et al., 2006). Its key virtue for us is that it contains only items on satisfaction with sexual drive and interest included in the general activities domain. This means that the significant correlation between improvements in sexual functioning and satisfaction with specific life domains which we found in this study is a genuine outcome and not an artifact of convergent validity between the IIEF and the Q-LES-Q, that is, it does not derive from overlap between the underlying constructs. This is also true for the psychological distress measure we used.
Finally, the relatively short trial period meant that we were not able to examine the effects of sildenafil on drinking patterns. This issue should be addressed in further longitudinal studies with a longer follow-up time.
In sum, the preliminary findings show that augmenting a standard alcoholism treatment with sildenafil had a marked beneficial effect on both ED and QoL, and was associated with a significant reduction in emotional distress. Moreover, the treatment entails little risk: adverse effects were few and minor. The implications of these findings in relation to the treatment intervention appropriate to this patient group are important. The information obtained in the study (it will be controlled in further controlled trial) is valuable for both clinicians and policy makers in developing innovative therapeutic strategies for men with alcohol dependence.
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ACKNOWLEDGEMENTS |
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This study was supported in part by independent research grant from Pfizer Pharmaceuticals Israel Ltd., and the Israeli Ministry of Immigrant Absorption (Dr A. Ponizovsky). We wish to thank Drs L. Averbuch, S. Marshansky, M. Dakhis, T. Azarch, M. Khinich, M. Lerman, L. Komarovsky, M. Patachov, S. Sonkin, S. Yavilevich, M. Bard, S. Epstein, and M. Rubinstein for their part in collecting the data. We also are grateful to our research assistant S. Rozen, to I. Radomislansky for her statistical assistance and to N. Steigman for his editing.
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References |
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