a treatment for ED were considered for inclusion, and their methodological quality was assessed using the Jadad score.

Transcription

1 . JOURNAL COMPILATION 2009 BJU INTERNATIONAL Sexual Medicine SYSTEMATIC REVIEW OF ACUPUNCTURE FOR ERECTILE DYSFUNCTION LEE et al. BJUI BJU INTERNATIONAL Acupuncture for treating erectile dysfunction: a systematic review Myeong Soo Lee*, Byung-Cheul Shin and Edzard Ernst *Department of Medical Research, Korea Institute of Oriental Medicine, Daejeon, South Korea, Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, Exeter, UK, and Department of Oriental Rehabilitation Medicine, School of Oriental Medicine, Pusan National University, Busan, South Korea Accepted for publication 21 November 2008 Study Type Therapy (systematic review) Level of Evidence 1a a treatment for ED were considered for inclusion, and their methodological quality was assessed using the Jadad score. inadequate study design, poor reporting of results, small sample size, and publication without appropriate peer review process. OBJECTIVE We evaluated the current evidence for the use of acupuncture to treat erectile dysfunction (ED). METHODS Systematic searches were conducted in 15 electronic databases, with no language restrictions. Hand-searches included conference proceedings and our files. All clinical studies of acupuncture as RESULTS Of the four studies included, one randomized controlled trial (RCT) showed beneficial effects of acupuncture compared with sham acupuncture in terms of response rate, while another RCT found no effects of acupuncture. The remaining two studies were uncontrolled clinical trials. Collectively these data showed that RCTs of acupuncture for ED are feasible but scarce. Most investigations had methodological flaws, e.g. CONCLUSION The evidence is insufficient to suggest that acupuncture is an effective intervention for treating ED. Further research is required to investigate whether there are specific benefits of acupuncture for men with ED. KEYWORDS acupuncture, erectile dysfunction, systematic review INTRODUCTION The prevalence of erectile dysfunction (ED) was estimated to be 322 million cases by the year 2005 [1]. The main risk factors for ED are age, cardiovascular disease, smoking, depression and diabetes mellitus [1]. Current medical interventions for managing ED include oral drugs, intrapenile therapies (intraurethral suppositories and intracavernosal injections) and implantation of a penile prosthesis [2,3]. Although considerable advances have been made, the ideal treatment for ED has not yet been identified. Acupuncture is a complementary medicine used for treating ED [4]. Traditionally, acupuncture, which has been often used to restore and maintain health through the stimulation of specific points on the body [5], has been reported to modulate nitric oxide (NO) related to the treatment of ED [2], and thus it is possible that acupuncture might be effective for treating ED. Currently there is no systematic review of acupuncture for treating ED, although a Cochrane protocol is available [6]. One of the therapeutic claims for acupuncture-induced NO is that it might enhance sexual function [7,8]. The aim of the present systematic review was to compile and critically evaluate the evidence from randomized controlled trials (RCTs) for or against the effectiveness of acupuncture for patients with ED. METHODS The following electronic databases were searched from inception until August 2008: Medline, CINAHL, EMBASE, PsycInfo, The Cochrane Library 2008 (Issue 3), six Korean Medical Databases (Korean Studies Information, DBPIA, Korea Institute of Science and Technology Information, Research Information Centre for Health Database, KoreaMed, and Korean National Assembly Library), and four Chinese medical databases (China Academic Journal, Century Journal Project, China Doctor/Master Dissertation Full Text DB, and China Proceedings Conference Full Text DB). The search terms used were based around two concepts; the first included all terms for acupuncture and the second included terms for ED. The two concepts were combined using the Boolean operator AND. Korean and Chinese terms for acupuncture and ED were used in the Korean and Chinese databases. Reference lists of all obtained papers were also searched, and our personal files were manually searched. Hard copies of all articles were obtained and read in full. All articles were included that reported a prospective clinical study in which men with any type of ED were treated with needle acupuncture or auricular acupuncture, with or without electrical stimulation. Trials testing transcutaneous electrical nerve stimulation, moxibustion (the burning of mugwort, known as moxa) and laser acupuncture were excluded. Studies comparing two different forms of acupuncture and those in which no clinical data were reported were also 366 JOURNAL COMPILATION 2009 BJU INTERNATIONAL 104, doi: /j x x

2 SYSTEMATIC REVIEW OF ACUPUNCTURE FOR ERECTILE DYSFUNCTION Publications Number Identified 80 Excluded after screening title and abstract 41 Reasons Not related to acupuncture 6 Not related to ED 8 Not clinical studies 25 In vivo studies 1 Duplicate publication 1 Full text for detailed evaluation 39 Excluded after reading the full text 35 Reasons: Case report or case series 25 CCTs, but excluded 2 Because of herbal acupuncture 1 Combining acupuncture with moxa 1 CCTs, but excluded 2 Because of comparing other type of acupuncture 1 Cannot retrieve 1 RCTs, but excluded 6 Because of part of a mixed intervention 3 Compared with another type of acupuncture 2 Herbal acupuncture 1 Included 4 RCTs 2 UCTs 2 excluded. No language restrictions were imposed. Dissertations and abstracts were included provided they contained sufficient detail. All articles were read by two independent reviewers (M.S.L. and B.C.S.) and data from the articles were validated and extracted according to predefined criteria. Allocation concealment was assessed using the Cochrane classification. As it is virtually impossible for an acupuncturist to be unaware of the treatment, we used a modified version of the Jadad score [9,10]. Points were awarded as follows: if the study described as randomized, 1 point; appropriate randomization method, 1 point; inappropriate randomization method, 1 point deducted; patient unaware of type of intervention, 1 point; evaluator unaware of type of intervention, 1 point; and description of withdrawals and discontinuations, 1 point. The highest possible score was 5 points. Patient blinding was assumed where the control intervention was indistinguishable from acupuncture, even if the word blinding did not occur in the report. The point for evaluator blinding was only given if specified in the text. Discrepancies were resolved through discussions between the reviewers and if needed, by seeking the opinion of the third author (E.E.). The response rates in the acupuncture and placebo arms were used as a basis for calculating the risk ratio, or relative risk (RR). The RR and 95% CI were calculated using the response rates for acupuncture (successful improvement of sexual function) as a basis using the Cochrane Collaboration s software (Review Manager Version 5.0 for Windows. Copenhagen: The Nordic Cochrane Centre). If appropriate, we then pooled data across studies; if the statistical heterogeneity was not excessive the τ 2, chi-square test and the Higgins I 2 test were used to assess heterogeneity [11]. Homogeneous datasets were statistically pooled using a random-effects model because of clinical heterogeneity between each study such as age, type of acupuncture, treatment duration and aetiology of ED. RESULTS TABLE 1 A flowchart of the trial selection process Eighty articles were identified, of which 76 were excluded for the reasons given in Table 1. The remaining four studies comprised two RCTs [12,13], and two were uncontrolled clinical trials (UCTs) [14,15]; the key data of the included studies are summarized in Table 2. Two trials originated from Turkey [13,15], one from Austria [12] and one from the Netherlands [14]. Two trials were conducted in patients with psychogenic ED [12,15], one in men with other than organic ED [13] and one in two types of ED [14]. The subjective outcome measures in these trials were the International Index of Erectile Function (IIEF) [12] and interview [12 15]. Of the two included RCTs [12,13], one [12] was given 3 points for the use of randomization, for reporting discontinuations and withdrawals, and patient blinding, and the other [13] was given 2 points for the use of randomization and patient blinding. All UCTs [14,15] scored 1 point as they reported withdrawals and discontinuations. None described details on allocation concealment. Engelhardt et al. [12] investigated the curative effect of acupuncture in patients with psychogenic ED in a cross-over trial. Patients were randomized into two groups, one receiving real acupuncture and the other receiving sham acupuncture. After 5 20 sessions the response rates were significantly better in the acupuncture than in the sham control group. The IIEF score was improved after acupuncture treatment compared with baseline. Aydin et al. [13] assessed the effectiveness of electro-acupuncture (EA) on the improvement in sexual activity by interviewing 60 patients with other than organic ED. Participants were allocated randomly into one of four parallel groups: EA (15), sham EA (14), hypnosis (16) and oral placebo (15). At the end of the treatment period there was no significant difference among the groups. The two UCTs [14,15] included in the present study assessed the effects of acupuncture on ED. One trial [14] showed that acupuncture had positive effects on the subjective response rate but no effects on the response of the partner. Another UCT [15] found that acupuncture improved sexual activity in patients with psychogenic ED (69%). The two RCTs [12,13] reported the therapeutic efficacy (improvement of erectile function) of acupuncture compared with sham acupuncture. One trial reported favourable JOURNAL COMPILATION 2009 BJU INTERNATIONAL 367

3 LEE ET AL. TABLE 2 A summary of clinical studies of acupuncture for ED Feature Study Engelhardt et al. [12] Aydin et al. [13] Kho et al. [14] Yaman et al. [15] Study design RCT, partial cross-over unclear RCT, parallel unclear UCT UCT Allocation concealment Jadad score* 3 ( ) 2 ( ) 1 ( ) 1 ( ) No. patients ED aetiology Psychogenic Non-organic (4 organic, 9 psychogenic, Psychogenic 3 discontinued) Duration of ED, months 23.8 (2 72) nr nr 37.7 (6 120) True intervention (n) AT (19) EA (3 Hz dc) (15) AT+EA (5 Hz, 10 ma, AT (29) constant current) (16) Regimen 20 min, 1 or 2/week 5 10 sessions, mean min, 2/week for 6 weeks 30 min, 2/week for 4 weeks) 20 min, total 10 sessions 3/week for week 1 then 2/week in following weeks if failed, another 10 sessions; mean 13.2 Control intervention Sham AT (11, as above) 1. Sham EA (3 Hz dc) NA NA Regimen Main outcome measures Results 4 10 sessions, mean 6.2 penetration, AT points unrelated to ED 1. Response rate (interview) erections sufficient for penetration and intercourse 2. IIEF-5 score 1. Effective response to AT in 13, vs placebo in 1, P = P < after AT vs baseline Non-AT points (14 men, penetration, as above) 2. Hypnosis ( 3/week) later once/month (16 men) 3. Oral placebo (vitamin pill) (15 men) Improvement in sexual activity (interview) +ve response EA (9, 60%); Sham EA (6, 43%) Hypnosis (12, 75%) Oral placebo (7, 47%) NS 1. Response by patient (diary & interview) 2. Response by partner (diary & interview) 3. Profiles of hormones 1. Improvement (7/13) 2. None of No changes Improvement in sexual activity (interview) Improvement 20/29 (69%) Adverse effect None (+) None (+) nr ( ) nr ( ) AT points True: KI6, KI27, CV4, CV6, SI4, SP6, BL23 Sham LR39, ST41, ST25 (3 AT points for True: ST30, ST36, KI6, CV4, CV6 CV4(EA), GV20(EA), SP6(EA), KI3(AT), BL32, LR1, LR11, PC6, ST38, CV2, GV20 headache) HT7 (AT) De-qi nr nr Considered Considered Stimulation and manipulation methods nr nr nr Rotation manipulation AT, acupuncture; dc, direct current; NA, not applicable; nr, not reported; NS, not significant; (+), mentioned in text; ( ), not mentioned in text; *Jadad scores were expressed as the total score (randomization + appropriate randomization methods + describing withdrawals and discontinuations + patient blinding + assessor blinding); Acupuncture points designated according to WHO guideline. effects of acupuncture [12], while the other [13] did not. The meta-analysis shows that the effect of the acupuncture on response rate was not statistically significantly superior to sham acupuncture (59 men, RR 2.73, 95% CI , P = 0.29) although there was heterogeneity in this model (χ 2 = 3.56, P = 0.06, I 2 = 72%) (Fig. 1). FIG. 1. A forest plot of acupuncture for ED, showing the response rate for acupuncture vs sham acupuncture. Study or Subgroup Aydin 1997 Engelhardt 2003 Acupuncture Events 9 13 Sham acupuncture Risk Ratio Total Events Total Weight M-H, Random, 95% CI % 1.40 [0.67, 2.91] % 7.53 [1.13, 50.00] Risk Ratio M-H, Random, 95% CI Total (95% CI) % 2.73 [0.42, 17.78] Total events 22 7 Heterogeneity: Tau 2 = 1.38; Chi 2 = 3.56, df = 1(P = 0.06); I 2 = 72% Test for overall effect: Z = 1.05 (P = 0.29) Favours sham AT Favours AT 368 JOURNAL COMPILATION 2009 BJU INTERNATIONAL

4 SYSTEMATIC REVIEW OF ACUPUNCTURE FOR ERECTILE DYSFUNCTION DISCUSSION Perhaps the most important finding of this systematic review is that there have been very few rigorous trials investigating the effects of acupuncture on ED. The results for response rate failed to show specific effects of acupuncture compared with sham acupuncture. Overall, our findings provide no convincing evidence that acupuncture, with or without electric stimulation, is beneficial for treating ED. We assessed the methodological quality of the primary studies using a modified Jadad scale [10], which allocates one point each for subject and assessor blinding separately. In the two RCTs [12,13], which used sham acupuncture, the patients were blinded for the type of treatment. Although all included RCTs adopted a placebo control, none reported the success of blinding. None reported the concealment of treatment allocation. Trials with inadequate blinding and inadequate allocation concealment might be subject to selection bias and are likely to generate exaggerated treatment effects [16,17]. Details of discontinuations and withdrawals were described in three trials [12,14,15]. One of the two included RCTs failed to report on discontinuations and this might lead to exclusion or attrition bias. Thus the reliability of the evidence presented here is clearly limited. None of the RCTs used a power calculation or adopted assessor blinding, and therefore detection bias is possible. Two of the four studies were UCTs, which are open to bias that often leads to false-positive results. The UCTs suggested that acupuncture improved sexual activity [14,15] but not the response of the partner [14]. Unfortunately, such data are highly susceptible to bias, and hence they provide little useful information on the value of acupuncture as a therapeutic intervention for ED. Two of the included trials reported details about ethical approval [12,14], while the others [13,15] did not. Self-reported subjective questionnaires completed by patients and their partner are the most convenient method of collecting data on ED. Three [13 15] of the included RCTs adopted questionnaires that assessed the symptoms of ED without testing validity and reliability, while others used validated inventories for ED. However, it seems important that only validated questionnaires are used. Unless the outcome measures used have established reliability and validity, data derived from them are subject to bias, and comparisons between the results of different studies are difficult. The extent to which acupuncture has therapeutic effects depending on the duration and frequency of acupuncture is unclear. The optimum dose of acupuncture is unknown. The duration of the interventions was short in most studies (<2 months). Arguably, longer treatment periods are required for acupuncture to have any chance of showing clinical effects. Future trials should therefore have sufficiently large samples, extended treatment and follow-up periods. Reports of adverse events with acupuncture were scarce. No adverse effects, due to acupuncture, were reported in both the reviewed RCTs, while the other studies did not assess or did not report them. The present review has some important limitations. Although strong efforts were made to retrieve all RCTs on the subject, we cannot be absolutely certain that our searches located all relevant RCTs. Moreover, selective publishing and reporting are other major causes for bias that must be considered. It is conceivable that several negative RCTs remain unpublished and thus the overall picture might be distorted [18,19]. Another limitation of our review was that we could not retrieve one possible non-rct written in Russian [20]. Even if this is positive, it would not influence our conclusion. Further limitations include the paucity and the often suboptimal methodological quality of the primary data. Some of the RCTs included in the present review were not successful in minimizing bias. These facts limit the conclusions of this systematic review. In conclusion, the results of our systematic review failed to determine if there are beneficial effects of acupuncture for treating ED. However, there were too few RCTs that could be included in this analysis, and the total sample size and the average methodological quality of the primary studies were too low to draw firm conclusions. ACKNOWLEDGEMENTS The authors specially thank Kate Boddy, Peninsula Medical School, Universities of Exeter & Plymouth, Exeter, UK for editing this manuscript. M. S. Lee was supported by the Korean Institute of Oriental Medicine (K08010). CONFLICT OF INTEREST None declared. REFERENCES 1 McVary KT. Clinical practice. Erectile dysfunction. N Engl J Med 2007; 357: Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: Tharyan P, Gopalakrishanan G. Erectile dysfunction. Clin Evid 2006: Aung HH, Dey L, Rand V, Yuan CS. Alternative therapies for male and female sexual dysfunction. Am J Chinese Med 2004; 32: National Center for Complementary and Alternative Medicine. An Introduction to Acupuncture. Available at: Accessed 23 September Liu J, Fei Y, Alraek T. Acupuncture for treatment of erectile dysfunction. Cochrane Database of Systematic Reviews 2008; CD Ma SX. Enhanced nitric oxide concentrations and expression of nitric oxide synthase in acupuncture points/ meridians. J Altern Complement Med 2003; 9: Ralt D. Intercellular communication, NO and the biology of Chinese medicine. Cell Comm Signaling 2005; 3: 8 9 Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: White AR, Ernst E. A systematic review of randomized controlled trials of acupuncture for neck pain. Rheumatology 1999; 38: Higgins JPT, Greens S eds. Cochrane handbook for systematic reviews of interventions [updated September 2006], in Cochrane Library, Issue 4. Chichester: John Wiley & Sons Ltd, Engelhardt PF, Daha LK, Zils T, Simak R, Konig K, Pfluger H. Acupuncture in the treatment of psychogenic erectile dysfunction: First results of a prospective randomized placebo-controlled study. Int J Impotence Res 2003; 15: JOURNAL COMPILATION 2009 BJU INTERNATIONAL 369

5 LEE ET AL. 13 Aydin S, Ercan M, Caskurlu T et al. Acupuncture and hypnotic suggestions in the treatment of non-organic male sexual dysfunction. Scand J Urol Nephrol 1997; 31: Kho HG, Sweep CG, Chen X, Rabsztyn PR, Meuleman EJ. The use of acupuncture in the treatment of erectile dysfunction. Int J Impot Res 1999; 11: Yaman LS, Kilic S, Sarica K, Bayar M, Saygin B. The place of acupuncture in the management of psychogenic impotence. Eur Urol 1994; 26: Day SJ, Altman DG. Statistics notes: blinding in clinical trials and other studies. BMJ 2000; 321: Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273: Ernst E, Pittler MH. Alternative therapy bias. Nature 1997; 385: Pittler MH, Abbot NC, Harkness EF, Ernst E. Location bias in controlled clinical trials of complementary/ alternative therapies. J Clin Epidemiol 2000; 53: Semashko GA, Istoshin NG, Tereshin AT. [Acupuncture as a method of male sexual disorders correction in neurasthenia]. Vopr Kurortol Fizioter Lech Fiz Kult 2007: 32 4 Correspondence: Myeong Soo Lee, Department of Medical Research, Korea Institute of Oriental Medicine, Daejeon , South Korea. drmslee@gmail.com, mslee@kiom.re.kr Abbreviations: ED, erectile dysfunction; (R)(C)(U)CT, (randomized) (controlled) (uncontrolled) clinical trial; IIEF, International Index of Erectile Function; EA, electroacupuncture; NO, nitric oxide; RR, relative risk. 370 JOURNAL COMPILATION 2009 BJU INTERNATIONAL