A comparative study of electroacupuncture at Zhongliao (BL33) and other acupoints for overactive bladder symptoms

Abstract

Electroacupuncture (EA) at Zhongliao (BL33) can improve the symptoms of overactive bladder (OAB), such as urinary frequency, urgency, and incontinence. However, its performance compared with other acupoints remains unclear. This study investigated the effects of EA at BL33 with deep needling on rats with OAB by detecting urodynamics in eight groups: no intervention group, D-BL33 group (deep needling at BL33), S-BL33 group (shallow needling at BL33), non-acupoint group (needling at the non-acupoint next to BL33), Weizhong (BL40) group, Sanyinjiao (SP6) group, Tongtian (BL7) group, and Hegu (LI4) group. Results revealed that EA at BL33 with deep needling, BL40, and SP6 prolonged the intercontraction interval (ICI) of rats with OAB (P=0.001, P=0.005, P=0.046, respectively, post-treatment vs. post-modeling). Furthermore, the change in ICI from post-modeling in the D-BL33 group was significantly greater than those of the no intervention and other EA groups (all P<0.01). Significantly shortened vesical micturition time (VMT) and elevated maximum detrusor pressure (MDP) were also observed in the D-BL33 group (P=0.017 and P=0.024, respectively, post-treatment vs. post-modeling). However, no statistically significant differences in the changes of VMT and MDP from post-modeling were observed between D-BL33 and the other EA groups. In conclusion, EA at BL33 with deep needling may inhibit acetic-acid-induced OAB more effectively.

Keywords

overactive bladder / electroacupuncture / acupuncture points

Introduction

Overactive bladder (OAB) is defined by the International Continence Society as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology” [ 1]. OAB is prevalent worldwide and is estimated to affect more than 400 million people [ 2]. OAB may compromise quality of life in terms of daily and work activities, sleep, self-esteem, mental health, sexual function, and relationships [ 3– 5].

International guidelines for OAB emphasize behavioral therapies as first-line treatments in combination with second-line therapy (pharmacologic management), such as oral anti-muscarinics or b₃-adrenoceptor agonists [ 6]. However, some patients cannot benefit from OAB medications because of poor efficacy, unacceptable adverse events, or lack of appropriate medication because of mobility issues, weight loss, weakness without medical cause, and cognitive deficits [ 7]. These patients may receive third-line treatments, such as tibial nerve stimulation (TNS) and sacral neuromodulation (SNS), which both offer lasting treatment effects [ 8– 14]. However, the widespread use of TNS is limited because it requires regular patient visits and is expensive. SNS is mainly limited by the risk of complications, such as migration of the lead, infection, and failure of the device. A popular acupuncture therapy for OAB in China is electroacupuncture (EA), in which needles are inserted into acupoints and a minimal electric stimulation based on both traditional meridian theory and neuroelectrophysiology is applied.

A recent systematic review confirmed that acupuncture improves the quality of life and urodynamic parameters of OAB patients with few side effects [ 15]. The most commonly used points in clinical trials are Shenshu (BL23), Pangguangshu (BL28), Shangliao (BL31), Ciliao (BL32), Zhongliao (BL33), and Sanyinjiao (SP6) [ 16– 23], which all belong to a similar somatic innervation area, particularly BL33. As a common intervention, EA at BL33 with deep needling can increase bladder capacity and suppress bladder overactivity [ 24– 26]. We previously described the method of manipulation for deep needling at BL33 in a clinical trial [ 27]. When needling deeply at BL33, the tip of the needle approaches the third sacral nerve root. Therefore, the underlying mechanism of EA and deep needling at BL33 may be similar to sacral nerve stimulation. They both stimulate the somatic afferent in the pudendal nerve to elicit inhibitory mechanisms. Therefore, we aimed to investigate the influences of needling at points in different nerve innervations or of different meridians on the effect of acupuncture. We also aimed to investigate if the depth of needling is a factor that affects therapeutic efficacy of EA. We set points in different nerve innervations and of different meridians as controls. We hypothesized that: (1) EA at BL33 could suppress bladder overactivity more effectively than BL40 (same nerve segment and meridian as BL33), SP6 (same nerve segment but of a different meridian than BL33), BL7 (different nerve segment but of the same meridian as BL33), LI4 (different nerve segment and meridian than BL33); and (2) deep needling in BL33, especially when the needle approaches the anterior branch of the second sacral nerve, is more effective than shallow needling.

Materials and methods

Animal

Animal experiments were conducted in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the China Academy of Chinese Medical Sciences. Adult male Sprague–Dawley rats (180–220 g) were purchased from Beijing Vitalriver Experimental Animal Technology Co. Ltd., China (Certificate No.11400700011923). Animals were housed in groups of three to four with ad libitum access to food and water under a 12 h/12 h light/dark cycle (darkness between 20:00 and 8:00) for 1 week prior to the experiment. Then, the rats were randomly divided into eight groups: no intervention group, D-BL33 group (deep needling at BL33), S-BL33 group (shallow needling at BL33), non-acupoint group (needling at the non-acupoint next to BL33), Weizhong (BL40) group, Sanyinjiao (SP6) group, Tongtian (BL7) group, and Hegu (LI4) group. Each group had six rats.

Cystometric analysis

All of the rats were initially anesthetized with urethane (10 ml/kg i.p., Sinopharm Chemical Reagents Co., Ltd., China). Supplementary anesthesia was administered if limb withdrawal was observed. Rats were placed on a thermostat control board (69001, Shenzhen RWD Life Science Co., Ltd., China) to maintain their body temperatures at approximately 38 °C.

A polyethylene catheter (PE-50) was inserted into the bladder from the dome and secured with a purse-string suture. Then, the bladder catheter was connected through a T-tube to a pressure transducer and a microinjection pump (Smiths Medical Instrument Co., Ltd., China). Cystometrograms were measured by a bridge amplifier (ML221, AD Instruments Shanghai Trading Co., Ltd., China) via a pressure transducer (MLT0380, AD Instruments Shanghai Trading Co., Ltd., China) and recorded continuously with Laboratory Chart Program Version 8.0.10 software and a computerized data acquisition system (PowerLab4/30, ML866, AD Instruments Shanghai Trading Co., Ltd., China).

Cystometry was performed with room-temperature saline at 6 ml/h. The following variables were continuously recorded during infusion: the intercontraction interval (ICI, indicating the interval between contractions), the vesical micturition time (VMT), basal pressure (BP), and maximum detrusor pressure (MDP). Baseline cystometry was performed by saline infusion (before-modeling). Then, 0.25% acetic acid (Tianjin Fuyu Chemical Co., Ltd., China) was infused at a constant infusion rate of 6 ml/h for 45 min, followed by another saline infusion for 45 min (post-modeling). The rats of the D-BL33, S-BL33, non-acupoint, BL40, SP6, BL7, and LI4 groups subsequently underwent EA stimulation. After the intervention, cystometrograms were recorded by continuous saline infusion for 45 min (post-treatment).

EA stimulation

A sterile disposable acupuncture needle (F 0.25 mm × 25 mm, Suzhou Medical Instruments Co., Ltd., China) was inserted unilaterally, vertically, or slightly obliquely (as necessary) into the bilateral acupoints (Table 1 and Fig. 1). The positive and negative poles of the EA stimulator were connected to the needle handle. After 5 min of EA stimulation at a frequency of 2/15 Hz by an EA stimulator (HANS-100, Shanghai Taicheng Technology and Development Co., Ltd., China), the acupuncture needle was immediately removed.

Statistical analysis

Data of the last eight micturition cycles in each period were included in statistical analysis. Data were expressed as the mean±standard error of the mean or median and were analyzed by SPSS 19.0 software (SPSS Inc., Chicago, IL, USA). The normality test (Shapiro–Wilk test) or homogeneity of variance test (Levene test) was performed before further analysis. If data followed normal distribution or homogeneity of variance conditions, the paired t test was performed to analyze the differences within a group; meanwhile, the differences between groups were compared by one-way ANOVA followed by Tukey HSD test for pairwise comparisons. If the data did not follow normal distribution or homogeneity of variance conditions, variable transformation or nonparametric test (Wilcoxon signed-rank test for the comparison of paired samples; Kruskal–Wallis H test for multiple comparisons of independent samples comparison followed by Nemenyi test for pairwise comparison) was performed. P<0.05 was defined as statistically significant.

Results

No rats died during the experiment. Six rats per group were included in the statistics. All the variables followed normal distribution and were presented as mean±standard error. Table 2 shows the ICI, VMT, BP, and MDP variables for each group. Fig. 2 shows the representative cystometrograms of an OAB rat and a rat in the group with EA at BL33 with deep needling.

(1) Before acetic acid instillation, no significant differences were noted in the cystometrogram measurements of the eight groups.

(2) After acetic acid infusion, ICI was shortened, VMT was prolonged, BP was elevated, and MDP decreased in each group. No significant differences were found among the eight groups.

(3) After intervention, ICI in the D-BL33, BL40, and SP6 groups was prolonged (P = 0.001, P = 0.005, P = 0.046, paired t test, respectively, post-treatment vs. post-modeling). Moreover, ICI in the D-BL33 group was prolonged to a level similar to that in the normal condition (P = 0.523, paired t test, post-treatment vs. post-modeling). In the D-BL33 group after intervention, the change in ICI from post-modeling was significantly greater than those in the no intervention and other EA groups (all, P<0.01, one-way ANOVA followed by Tukey HSD test for pairwise comparisons), as shown in Fig. 3. VMT was shortened and MDP was elevated significantly in the D-BL33 group (P = 0.017 and P = 0.024, paired t test, respectively, post-treatment vs. post-modeling). However, among the eight groups, no statistically significant differences were found in the changes in VMT and MDP from post-modeling and there was no significant difference in BP before and after intervention.

After intervention, ICI in the D-BL33, BL40, and SP6 groups was prolonged (P = 0.001, P = 0.005, P = 0.046, paired t test, respectively, post-treatment vs. post-modeling); after EA at BL33 with deep needling, the change in ICI from post-modeling was significantly greater than those in other interventions (all, P<0.01, one-way ANOVA followed by Tukey HSD test for pairwise comparisons); VMT was shortened and MDP was elevated significantly in the D-BL33 group (P = 0.017 and P = 0.024, paired t test, respectively, post-treatment vs. post-modeling). However, no significant difference was observed in the change from post-modeling in the VMT, BP, or MDP between interventions.

After EA at BL33 with deep needling, the change in ICI from post-modeling was significantly greater than those in other interventions (all, P<0.01, one-way ANOVA followed by Tukey HSD test for pairwise comparisons).

Discussion

We induced a stable and reliable OAB rat model by bladder perfusion with acetic acid, which caused similar symptoms as OAB significantly reduced ICI; these effects are similar to those reported by previous studies [ 29– 32]. Bladder perfusion with acetic acid also significantly prolonged VMT, elevated BP, and lowered MDP in some groups. However, the change in MDP was different from previous studies; this difference likely resulted from differences in sample size, anesthesia used, or manual operation. After intervention, ICI was prolonged in the EA at BL33 with deep needling, EA at BL40, and EA at SP6 groups. ICI in the D-BL33 group was prolonged by 112.84%±9.88% compared with the normal level. The change in ICI from post-modeling in the EA at BL33 with deep needling group was significantly greater than those in the no intervention and in the other intervention groups. Meanwhile, EA at BL33 with deep needling shortened VMT and elevated MDP. Similar changes in VMT and MDP were not observed after other interventions. These results implied that EA at BL33 with deep needling could effectively inhibit bladder overactivity, thus reducing urination frequency; this result is similar to those of other studies [ 30, 33].

In a previous study [ 34], acupuncture-like stimulation was applied to the perineal area in urethane-anesthetized rats. The treatment inhibited both the rhythmic micturition contractions and rhythmic burst that discharge the pelvic efferent nerve, without significantly changing hypogastric efferent nerve activity. These findings indicate that the inhibition of rhythmic micturition contractions after acupuncture-like stimulation of the perineal area is a reflex response characterized by segmental organization. The main nerve segments controlling the rat bladder are S1–S4. BL33 is on the course of the anterior branch of the second sacral nerve; therefore, deep EA on BL33 can directly stimulate the second sacral nerve. This process is similar to sacral neuromodulation [ 35, 36], which may act directly upon the nerves, or alter or modulate the nerve activity of the bladder. EA at BL40 or SP6 has a weaker suppressive effect on OAB, which may be attributed to stimulating the peripheral afferent nerve; this blocks the competing abnormal visceral afferent signals from the bladder and prevents reflex bladder hyperactivity [ 37– 40]. BL7 and LI4 belong to different nerve segments as BL33 or the bladder, and neither has a similar effect as BL33. Therefore, the direct stimulation of the sacral nerve through EA at BL33 with deep needling may be the main pathway for inhibiting OAB.

In traditional Chinese medicine, OAB symptoms result from bladder dysfunction. In the meridian theory, the acupoints pertaining to the bladder meridian and located on the lumbosacral region (adjacent to the bladder) are preferred for acupuncture in patients with OAB. BL33, BL40, and BL7 all belong to the bladder meridian. BL33 is located closer to the bladder than BL40 and BL7. SP6 and LI4 belong to the spleen meridian and the large intestine meridian, respectively. In our study, both BL7 and LI4 were invalid, and BL40 had a weaker inhibiting effect on OAB. These results support the meridian theory that an EA point location farther from the bladder has a weaker influence. However, the weaker effect of SP6 can still suppress OAB. This suppressive effect likely resulted from the location of SP6 on the same nerve segment as the bladder.

The small sample size, different anesthesia, and differences in manual operation may have affected our results. In future work, we could compare EA with sacral neuromodulation and explore the mechanism of EA at BL33 for OAB. In conclusion, we propose that EA at BL33 with deep needling may inhibit OAB more effectively.

References

[1] Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J Pelvic Floor Dysfunct 2010; 21(1): 5–26

[2] Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011; 108(7): 1132–1138

[3] Coyne KS, Sexton CC, Irwin DE, Kopp ZS, Kelleher CJ, Milsom I. The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the EPIC study. BJU Int 2008; 101(11): 1388–1395

[4] Kannan H, Radican L, Turpin RS, Bolge SC. Burden of illness associated with lower urinary tract symptoms including overactive bladder/urinary incontinence. Urology 2009; 74(1): 34–38

[5] Sexton CC, Coyne KS, Vats V, Kopp ZS, Irwin DE, Wagner TH. Impact of overactive bladder on work productivity in the United States: results from EpiLUTS. Am J Manag Care 2009; 15(4 Suppl): S98–S107

[6] Gormley EA, Lightner DJ, Faraday M, Vasavada SP; American Urological Association; Society of Urodynamics, Female Pelvic Medicine. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol 2015; 193(5): 1572–1580

[7] Sternberg SA, Wershof Schwartz A, Karunananthan S, Bergman H, Mark Clarfield A. The identification of frailty: a systematic literature review. J Am Geriatr Soc 2011; 59(11): 2129–2138

[8] Siegel S, Noblett K, Mangel J, Griebling TL, Sutherland SE, Bird ET, Comiter C, Culkin D, Bennett J, Zylstra S, Berg KC, Kan F, Irwin CP. Results of a prospective, randomized, multicenter study evaluating sacral neuromodulation with InterStim therapy compared to standard medical therapy at 6-months in subjects with mild symptoms of overactive bladder. Neurourol Urodyn 2015; 34(3): 224–230

[9] Finazzi-Agrò E, Petta F, Sciobica F, Pasqualetti P, Musco S, Bove P. Percutaneous tibial nerve stimulation effects on detrusor overactivity incontinence are not due to a placebo effect: a randomized, double-blind, placebo controlled trial. J Urol 2010; 184(5): 2001–2006

[10] Souto SC, Reis LO, Palma T, Palma P, Denardi F. Prospective and randomized comparison of electrical stimulation of the posterior tibial nerve versus oxybutynin versus their combination for treatment of women with overactive bladder syndrome. World J Urol 2014; 32(1): 179–184

[11] Peters KM, Carrico DJ, MacDiarmid SA, Wooldridge LS, Khan AU, McCoy CE, Franco N, Bennett JB. Sustained therapeutic effects of percutaneous tibial nerve stimulation: 24-month results of the STEP study. Neurourol Urodyn 2013; 32(1): 24–29

[12] Peters KM, Carrico DJ, Wooldridge LS, Miller CJ, MacDiarmid SA. Percutaneous tibial nerve stimulation for the long-term treatment of overactive bladder: 3-year results of the STEP study. J Urol 2013; 189(6): 2194–2201

[13] Yoong W, Shah P, Dadswell R, Green L. Sustained effectiveness of percutaneous tibial nerve stimulation for overactive bladder syndrome: 2-year follow-up of positive responders. Int Urogynecol J Pelvic Floor Dysfunct 2013; 24(5): 795–799

[14] Peters KM, Shen L, McGuire M. Effect of sacral neuromodulation rate on overactive bladder symptoms: a randomized crossover feasibility study. Low Urin Tract Symptoms 2013; 5(3): 129–133

[15] Olivera CK, Meriwether K, El-Nashar S, Grimes CL, Chen CC, Orejuela F, Antosh D, Gleason J, Kim-Fine S, Wheeler T, McFadden B, Balk EM, Murphy M; Systematic Review Group for the Society of Gynecological Surgeons. Nonantimuscarinic treatment for overactive bladder: a systematic review. Am J Obstet Gynecol 2016; 215(1): 34–57

[16] Engberg S, Cohen S, Sereika SM. The efficacy of acupuncture in treating urge and mixed incontinence in women: a pilot study. J Wound Ostomy Continence Nurs 2009; 36(6): 661–670

[17] Emmons SL, Otto L. Acupuncture for overactive bladder: a randomized controlled trial. Obstet Gynecol 2005; 106(1): 138–143

[18] Philp T, Shah PJ, Worth PH. Acupuncture in the treatment of bladder instability. Br J Urol 1988; 61(6): 490–493

[19] Bergström K, Carlsson CP, Lindholm C, Widengren R. Improvement of urge- and mixed-type incontinence after acupuncture treatment among elderly women— a pilot study. J Auton Nerv Syst 2000; 79(2-3): 173–180

[20] Chang PL. Urodynamic studies in acupuncture for women with frequency, urgency and dysuria. J Urol 1988; 140(3): 563–566

[21] Kelleher C, Filshie J, Burton G, Khullar V, Cardozo L. Acupuncture and the treatment of irritative bladder symptoms. Acupunct Med 1994; 12(1): 9–12

[22] Yuan Z, He C, Yan S, Huang D, Wang H, Tang W. Acupuncture for overactive bladder in female adult: a randomized controlled trial. World J Urol 2015; 33(9): 1303–1308

[23] Aydoğmuş Y, Sunay M, Arslan H, Aydın A, Adiloğlu AK, Şahin H. Acupuncture versus solifenacin for treatment of overactive bladder and its correlation with urine nerve growth factor levels: a randomized, placebo-controlled clinical trial. Urol Int 2014; 93(4): 437–443

[24] Bosch JLHR, Groen J. Sacral (S3) segmental nerve stimulation as a treatment for urge incontinence in patients with detrusor instability: results of chronic electrical stimulation using an implantable neural prosthesis. J Urol 1995; 154(2 Pt 1): 504–507

[25] Kitakoji H, Terasaki T, Honjo H, Odahara Y, Ukimura O, Kojima M, Watanabe H. Effect of acupuncture on the overactive bladder. Jpn J Urol (Nihon Hinyokika Gakkai Zasshi) 1995; 86(10): 1514–1519 (in Japanese)

[26] Honjo H, Kawauchi A, Ukimura O, Soh J, Mizutani Y, Miki T. Treatment of monosymptomatic nocturnal enuresis by acupuncture: a preliminary study. Int J Urol 2002; 9(12): 672–676

[27] Liu Z, Zhou K, Wang Y, Pan Y. Electroacupuncture improves voiding function in patients with neurogenic urinary retention secondary to cauda equina injury: results from a prospective observational study. Acupunct Med 2011; 29(3): 188–192

[28] Yu SG, Guo Y. Experimental Acupuncture Science. Shanghai: Shanghai scientific & technical publishers, 2009

[29] Mitsui T, Kakizaki H, Matsuura S, Ameda K, Yoshioka M, Koyanagi T. Afferent fibers of the hypogastric nerves are involved in the facilitating effects of chemical bladder irritation in rats. J Neurophysiol 2001; 86(5): 2276–2284

[30] Hino K, Honjo H, Nakao M, Kitakoji H. The effects of sacral acupuncture on acetic acid-induced bladder irritation in conscious rats. Urology 2010; 75(3): 730–734

[31] Su X, Nickles A, Nelson DE. Neuromodulation attenuates bladder hyperactivity in a rat cystitis model. BMC Urol 2013; 13(1): 70

[32] Zhang X, Igawa Y, Ishizuka O, Nishizawa O, Andersson KE. Effects of resiniferatoxin desensitization of capsaicin-sensitive afferents on detrusor over-activity induced by intravesical capsaicin, acetic acid or ATP in conscious rats. Naunyn Schmiedebergs Arch Pharmacol 2003; 367(5): 473–479

[33] Wang H, Tanaka Y, Kawauchi A, Miki T, Kayama Y, Koyama Y. Acupuncture of the sacral vertebrae suppresses bladder activity and bladder activity-related neurons in the brainstem micturition center. Neurosci Res 2012; 72(1): 43–49

[34] Sato A, Sato Y, Suzuki A. Mechanism of the reflex inhibition of micturition contractions of the urinary bladder elicited by acupuncture-like stimulation in anesthetized rats. Neurosci Res 1992; 15(3): 189–198

[35] Noblett K, Siegel S, Mangel J, Griebling TL, Sutherland SE, Bird ET, Comiter C, Culkin D, Bennett J, Zylstra S, Kan F, Berg KC. Results of a prospective, multicenter study evaluating quality of life, safety, and efficacy of sacral neuromodulation at twelve months in subjects with symptoms of overactive bladder. Neurourol Urodyn 2016; 35(2): 246–251

[36] Wood LN, Anger JT. Urinary incontinence in women. BMJ 2014; 349: g4531

[37] van Balken MR, Vergunst H, Bemelmans BL. The use of electrical devices for the treatment of bladder dysfunction: a review of methods. J Urol 2004; 172(3): 846–851

[38] Kurpad R, Kennelly MJ. The evaluation and management of refractory neurogenic overactive bladder. Curr Urol Rep 2014; 15(10): 444

[39] Chancellor MB, Chartier-Kastler EJ. Principles of sacral nerve stimulation (SNS) for the treatment of bladder and urethral sphincter dysfunctions. Neuromodulation 2000; 3(1): 16–26

[40] Kessler TM, La Framboise D, Trelle S, Fowler CJ, Kiss G, Pannek J, Schurch B, Sievert KD, Engeler DS. Sacral neuromodulation for neurogenic lower urinary tract dysfunction: systematic review and meta-analysis. Eur Urol 2010; 58(6): 865–874

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