Objectives To assess the effectiveness and safety of acupuncture for hiccups following stroke.
Methods Medline, Embase, CENTRAL, CINAHL, and four Chinese medical databases were searched from their inception to 1 June 2015. The dataset included randomised controlled trials (RCTs) with no language restrictions that compared acupuncture as an adjunct to medical treatment (effectiveness) or acupuncture versus medical treatment (comparative effectiveness) in stroke patients with hiccups. The Cochrane risk of bias tool was used to assess the methodological quality of the trials.
Results Out of 436 potentially relevant studies, five met the inclusion criteria. When acupuncture was compared with other interventions (as sole or adjunctive treatment), meta-analysis revealed a significant difference in favour of cessation of hiccups within a specified time period (CHWST) following intervention when used as an adjunct (risk ratio (RR) 1.59, 95% CI 1.16 to 2.19, I2=0%), but not when used alone (RR 1.40, 95% CI 0.79 to 2.47, I2=65%, ie, high heterogeneity). No safety information was reported in these studies.
Conclusions Our systematic review and meta-analysis suggests that acupuncture may be an effective treatment for patients suffering from hiccups following stroke when used as an adjunct to medical treatment. However, due to the limited number of RCTs and poor methodology quality, we cannot reach a definitive conclusion, hence further large, rigorously designed trials are needed.
- SYSTEMATIC REVIEWS
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A hiccup is a sudden-onset inspiration that is characterised by initial contraction of the diaphragm and intercostal muscles followed by abrupt closure of the glottis.1 It is fairly common, usually transient and self-limited, although sometimes it may become protracted. Hiccups can be divided into three categories depending on the duration of the episode: acute (lasting from a few minutes up to 48 h); persistent (lasting >48 h but <2 months); and intractable (lasting >2 months).2 ,3 Commonly associated symptoms include vomiting, exhaustion, fatigue, insomnia, anxiety, depression, malnutrition, weight loss, dehydration, and even death in extreme situations.3–7 Available treatments for hiccups include metoclopramide,8 chlorpromazine,9 sodium valproate,10 and nifedipine,11 all of which have limited efficacy.
Stroke affects many people in China, the UK, and the USA.12–14 Stroke patients often experience various complications that may seriously affect their quality of life, including intractable hiccups.15 In China, acupuncture has historically been utilised to treat hiccups and other stroke symptoms and, as part of present day standard of care, stroke patients frequently receive acupuncture during their rehabilitation.15 ,16
Two previous systematic reviews (SRs) have sought to determine the effectiveness of acupuncture in the treatment of hiccups.17 ,18 One SR focused on hiccups in cancer patients and found limited evidence that acupuncture was effective compared with conventional therapy (intramuscular injections with medications such as metoclopramide, methylphenidate, ibrotamide, and oral perphenazine and oryzanol); however, the total number of included studies was small and their methodological quality was poor.17 The other SR focused on the effectiveness of various pharmacological and non-pharmacological interventions and concluded that there was insufficient evidence to support treatment using any of the interventions studied.18 In addition, a case series of cancer patients using acupuncture for the treatment of persistent hiccups found that it may be a clinically useful, safe and low-cost therapy in this particular patient population.19
Several clinical studies have also described the use of acupuncture for the treatment of refractory hiccups in stroke patients,20–24 although their quality has not been evaluated systematically. Furthermore, to date, no SR or meta-analysis has been conducted to address specifically the potential role of acupuncture for the treatment of hiccups in stroke patients. The aim of this study was to critically evaluate the effectiveness and safety of acupuncture for stroke patients with hiccups and thereby contribute to the evidence base for clinical acupuncture practice.
This SR was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) database on 16 December 2014 (registration no. CRD42014015481)25 and published as a protocol.26 It was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines.27
We searched Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and four Chinese medical databases, namely the Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), which includes the China Academic Journals (CAJ) database, VIP Information, and Wanfang Data, from their inception to 1 June 2015, using the following terms, individually or combined: ‘acupuncture’; ‘electroacupuncture’; ‘scalp acupuncture’; ‘stroke’; ‘apoplexy’; ‘cerebrovascular’; ‘cerebral’; ‘hiccup’; ‘hiccough’; and ‘singultus’. There were no language restrictions. Additionally, reference lists of all obtained papers were manually reviewed to identify further articles of relevance. Both published and unpublished studies were considered for critical evaluation. Details of the search strategy for CENTRAL is shown in table 1.
Selection of studies
Two authors (JHY and ML) independently identified eligible articles. In order to be included, studies needed to: (1) be randomised controlled trials (RCTs); (2) incorporate an intervention group receiving acupuncture (either as a sole treatment or as an adjunct to medical treatment); (3) have a control group receiving no treatment (effectiveness trial) or medical treatment (comparative effectiveness trial); and (4) involve patients suffering from hiccups following stroke (regardless of age, gender or race).
Articles were excluded if any of the following criteria were identified: (1) duplication; (2) review articles; (3) case reports; (4) hiccups associated with cancer or other unclear mechanisms; (5) cluster-randomised or cross-over study design; (6) sham-controlled trials. Disagreements between the two authors were resolved by discussion with a third author (ZRS) to achieve consensus.
Data extraction and management
The primary outcome measure was cessation of hiccups within a specified time period (CHWST) following the intervention. The secondary outcome was the rate of adverse events. Two authors (YMW and JL) independently extracted data from eligible studies according to predefined criteria and settled any discrepancies through discussion with a third author (QHZ), who also verified the extracted data.26 Two authors (JHY and QHZ) used the Cochrane risk-of-bias tool to independently assess the methodological quality of the included RCTs.28 Any discrepancies were resolved by discussion with a third author (BG). The original study authors were contacted to acquire missing data where necessary.
Data synthesis and analysis
Dichotomous and continuous outcomes were presented as the risk ratio (RR) and mean difference, respectively, each with 95% CIs. The Higgins I² test was used to assess the heterogeneity of the included trials. Data were pooled using a fixed effects model when I² values were <50%.29 Otherwise, heterogeneity was considered to be significant and therefore a random effects model was used. In such cases, a subgroup analysis was performed to identify and explain heterogeneity. We planned to examine for publication bias if at least 10 studies were included using Egger's regression method30 and to perform a sensitivity analysis to determine the robustness of any treatment effect by removing low quality studies.
A total of 436 potentially relevant studies were identified, of which five met the inclusion criteria (figure 1). The characteristics of all included RCTs, including the acupuncture point selection and other information related to treatments, are listed in table 2.20–24 The average number of needles used per session and the treatment rationale were not reported. All five RCTs originated from China, were published in Chinese, and used CHWST as the primary outcome.20–24 Two studies directly compared acupuncture against pharmacological interventions, while the other three evaluated acupuncture as an adjunct to pharmacological intervention (acupuncture plus medication vs medication alone). The number of included studies (<10) was insufficient to be able to reliably assess for publication bias using a funnel plot.
The Cochrane risk of bias summary is presented in figure 2. All five RCTs reported appropriate random sequence generation.20–24 No trials reported allocation concealment.20–24 As these studies were not sham-controlled, it was not feasible to blind the participant or the therapist providing the acupuncture. Accordingly, we determined that the risk of performance bias was low using the Cochrane tool.20–24 Four studies failed to report who measured the outcomes,20–21 ,23–24 while one study simply stated that the “outcome assessors” measured outcomes.22 None of the studies reported on the blinding of outcome assessors, therefore the risk of detection bias was considered to be unclear. No participants were reported to have withdrawn from either group in any study, and none of the studies reported whether there were any adverse events or not. With respect to selective reporting bias, all five trials failed to publish the study protocol before their initiation. Furthermore, no trials reported ethical review board approval or prospective registration, which is now a requirement of the revised Declaration of Helsinki.31 Neither did any of the trials report sample size calculation.
All five studies measured the effect of acupuncture (alone or in combination with pharmacological treatment) compared with pharmacological treatment alone on the primary outcome measure of CHWST. Meta-analysis of the studies, which included 259 subjects in total, yielded evidence of effectiveness with respect to CHWST in favour of acupuncture when provided as an adjunct to pharmacological treatment (RR 1.59, 95% CI 1.16 to 2.19, n=3 studies, n=136 participants, I2=0%; figure 3A); however, acupuncture did not appear to be effective as an isolated intervention compared to oral baclofen (RR 1.40, 95% CI 0.79 to 2.47, n=2 studies, n=123 participants, I2=65%, ie, high heterogeneity; figure 3B). With respect to the type of acupuncture used, one study of manual acupuncture (MA)23 demonstrated a significant effect on CHWST (RR 1.94, 95% CI 1.09 to 3.45), while another of electroacupuncture (EA)20 did not (RR 1.11, 95% CI 0.77 to 1.58). None of the studies reported on safety aspects.
Several RCTs have tested the effectiveness of acupuncture for stroke patients with hiccups, but unfortunately none of these studies has been methodologically rigorous. Our meta-analysis suggests that acupuncture is effective only when used as an adjunctive intervention; however, the small sample size and poor methodological quality of the included trials prevent us from drawing any firm conclusions. Additionally, the apparent lack of ethical approval is concerning. It is unclear whether in fact there was no ethical approval, or if this was simply not reported. However, this represents a significant shortcoming and is not in keeping with current standards of reporting.31 None of the included RCTs attempted to report allocation concealment, therefore the evidence is of limited generalisability.32 Blinding was irrelevant as none of the trials was sham-controlled.
All of the studies were conducted in China. In the past, the Chinese literature has been criticised due to apparent publication bias;33 however, in this review, the reporting of several negative studies suggests that publication bias was not present in this instance. In this SR, the data from the five studies were pooled and subdivided into those testing effectiveness and comparative effectiveness, respectively. Two studies evaluated the use of acupuncture as a single intervention, with high heterogeneity noted. One of these studies (of MA) was positive23 while the other one (of EA) was negative.20 Among those studies where acupuncture was combined with pharmacological treatment regimens, one was positive22 and two were negative.21 ,24
It is interesting that the three positive studies, irrespective of whether acupuncture was used as an adjunctive or sole treatment, utilised the acupuncture point GV2622–24 while the two negative studies did not.20 ,21 Thus, it is possible that needling at this particular location may play a role in the relief of hiccups following stroke. Recent studies have found that acupuncture at GV26 can decrease vagal excitability, thereby relieving or stopping hiccups.34 In addition, the point PC6 was also used in four of the studies. Acupuncture at this location can stimulate the median nerve, resulting in modulation of vagal tone, which may in turn modulate sympathetic outflow.35 The hiccup reflex arc has been described as consisting of three components: (1) the afferent limb, including the phrenic, vagus and sympathetic nerves, which convey somatic and visceral sensory signals; (2) the central processing in the midbrain; and (3) the efferent limb, which involves the motor fibres of the phrenic and accessory nerves, which innervate the diaphragm and intercostal muscles, respectively.36 Thus, one potential mechanism of action underlying the acupuncture intervention is related to vagal stimulation and a decrease in sympathetic outflow. Disturbances in autonomic regulation are commonly encountered in patients suffering from stroke.37 Thus it is possible that acupuncture may be more effective in these patients, compared to other subtypes of patients suffering from chronic hiccups.
In order to facilitate the design of future studies, we conducted a sample size calculation based upon the existing data. We pooled the data from all five studies with respect to complete responders (total cessation of hiccups). The effect size was calculated at 0.23, which is considered to be moderate to weak. We estimated that 154 subjects would be required to determine treatment effectiveness with 95% confidence at an α level of 0.05 and 80% power. An important caveat of this calculation is the fact that the treatment protocols (including acupuncture points, type of acupuncture, and frequency of treatment) differed significantly between the included studies.
In summary, this study has generated encouraging data regarding the comparative effectiveness of acupuncture when utilised as an adjunctive treatment for hiccups after stroke, but no evidence of the effectiveness of acupuncture as an isolated intervention for this condition. However, there are some limitations that must be acknowledged. Firstly, incomplete information may have limited the quality and validity of the results. Secondly, the limited number of RCTs and small sample sizes prevent us from making definitive judgments. Thirdly, all the trials were carried out in China, where cultural factors, beliefs, high acupuncture dosing in studies, and positive reporting bias may each contribute to the very low rate of negative results reported.38 Furthermore, none of the included studies utilised sham acupuncture protocols, thus the present review cannot assess the efficacy of acupuncture in this setting (ie, specific effects). The findings suggest that acupuncture may be an effective clinical intervention for patients with intractable hiccups following stroke, but do not allow us to separate the components of expectation and belief in the treatment.39 Future studies of the effects of acupuncture treatment in patients with hiccups after stroke should consider both a ‘top down’ approach looking at the utility and clinical effectiveness of acupuncture as a whole system, as well as a ‘bottom up’ approach investigating the mechanisms of action and efficacy of the treatment compared to sham acupuncture.40 Such studies should use an adequate sample size and sound research methodology, and report their results according to the Revised Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) criteria.41
The evidence that acupuncture is an effective treatment for hiccups after stroke is inconclusive. Even though some studies showed positive effects, the quality of included trials was poor and too many significant caveats exist to be able to draw firm conclusions. Further high quality RCTs, as well as studies investigating acupuncture mechanisms, are needed.
JL, ML, JY contributed equally.
Contributors JHY, ML and JL contributed equally to this work. QHZ, ZRS and JHY conceived the study and designed the study protocol. QHZ, BG and JHY drafted the manuscript. ZRS and QHZ sought funding. All authors contributed to the further writing of the manuscript as well as read and approved the final manuscript.
Funding The study was supported by the Foundation of Heilongjiang University of Chinese Medicine (grant no. 2012RCQ64 and 2012RCL01) and the Foundation of Graduate Innovative Plan of Heilongjiang Province (grant no. YJSCX2012-357HLJ).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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