BACKGROUND: The placebo response of sham acupuncture in patients with primary dysmenorrhea is a substantial factor associated with analgesia. However, the magnitude of the placebo response is unclear. OBJECTIVE: This meta-analysis assessed the effects of sham acupuncture in patients with primary dysmenorrhea and the factors contributing to these effects. SEARCH STRATEGY: PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were searched from inception up to August 20, 2022. INCLUSION CRITERIA: Randomized controlled trials (RCTs) using sham acupuncture as a control for female patients of reproductive age with primary dysmenorrhea were included. DATA EXTRACTION AND ANALYSIS: Pain intensity, retrospective symptom scale, and health-related quality of life were outcome measures used in these trials. Placebo response was defined as the change in the outcome of interest from baseline to endpoint. We used standardized mean difference (SMD) to estimate the effect size of the placebo response. RESULTS: Thirteen RCTs were included. The pooled placebo response size for pain intensity was the largest (SMD = -0.99; 95% confidence interval [CI], -1.31 to -0.68), followed by the retrospective symptom scale (Total frequency rating score: SMD = -0.20; 95% CI, -0.80 to -0.39. Average severity score: SMD = -0.35; 95% CI, -0.90 to -0.20) and physical component of SF-36 (SMD = 0.27; 95% CI, -0.17 to 0.72). Studies using blunt-tip needles, single-center trials, studies with a low risk of bias, studies in which patients had a longer disease course, studies in which clinicians had < 5 years of experience, and trials conducted outside Asia were more likely to have a lower placebo response. CONCLUSION Strong placebo response and some relative factors were found in patients with primary dysmenorrhea. PROSPERO registration number: CRD42022304215. Please cite this article as: Sun CY, Xiong ZY, Sun CY, Ma PH, Liu XY, Sun CY, Xin ZY, Liu BY, Liu CZ, Yan SY. Placebo response of sham acupuncture in patients with primary dysmenorrhea: A meta-analysis. J Integr Med. 2023; 21(5): 455-463.
Female ; Humans ; Dysmenorrhea/therapy* ; Acupuncture Therapy ; Pain Management ; Needles ; Placebo Effect

In recent years, some large rigorous acupuncture randomized controlled trials (RCTs) frequently draw the conclusion that the therapeutic effects of acupuncture is equivalent to placebo effect, which has aroused wide attention and controversy. Thus, some studies attempted to assess the adequacy of acupuncture regimen in clinical trials. In this study, the concept of acupuncture regimen adequacy in clinical trials is clarified and the research status and limitations are summarized. Moreover, the suggestions in the future researches are proposed in association with clinical practice characteristics of acupuncture, i.e. classifying assessment according to different types of acupuncture; conducting the assessment according to the treatment characteristics of different types of acupuncture; assessing the maturity of acupuncture regimens; evaluating the rationality of the control group according to the purpose of the study; and focusing on domains evaluation.
Acupuncture Therapy ; Clinical Trials as Topic ; Placebo Effect

BACKGROUND: Menopausal symptoms have remarkable negative effects on women's quality of life, justifying the need to assess various therapeutic options. This research aimed to determine the effectiveness of Vitex agnus-castus extracts in alleviating menopausal symptoms in comparison with that of placebo. METHODS: This study was a randomized controlled double-blind clinical trial with a study group of 52 women referred to a clinic in Kermanshah in 2017. The participants were randomly divided into two groups: Vitex group (26 subjects) and placebo group (26 subjects). Menopausal symptoms were assessed using the Greene Scale before and 8 weeks after the intervention. RESULTS: After the intervention, the mean scores for total menopausal disorder, anxiety, and vasomotor dysfunction were significantly lower in the Vitex group than in the placebo group (P<0.05). The mean scores of the variables of somatic complications, depression, and sexual dysfunction did not show significant differences between the Vitex and placebo groups (P>0.05). CONCLUSION: Administration of Vitex agnus-castus extracts as a phytoestrogenic medicine can alleviate menopausal symptoms in women.
Anxiety Disorders ; Depression ; Double-Blind Method ; Female ; Humans ; Menopause ; Phytoestrogens ; Placebo Effect ; Quality of Life ; Vitex

PURPOSE: Inhaled corticosteroids (ICSs) are often considered an empirical therapy in the management of patients with cough. However, ICS responsiveness is difficult to interpret in daily clinical practice, as the improvements may include placebo effects or self-remission. We aimed to evaluate ICS and placebo treatment effects in adult patients with cough. METHODS: Electronic databases were searched for studies published until June 2018, without language restriction. Randomized controlled trials reporting the effects of ICSs compared with placebo in adult patients with cough were included. Random effects meta-analyses were conducted to estimate the treatment effects. Therapeutic gain was calculated by subtracting the percentage change from baseline in the cough score in the ICS treatment group from that in the placebo treatment group. RESULTS: A total of 9 studies were identified and 8 studies measuring cough severity outcomes were included for meta-analyses. Therapeutic gain from ICSs ranged from −5.0% to +94.6% across the studies included; however, it did not exceed +22%, except for an outlier reporting very high therapeutic gains (+45.6% to +94.6%, depending on outcomes). Overall ICS treatment effects in cough severity outcomes were small-to-moderate (standardized mean difference [SMD], −0.38; 95% confidence interval [CI], −0.54, −0.23), which were comparable between subacute and chronic coughs. However, pooled placebo treatment effects were very large in subacute cough (SMD, −2.58; 95% CI, −3.03, −2.1), and modest but significant in chronic cough (SMD, −0.46; 95% CI, −0.72, −0.21). CONCLUSIONS: Overall therapeutic gain from ICSs is small-to-moderate. However, placebo treatment effects of ICS are large in subacute cough, and modest but still significant in chronic cough. These findings indicate the need for careful interpretation of ICS responsiveness in the management of cough patients in the clinic, and also for rigorous patient selection to identify ICS-responders.
Adrenal Cortex Hormones ; Adult ; Cough ; Humans ; Overall ; Patient Selection ; Placebo Effect ; Steroids

OBJECTIVETo investigate the influence of the depth of skin press in blunt tip placebo acupuncture needles on patient blinding and its relationship to needle diameter.

METHODSForty healthy volunteers were enrolled as subjects for patient blinding. Four acupuncturists applied the following needles randomly at three points in each forearm: 0.18 mm and 0.25 mm diameter penetrating needles inserted to a depth of 5 mm, and 0.18 mm and 0.25 mm diameter skin-touch needles depressing the skin at the acupoint to a depth of 1 mm and 2 mm from the skin surface. The subjects reported their guesses at the nature of needles they received, and rated needle pain and de qi. A blinding index was calculated to define the success of blinding for subjects.

RESULTSThe blinding status of subjects for 1 mm press needles of 0.18 mm diameter was "random guess", but "unblinded" for 1 mm press needles of 0.25 mm diameter. For 2 mm press needles of both diameters, the blinding status was "opposite guess" and the blinding status for penetrating needles of both diameters was "unblinded." The percentages of "felt pain" with 2 mm press needles of both diameters were similar to that with penetrating needles, but those were not similar for 1 mm press needles. The frequency of de qi occurrence with 2 mm press needles of 0.18 mm diameter was similar to that of penetrating needles of both diameters.

CONCLUSIONPlacebo needles of 2 mm press made more subjects guess that the needles penetrated the skin than 1 mm press needles. The use of small diameter needles increased patient blinding.

Acupuncture Points ; Acupuncture Therapy ; instrumentation ; methods ; Adult ; Female ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Needles ; statistics & numerical data ; Placebo Effect ; Sensation ; Young Adult

Functional dyspepsia is one of the most common bowel disorders as prevalent of 7.7% Korean population. The cardinal manifestations include bothersome postprandial fullness, early satiation, epigastric burning or pain. These features are chronic and should be presented recurrently with no other compatible organic disease to explain the symptoms. Even though it is not life-shortening, functional dyspepsia usually make the health-related quality of life worse especially if other functional bowel disorder coexist. The coexistence of functional bowel disorders is called as 'overlap syndrome'. Anxiety, somatization and insomnia is more prevalent in overlap syndrome compared with sole functional bowel disorder. Therefore, it is worthwhile that physician interviews and elucidates whether the dyspeptic patient had other kinds of functional bowel disorders, and manages the underlying psychotic pathology. Placebo effect is large in functional dyspepsia, and there is only four kinds of prokinetics that is proven to be superior to placebo. Adverse events relating prolonged administration of prokinetics sometimes fatal or irreversible, physician willing to describe prokinetics should be familiar to the possible adverse effects and the relating risk factors. Pathologic acid reflux is not uncommon in functional dyspepsia, and acid-suppressant is equivalent to the prokientics in most of dyspeptic patients.
Anxiety ; Burns ; Drug-Related Side Effects and Adverse Reactions ; Dyspepsia* ; Humans ; Pathology ; Placebo Effect ; Quality of Life ; Risk Factors ; Satiation ; Sleep Initiation and Maintenance Disorders

The effect of hydroxychloroquine (HCQ) on dry eye has not been fully determined. This study aimed to compare the 12-week efficacy of HCQ medication with that of a placebo in the management of dry eye in primary Sjögren's syndrome (pSS). A double-blind, randomized control study was conducted in 39 pSS subjects from May 2011 through August 2013. pSS was diagnosed based on the classification criteria of the American-European Consensus Group. Subjects received 300 mg of HCQ or placebo once daily for 12 weeks and were evaluated at baseline, 6, and 12 weeks, with a re-visit at 16 weeks after drug discontinuance. The fluorescein staining score, Schirmer test score, tear film break-up time (TBUT), and ocular surface disease index (OSDI) were measured, and tears and blood were collected for ESR, IL-6, IL-17, B-cell activating factor (BAFF), and Th17 cell analysis. Color testing was performed and the fundus was examined to monitor HCQ complications. Twenty-six subjects completed the follow-up. The fluorescein staining score and Schirmer test score did not differ significantly. The OSDI improved with medication in the HCQ group but was not significantly different between the groups. TBUT, serum IL-6, ESR, serum and tear BAFF, and the proportion of Th17 cells did not change in either group. HCQ at 300 mg daily for 12 weeks has no apparent clinical benefit for dry eye and systemic inflammation in pSS (ClinicalTrials.gov. NCT01601028).
Aged ; B-Cell Activating Factor/analysis/blood ; Blood Sedimentation ; Double-Blind Method ; Drug Administration Schedule ; Dry Eye Syndromes/complications/*drug therapy ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Hydroxychloroquine/*therapeutic use ; Interleukin-16/analysis/blood ; Interleukin-17/analysis/blood ; Male ; Middle Aged ; Placebo Effect ; Prospective Studies ; Sjogren's Syndrome/*complications/diagnosis ; Th17 Cells/cytology/immunology ; Treatment Outcome

Pharmacotherapy has been constantly chosen by the clinician among the available treatment options for tinnitus. Medications that have been prescribed off-label to treat tinnitus can be grouped into several categories: benzodiazepines, antidepressants, anticonvulsants, N-methyl-D-aspartate (NMDA) receptor antagonists, dopamine receptor modulators, muscle relaxants, and others. In this article, a wide variety of compounds once used in the treatment of tinnitus and evidenced by clinical trials are reviewed with respect to the mechanisms of action and the drug efficacy. Only a few of the various pharmacological interventions investigated have some beneficial effects against tinnitus: clonazepam, acamprosate, neramexan, and sulpiride. Sertraline and pramipexole were effective in subgroups of patients with psychiatric symptoms or presbycusis. However, no agents have been identified to provide a reproducible long-term reduction of tinnitus in excess of placebo effects. In rodent tinnitus models, L-baclofen, memantine, and KCNQ2/3 channel activators have been demonstrated to reduce tinnitus development. Limitation of the use of an effective high dosage during a longer treatment duration due to dose-dependent side effects of the centrally acting drugs may influence the results in clinical studies. More effective and safer innovative agents should be developed based on the further understanding of tinnitus neural mechanisms and valid animal models, and should be supported by improved clinical trial methodology. The management of tinnitus patients through a tailored treatment approach depending on the detailed classification of tinnitus subtypes will also lead to better treatment outcomes.
Anticonvulsants ; Antidepressive Agents ; Benzodiazepines ; Classification ; Clonazepam ; Dopamine Agonists ; Dopamine Antagonists ; Drug Therapy ; Humans ; Memantine ; Models, Animal ; N-Methylaspartate ; Placebo Effect ; Presbycusis ; Rodentia ; Sertraline ; Sulpiride ; Tinnitus*

The application of placebo acupuncture in randomized controlled trials in the past 10 years (2004-2014) in foreign countries was systematically reviewed to summarize the design of placebo acupuncture; according to category of diseases, advantages and disadvantages were analyzed to explore an ideal placebo acupuncture set. By retrieval in PubMed, EMBASE and OVID databases, the clinical study literature which met the inclusion criteria was searched, and the category of diseases, design of placebo acupuncture and clinical efficacy were analyzed. Totally 29 articles were included. The pain was the leading disease in category of diseases; the most commonly used application of placebo acupuncture design was telescopiform sliding blunt needle, accounting for 45. 16%; the treatment locations were non-acupoints mostly; in the needling depth, approximately 60. 00% selected non-penetrating needling and 26. 67% selected superficial needling; 28 articles indicated that acupuncture and placebo acupuncture had clinical effects, accounting for 96. 55%; 37. 93% of articles indicated acupuncture was superior to placebo acupuncture and 37. 93% of articles indicated acupuncture was not superior to placebo acupuncture. It is concluded that the design of placebo acupuncture should consider multiple factors, including main symptoms, operability, security, blinding and specific effects, and the objective indices should be selected for outcome evaluation.
Acupuncture Therapy ; instrumentation ; methods ; standards ; Humans ; Internationality ; Needles ; Placebo Effect ; Randomized Controlled Trials as Topic ; standards

BACKGROUND/AIMS: Functional dyspepsia (FD) is a gastrointestinal disorder in which the patient suffers from chronic abdominal symptoms despite the absence of organic disease. Benachio Q solution (soln.)(R) is a new prokinetic herbal medicine. The aim of the present study is to determine the efficacy and safety of Benachio Q soln.(R) in patients with postprandial distress syndrome (PDS) subtype in FD. METHODS: A single-center, randomized, double-blind, placebo-controlled pilot study was performed in 20 patients with PDS. Patients were assigned to receive either Benachio Q soln.(R) or placebo three times a day. After 4 weeks of treatment, the data on response rates, symptoms severity of PDS and gastric emptying time were analyzed to evaluate its efficacy. Adverse events, laboratory tests and vital sign were analyzed to assess its safety. RESULTS: Nine patients were assigned to Benachio group and 10 patients to placebo group. The response rate after 4 weeks was 44.4% and 20.0% in Benachio and placebo group, respectively (p=0.350). The response rate during the first week in Benachio group was better compared to that of placebo group with marginal difference (33.3% vs. 0.0%, p=0.087). Changes of severity score in early satiety on second and third week were -1.8+/-0.6, -1.9+/-0.4 and -1.3+/-0.5, -1.4+/-0.6 in Benachio and placebo group, respectively (p=0.059 vs. p=0.033). No adverse event was observed. CONCLUSIONS: The new herbal drug, Benachio Q soln.(R) seems to improve the symptoms of PDS subtype in FD and could be used safely. Further larger trial is needed in the future.
Adult ; Double-Blind Method ; Drug Administration Schedule ; Dyspepsia/*drug therapy/pathology ; Female ; Gastrointestinal Agents/*therapeutic use ; *Herbal Medicine ; Humans ; Male ; Middle Aged ; Pilot Projects ; Placebo Effect ; Postprandial Period ; Severity of Illness Index ; Treatment Outcome