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A Placebo-Controlled Double-Blind Randomized Trial with Individualized Homeopathic Treatment Using a Symptom Cluster Approach in Women with Premenstrual Syndrome
Abstract
Background:
In a double-blind placebo-controlled randomized trial with parallel groups, the efficacy of individually prescribed homeopathic medicines was evaluated in women with premenstrual syndrome (PMS).
Methods:
In an outpatient department of a university clinic in Jerusalem, Israel (1996-1999), women with PMS, aged 18 to 50 years, entered a 2-month screening phase with prospective daily recording of premenstrual symptoms by the Menstrual Distress Questionnaire (MDQ). They were included after being diagnosed with PMS. A reproducible treatment protocol was used: women received a homeopathic prescription based on symptom clusters identified in a questionnaire. The symptoms were verified during a complementary, structured, interview. Only women whose symptoms matched the symptom profile of one of 14 pre-selected homeopathic medicines were included. Each participant was administered active medicine or placebo via random allocation. Primary outcome measures were differences in changes in mean daily premenstrual symptom (PM) scores by the MDQ. Analysis was by intention-to-treat.
Results:
A total of 105 women were included: 49 were randomized to active medicine and 56 to placebo. Forty-three women in the active medicine group and 53 in the placebo group received the allocated intervention with at least one follow-up measurement and their data were analyzed. Significantly greater improvement of mean PM scores was measured in the active medicine group (0.443 [standard deviation, SD, 0.32] to 0.287 [SD, 0.20]) compared to placebo (0.426 [SD, 0.34] to 0.340 [SD, 0.39]); p = 0.043.
Conclusions:
Individually prescribed homeopathic medicines were associated with significantly greater improvement of PM scores in women with PMS, compared to placebo. Replication, with larger sample size and other refinements, is recommended to confirm the efficacy of this treatment in other settings.
... To limit some of these variables, some authors have therefore used more easily reproducible HMP selection strategies, such as symptom cluster or other semi-individualized approaches, some within an explanatory trial design [15][16][17][18] . Others have adopted a pragmatic study approach to test the effectiveness of individualized homeopathy as experienced in clinical practice, compared to usual care, using randomized designs such as comparative effectiveness research (CER) [18][19][20] , trials with an observational run-in-phase 21 , and trials within cohorts (TwiCs) 13,22,23 , as well as non-randomized cohort designs 24 . ...
... Furthermore, it describes differences in methodological issues between trials in human and veterinary homeopathy. It hopes to inspire and encourage researchers to formulate precise research questions and presents guidelines for future homeopathy RCTs based on 1) existing guidelines for the planning 6,38,40,41 and reporting of clinical trials, especially RCTs [42][43][44] , 2) the RedHot-criteria, i.e. the supplemental CONSORT statement for reporting data on homeopathic interventions 45 , and 3) literature on existing innovative trial designs for researching homeopathic treatment 13,[15][16][17][18]21,22,23 . ...
... Pre-trial observational studies and feasibility trials are recommended 5,13,15,17,42,[57][58][59] . For homeopathy, this has brought valuable information for the conduct of upcoming larger trials 13,[15][16][17][18] and allows realistic estimation of necessary resources and sample size. ...
Background:
Randomised controlled trials (RCTs) are an established research method to investigate the effects of an intervention. Several recent systematic reviews and meta-analyses of RCTs with homeopathic interventions have identified shortcomings in design, conduct, analysis, and reporting of trials. Guidelines for RCTs in homeopathic medicine are lacking.
Objectives:
This paper aims to fill this gap in order to enhance the quality of RCTs in the field of homeopathy.
Methods:
Identification of the homeopathy-specific requirements for RCTs by reviewing literature and experts' communications. Systematization of the findings using a suitable checklist for planning, conducting, and reporting RCTs, namely the SPIRIT statement, and high-quality homeopathy RCTs as examples. Cross-checking of the created checklist with the RedHot-criteria, the PRECIS criteria, and a qualitative evaluation checklist. Consideration of the REFLECT statement and the ARRIVE Guidelines 2.0 for veterinary homeopathy.
Results:
Recommendations for future implementation of RCTs in homeopathy are summarized in a checklist. Alongside, identified useful solutions to the issues encountered when designing and conducting homeopathy RCTs are presented.
Conclusions:
The formulated recommendations present guidelines additional to those in the SPIRIT checklist, on how to better plan, design, conduct, and report RCTs in homeopathy.
... 46 We have reported here the homeopathic medicines most frequently prescribed for ATH, and can be considered as a shortlist of best candidates for testing in future controlled trials without compromising the basic homeopathic principle of individualization. A similar 'symptom cluster' method was used in the clinical trials by Yakir et al, 47,48 who preidentified a small group of homeopathic medicines as the most likely to be relevant in the treatment of pre-menstrual syndrome. For ATH, we would suggest Calc carb, Phosphorus, Silicea, Sulphur, Calc phos, Pulsatilla, Lycopodium and Tuberculinum. ...
Background Globally, adenotonsillar hypertrophy (ATH) is one of the most prevalent upper respiratory tract disorders of children, with associated troublesome symptoms such as sleep apnea and cognitive disturbances. In this study, we evaluated the potential role of individualized homeopathic medicines in the management of symptomatic ATH in children.
Methods A multicenter prospective observational study was conducted at five institutes under the Central Council for Research in Homoeopathy, India. Primary and secondary outcomes (symptom score for adenoids, other symptoms of ATH, Mallampati score, tonsillar size, Sleep-Related Breathing Disorder of the Paediatric Sleep Questionnaire [SRBD-PSQ]) were assessed through standardized questionnaires at baseline and at 3, 6, 9 and 12 months. Radiological investigations for assessing the adenoid/nasopharyngeal (A/N) ratio were carried out at baseline, 6 and 12 months. All analyses were carried out using an intention-to-treat approach.
Results A total of 340 children were screened and 202 children suffering from ATH were enrolled and followed up monthly for 12 months. Each patient received individualized homeopathic treatment based on the totality of symptoms. Statistically significant reductions in adenoid symptom score, Mallampati score (including tonsillar size), SRBD-PSQ sleep quality assessment and A/N ratio were found over time up to 12 months (p < 0.001). Homeopathic medicines frequently indicated were Calcarea carbonicum, Phosphorus, Silicea, Sulphur, Calcarea phosphoricum, Pulsatilla, Lycopodium and Tuberculinum. No serious adverse events were recorded during the study period.
Conclusion This study suggests that homeopathic medicines may play a beneficial role in the management of symptomatic ATH in children. Well-designed comparative trials are warranted.
... One such example highlighted by Dr van der Werf was the 'symptom cluster approach', whereby patients are only included in the study if their symptoms match the clinical picture of a range of pre-selected homeopathic medicines. 1 This method facilitates replication as well as reducing the risk of prescribing errors by physicians. She also emphasised the value of real-world evidence data, as a complement to evidence from RCTs, in order to provide a comprehensive and meaningful evidence base for homeopathy. ...
The Homeopathy Research Institute (HRI) welcomed more than 450 people from 35 countries to their first online event on June 25, 2022. The one-day programme featured an excellent line-up of international speakers and provided a unique interactive platform in keeping with the theme of the event – Key Collaborations in Homeopathy Research. Scientists from a range of different research fields gave an exceptional insight into the current status of homeopathy research. Here we give an overview of the most significant findings in both clinical and basic research presented during HRI Online 2022.
Premenstrual dysphoric disorder (PMDD), a form of premenstrual syndrome (PMS), is a severe health disturbance that affects a patient’s emotions; it is caused by periodic psychological symptoms, and its pathogenesis remains unclear. As depression-like symptoms are found in a majority of clinical cases, a reliable animal model of premenstrual depression is indispensable to understand the pathogenesis. Herein, we describe a novel rat model of premenstrual depression, based on the forced swimming test, with a regular estrous cycle. The results showed that in the estrous cycle, the depression-like behavior of rats occurred in the non-receptive
phase and disappeared in the receptive phase. Following ovariectomy, the depression-like symptoms disappeared and returned after a hormone priming regimen. Moreover, fluoxetine, an anti-depressant, could reverse the behavioral symptoms in these model rats with normal estrous cycle. Further, the model rats showed significant changes in the serum levels of estrogen and progesterone, hippocampal levels of allopregnanolone, 5-hydroxytryptamine, norepinephrine, and γ-aminobutyric acid (GABA), and in the expression of GABAA receptor 4α subunit, all of which were reversed to physiological levels by fluoxetine.
Overall, we established a reliable and standardized rat model of premenstrual depression, which may facilitate the elucidation of PMS/PMDD pathogenesis and development of related therapies.
Abstract
Background: A large proportion (8-32%) of women in the fertile age suffers from premenstrual syndrome/
symptoms (PMS/S). Individualized homeopathy could offer relief and this should be further investigated. Semistandardized treatment with a limited number of homeopathic medicines and strictly defined prescription criteria could minimize prescription variability and increase reproducibility of the individualized treatment.
Objective: In an extension of a previous pilot study, the utility of a semi-standardized algorithm with 11 medicines
for individualized homeopathic treatment of women with PMS/S was further evaluated in daily practice with 9 months follow-up.
Methods: Women completed symptom diaries during to 2 months to confirm PMS/S. Women diagnosed with
PMS/S were included, consulted a homeopathic physician and completed a questionnaire with keynote symptoms for 11 homeopathic medicines. A computerized algorithm would process the answers and indicate the first homeopathic prescription. At follow-up visits change of prescription was possible. Main outcome measures were frequencies and proportions of (non-) algorithm-based prescriptions during the study and percentage of responders (≥ 50% drop in PMS scores). Secondary outcome measures were mean changes in PMS scores over time.
Results: 77 women were included, 52 completed the study. The usefulness of the semi-standardized treatment
protocol was confirmed. In 30 (57.5%) of the 52 analyzed women, PMS scores had dropped by ≥ 50%. For the
estimated mean changes in PMS scores, it made no difference if women had used one or more of the 11 algorithm-based or also other homeopathic medicines (p=0.765). A significant association was found between symptom severity at baseline and changes in mean PMS scores (p<0.001).
Conclusions: A semi-standardized individualized homeopathic treatment of women with PMS/S with 11 medicines proved useful in daily homeopathic practice, with improved reproducibility of individualized treatment.
This treatment could be further tested in effectiveness research.
Homeopathic aggravation is the exacerbation of some symptoms or the whole pathological situation, followed by improvement of the patient's conditions.
To evaluate the typology, intensity and frequency of homeopathic aggravation, especially with Quinquagintamillesimal (Q, LM) potencies and its prognostic value.
The homeopathic prescription strategy evaluated consists in the administration of a single homeopathic medicine in Q dilutions, starting with 6Q, then a progressive scale of Q potencies. Patients whose symptoms could be attributed to a wrong and inappropriate prescription, according to the criteria previously described, were excluded.
Data was collected on 1108 patients consecutively visited from 3rd October 2002 to 31st December 2007, and 441 cases followed for at least 2 months (40% of total cases). 63 of these cases (14%) reported homeopathic aggravation: 7% reported 'slight', 5% 'medium', 2% 'intense' and 0.4% 'very intense' aggravation. Homeopathic aggravation was present in 21% of paediatric patients (≤ 14 years). About 50% of the cases manifested homeopathic aggravation 1 or 2 days after the prescription and for 67% of patients the symptoms lasted 1 week or less. Patients with aggravation of the original disease had significantly greater improvement than those patients showing the aggravation of other, new or different, symptoms or conditions, or no aggravation.
These data show that homeopathic aggravation with Q potencies is quite frequent in homeopathic clinical practice and seems to be associated with better treatment outcome.
Combined oral contraceptives are a common method of contraception, but they carry a risk of venous and arterial thrombosis. We assessed whether use of drospirenone was associated with an increase in thrombotic risk relative to third-generation combined oral contraceptives.
Using computerized records of the largest health care provider in Israel, we identified all women aged 12 to 50 years for whom combined oral contraceptives had been dispensed between Jan. 1, 2002, and Dec. 31, 2008. We followed the cohort until 2009. We used Poisson regression models to estimate the crude and adjusted rate ratios for risk factors for venous thrombotic events (specifically deep vein thrombosis and pulmonary embolism) and arterial thromboic events (specifically transient ischemic attack and cerebrovascular accident). We performed multivariable analyses to compare types of contraceptives, with adjustment for the various risk factors.
We identified a total of 1017 (0.24%) venous and arterial thrombotic events among 431,223 use episodes during 819 749 woman-years of follow-up (6.33 venous events and 6.10 arterial events per 10,000 woman-years). In a multivariable model, use of drospirenone carried an increased risk of venous thrombotic events, relative to both third-generation combined oral contraceptives (rate ratio [RR] 1.43, 95% confidence interval [CI] 1.15-1.78) and second-generation combined oral contraceptives (RR 1.65, 95% CI 1.02-2.65). There was no increase in the risk of arterial thrombosis with drospirenone.
Use of drospirenone-containing oral contraceptives was associated with an increased risk of deep vein thrombosis and pulmonary embolism, but not transient ischemic attack or cerebrovascular attack, relative to second- and third-generation combined oral contraceptives.
Alternative therapies in general, and homeopathy in particular, lack clear scientific evaluation of efficacy. Controlled clinical trials are urgently needed, especially for conditions that are not helped by conventional methods. The objective of this work was to assess the efficacy of homeopathic treatment in relieving symptoms associated with premenstrual syndrome (PMS). It was a randomised controlled double-blind clinical trial. Two months baseline assessment with post-intervention follow-up for 3 months was conducted at Hadassah Hospital outpatient gynaecology clinic in Jerusalem in Israel 1992-1994. The subjects were 20 women, aged 20-48, suffering from PMS. Homeopathic intervention was chosen individually for each patient, according to a model of symptom clusters. Recruited volunteers with PMS were treated randomly with one oral dose of a homeopathic medication or placebo. The main outcome measure was scores of a daily menstrual distress questionnaire (MDQ) before and after treatment. Psychological tests for suggestibility were used to examine the possible effects of suggestion. Mean MDQ scores fell from 0.44 to 0.13 (P<0.05) with active treatment, and from 0.38 to 0.34 with placebo (NS). (Between group P=0.057). Improvement >30% was observed in 90% of patients receiving active treatment and 37.5% receiving placebo (P=0.048). Homeopathic treatment was found to be effective in alleviating the symptoms of PMS in comparison to placebo. The use of symptom clusters in this trial may offer a novel approach that will facilitate clinical trials in homeopathy. Further research is in progress.
The growing popularity of complementary medicine has been accompanied by a call for controlled clinical studies to examine the efficacy and validity of its various methods. The difficulties encountered in applying the evaluation methods of conventional medicine to complementary medicine are the result of the different paradigms underlying these two methods of medicine, and the differences in the healing process. This paper attempts to bridge the gap between these two approaches and to suggest a possibility to use conventional research methodology in clinical studies of classical homeopathy. Two methods are described. One is the randomization into a placebo or a treatment group after an individual remedy is chosen for each patient. This method requires an experienced homeopath and is reproducible only by the same homeopath in the same population. On the other hand, the expected success rate will be high. Another method is prescribing and treating according to so-called keynotes, a set of symptoms known to respond to a particular remedy that must be present in a patient in order to elicit a reaction from the remedy. This method is more suitable to a conventional design of a clinical study and is reproducible by anyone. Yet the expected success rate is much lower. Some general design issues that may have a particular impact on clinical trials of classical homeopathy are discussed, including the need for sufficiently powered trials to detect relatively small effects, strategies to deal with patient preference and embracing the use of "active-control" pragmatic trial designs.
On the range of diagnoses, course of treatment, and long-term outcome in patients who chose to receive homeopathic medical treatment very little is known. We investigated homeopathic practice in an industrialized country under everyday conditions.
In a prospective, multicentre cohort study with 103 primary care practices with additional specialisation in homeopathy in Germany and Switzerland, data from all patients (age > 1 year) consulting the physician for the first time were observed. The main outcome measures were: Patient and physician assessments (numeric rating scales from 0 to 10) and quality of life at baseline, and after 3, 12, and 24 months.
A total of 3,981 patients were studied including 2,851 adults (29% men, mean age 42.5 +/- 13.1 years; 71% women, 39.9 +/- 12.4 years) and 1,130 children (52% boys, 6.5 +/- 3.9 years; 48% girls, 7.0 +/- 4.3 years). Ninety-seven percent of all diagnoses were chronic with an average duration of 8.8 +/- 8 years. The most frequent diagnoses were allergic rhinitis in men, headache in women, and atopic dermatitis in children. Disease severity decreased significantly (p < 0.001) between baseline and 24 months (adults from 6.2 +/- 1.7 to 3.0 +/- 2.2; children from 6.1 +/- 1.8 to 2.2 +/- 1.9). Physicians' assessments yielded similar results. For adults and young children, major improvements were observed for quality of life, whereas no changes were seen in adolescents. Younger age and more severe disease at baseline were factors predictive of better therapeutic success.
Disease severity and quality of life demonstrated marked and sustained improvements following homeopathic treatment period. Our findings indicate that homeopathic medical therapy may play a beneficial role in the long-term care of patients with chronic diseases.
Objectives:
Premenstrual syndrome and premenstrual dysphoric disorder (PMS/PMDD) bother a substantial number of women. Homeopathy seems a promising treatment, but it needs investigation using reliable study designs. The feasibility of organizing an international randomized pragmatic trial on a homeopathic add-on treatment (usual care [UC] + HT) compared with UC alone was evaluated.
Design:
A multicenter, randomized, controlled pragmatic trial with parallel groups.
Settings/location:
The study was organized in general and private homeopathic practices in the Netherlands and Sweden and in an outpatient university clinic in Germany.
Subjects:
Women diagnosed as having PMS/PMDD, based on prospective daily rating by the daily record of severity of problems (DRSP) during a period of 2 months, were included and randomized.
Interventions:
Women were to receive UC + HT or UC for 4 months. Homeopathic medicine selection was according to a previously tested prognostic questionnaire and electronic algorithm. Usual care was as provided by the women's general practitioner according to their preferences.
Outcome measures:
Before and after treatment, the women completed diaries (DRSP), the measure yourself concerns and well-being, and other questionnaires. Intention-to-treat (ITT) and per protocol (PP) analyses were performed.
Results:
In Germany, the study could not proceed because of legal limitations. In Sweden, recruitment proved extremely difficult. In the Netherlands and Sweden, 60 women were randomized (UC + HT: 28; UC: 32), data of 47/46 women were analyzed (ITT/PP). After 4 months, relative mean change of DRSP scores in the UC + HT group was significantly better than in the UC group (p = 0.03).
Conclusions:
With respect to recruitment and different legal status, it does not seem feasible to perform a larger, international, pragmatic randomized trial on (semi-)individualized homeopathy for PMS/PMDD. Since the added value of HT compared with UC was demonstrated by significant differences in symptom score changes, further studies are warranted.
Observational, prospective study to describe the homeopathic management of premenstrual syndrome (PMS) by a group of French physicians.
Women with PMS for >3 months were prescribed individualized homeopathic treatment. The intensity of 10 clinical symptoms of PMS was scored individually at inclusion and at a 3-6 month follow-up visit: absent = 0, mild = 1, moderate = 2, severe = 3. Total symptom score (range: 0-30) was calculated and compared for each patient at inclusion and at follow-up. PMS impact on daily activities (quality of life, QoL) was compared at inclusion and follow-up as: none, mild, moderate, severe, very severe.
Twenty-three women were prescribed homeopathic treatment only (mean age: 39.7 years). Folliculinum (87%) was the most frequently prescribed homeopathic medicine followed by Lachesis mutus (52.2%). The most common PMS symptoms (moderate or severe) at inclusion were: irritability, aggression and tension (87%), mastodynia (78.2%) and weight gain and abdominal bloating (73.9%); and the most common symptoms at follow-up were: irritability, aggression and tension (39.1%), weight gain and abdominal bloating (26.1%) and mastodynia (17.4%). Mean global score for symptom intensity was 13.7 at inclusion and 6.3 at follow-up. The mean decrease in score (7.4) was statistically significant (p < 0.0001). Twenty-one women reported that their QoL also improved significantly (91.3%; p < 0.0001).
Homeopathic treatment was well tolerated and seemed to have a positive impact on PMS symptoms. Folliculinum was the most frequent homeopathic medicine prescribed. There appears to be scope for a properly designed, randomized, placebo-controlled trial to investigate the efficacy of individual homeopathic medicines in PMS.
Premenstrual syndrome (PMS) is a common problem. Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome. Combined oral contraceptives, which provide both progestin and estrogen, have been examined for their ability to relieve premenstrual symptoms. An oral contraceptive containing drospirenone and a low estrogen dose has been approved for treating PMDD in women who choose oral contraceptives for contraception.
To review all randomized controlled trials comparing a combined oral contraceptive containing drospirenone to a placebo or another combined oral contraceptive for effect on premenstrual symptoms.
We searched for studies of drospirenone and premenstrual syndrome in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, and POPLINE (20 Dec 2011); EMBASE, LILACS, PsycINFO, ClinicalTrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (02 Mar 2011). We also examined references lists of relevant articles and wrote to known investigators to find other trials.
We included randomized controlled trials in any language that compared a combined oral contraceptive (COC) containing drospirenone with a placebo or with another COC for effect on premenstrual symptoms. The primary outcome included affective and physical premenstrual symptoms that were prospectively recorded. Adverse events related to combined oral contraceptive use were examined.
Two review authors independently extracted data and assessed study quality. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI). For dichotomous outcomes, the Peto odds ratio (OR) with 95% CI was calculated.
We included five trials with a total of 1920 women. Two placebo-controlled trials of women with PMDD showed less severe premenstrual symptoms after three months with drospirenone 3 mg plus ethinyl estradiol 20 μg than with placebo (MD -7.92; 95% CI -11.16 to -4.67). The drospirenone group had greater mean decreases in impairment of productivity (MD -0.31; 95% CI -0.55 to -0.08), social activities (MD -0.29; 95% CI -0.54 to -0.04), and relationships (MD -0.30; 95% CI -0.54 to -0.06). Side effects more common with the use of the drospirenone COC contraceptive were nausea, intermenstrual bleeding, and breast pain. The respective odds ratios were 3.15 (95% CI 1.90 to 5.22), 4.92 (95% CI 3.03 to 7.96), and 2.67 (95% CI 1.50 to 4.78). Total adverse events related to the study drug were more likely for the drospirenone COC group (OR 2.36; 95% CI 1.62 to 3.44). Three trials studied the effect of drospirenone 3 mg plus ethinyl estradiol 30 μg on less severe symptoms. A placebo-controlled six-month trial had insufficient data for primary outcome analysis. Another six-month study used levonorgestrel 150 µg plus ethinyl estradiol 30 µg for the comparison group but did not provide enough data on premenstrual symptoms. In a two-year trial, the drospirenone COC group had similar premenstrual symptoms to the comparison group given desogestrel 150 µg plus ethinyl estradiol 30 µg (OR 0.87; 95% CI 0.63 to 1.22). The groups were also similar for adverse events related to treatment (OR 1.02; 95% CI 0.78 to 1.33).
Drospirenone 3 mg plus ethinyl estradiol 20 μg may help treat premenstrual symptoms in women with severe symptoms, that is, premenstrual dysphoric disorder. The placebo also had a large effect. We do not know whether the combined oral contraceptive works after three cycles, helps women with less severe symptoms, or is better than other oral contraceptives. Larger and longer trials of higher quality are needed to address these issues. Trials should follow CONSORT guidelines.
Individualised homeopathy involves a large number of possible medicines. For clinical research purposes it is desirable to limit this number, create more consistency between prescribers and optimising the accuracy of prescription. Using a semi-standardised treatment protocol, we aimed to improve homeopathic management of targeted subgroups of women with premenstrual syndrome/symptoms (PMS/S).
To design a semi-standardised protocol for individualised prescribing in PMS/S with a limited number of homeopathic medicines, and to explore the feasibility of working with it in daily homeopathic practice.
With help of an expert panel, homeopathic medicines were selected, as well as predictive symptoms and characteristics (keynotes) for each medicine. With those, we designed a patient questionnaire and a diagnostic algorithm. The patient questionnaire contained 123 questions, representing potential predictive symptoms for 11 homeopathic medicines for PMS/S. The medicines selected (in rank order) were Sep, Nat-m, Lach, Cimic, Lac-c, Puls, Calc, Lil-t, Mag-p, Mag-c, Phos. In a feasibility study 20 homeopathic doctors used the protocol in daily practice. The diagnosis was confirmed by daily rating of pre-defined symptoms during two consecutive menstrual cycles. The acceptability and feasibility of the protocol were evaluated after 3 months follow-up, at which time we also measured changes in premenstrual symptom scores and patient-reported changes in symptoms and general health.
The doctors mostly complied with the protocol and valued the computerised diagnostic algorithm as a useful tool for homeopathic medicine selection. 33 patients completed 3 months follow-up. By then, 19 patients still taking the first medicine on the basis of the algorithm. We received valid symptom records of 30 patients. Premenstrual symptom scores dropped by 50% or more in 12 patients and by 30-50% in 6 patients; scores dropped by less than 30% or increased in 12 patients. Recruitment of patients (n=38 in 9 months) proved difficult. Adherence to the diaries and the questionnaire was satisfactory.
It is feasible to use a semi-standardised protocol for individualised homeopathic prescribing in PMS, in daily practice. Its predictive value and the percentage of women with PMS/S helped by the selected medicines remain to be evaluated in further research. In future research, active promotion will be needed to recruit patients.
Placebo effects have an ambiguous reputation, as they are associated with sham treatment and deceit on the one hand and as interesting phenomena, which might be clinically relevant on the other. The goal of this paper is to demonstrate that placebo effects are relevant and can be used as an effective part of many treatments by using communication targeting placebo effect mechanisms. We examined the history of placebos and the placebo effect, addressing common misconceptions and disentangling ambiguities. We then reviewed whether the placebo effect can be robustly shown in the current literature, and zoomed in on the plausible mechanisms (conditioning, expectancies and affect manipulation) through which the placebo effect might be produced. Observing the link with the doctor-patient communication literature, and pleading for a better integration of the two research traditions we conclude by setting out a research agenda for testing the role of communication in placebo effects.
Background:
Premenstrual syndrome (PMS) is a common cause of physical, psychological and social problems in women of reproductive age. The key characteristic of PMS is the timing of symptoms, which occur only during the two weeks leading up to menstruation (the luteal phase of the menstrual cycle). Selective serotonin reuptake inhibitors (SSRIs) are increasingly used as first line therapy for PMS. SSRIs can be taken either in the luteal phase or else continuously (every day). SSRIs are generally considered to be effective for reducing premenstrual symptoms but they can cause adverse effects.
Objectives:
The objective of this review was to evaluate the effectiveness and safety of SSRIs for treating premenstrual syndrome.
Search methods:
Electronic searches for relevant randomised controlled trials (RCTs) were undertaken in the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, and CINAHL (February 2013). Where insufficient data were presented in a report, attempts were made to contact the original authors for further details.
Selection criteria:
Studies were considered in which women with a prospective diagnosis of PMS, PMDD or late luteal phase dysphoric disorder (LPDD) were randomised to receive SSRIs or placebo for the treatment of premenstrual syndrome.
Data collection and analysis:
Two review authors independently selected the studies, assessed eligible studies for risk of bias, and extracted data on premenstrual symptoms and adverse effects. Studies were pooled using random-effects models. Standardised mean differences (SMDs) with 95% confidence intervals (CIs) were calculated for premenstrual symptom scores, using separate analyses for different types of continuous data (that is end scores and change scores). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes. Analyses were stratified by type of drug administration (luteal or continuous) and by drug dose (low, medium, or high). We calculated the number of women who would need to be taking a moderate dose of SSRI in order to cause one additional adverse event (number needed to harm: NNH). The overall quality of the evidence for the main findings was assessed using the GRADE working group methods.
Main results:
Thirty-one RCTs were included in the review. They compared fluoxetine, paroxetine, sertraline, escitalopram and citalopram versus placebo. SSRIs reduced overall self-rated symptoms significantly more effectively than placebo. The effect size was moderate when studies reporting end scores were pooled (for moderate dose SSRIs: SMD -0.65, 95% CI -0.46 to -0.84, nine studies, 1276 women; moderate heterogeneity (I(2) = 58%), low quality evidence). The effect size was small when studies reporting change scores were pooled (for moderate dose SSRIs: SMD -0.36, 95% CI -0.20 to -0.51, four studies, 657 women; low heterogeneity (I(2)=29%), moderate quality evidence).SSRIs were effective for symptom relief whether taken only in the luteal phase or continuously, with no clear evidence of a difference in effectiveness between these modes of administration. However, few studies directly compared luteal and continuous regimens and more evidence is needed on this question.Withdrawals due to adverse effects were significantly more likely to occur in the SSRI group (moderate dose: OR 2.55, 95% CI 1.84 to 3.53, 15 studies, 2447 women; no heterogeneity (I(2) = 0%), moderate quality evidence). The most common side effects associated with a moderate dose of SSRIs were nausea (NNH = 7), asthenia or decreased energy (NNH = 9), somnolence (NNH = 13), fatigue (NNH = 14), decreased libido (NNH = 14) and sweating (NNH = 14). In secondary analyses, SSRIs were effective for treating specific types of symptoms (that is psychological, physical and functional symptoms, and irritability). Adverse effects were dose-related.The overall quality of the evidence was low to moderate, the main weakness in the included studies being poor reporting of methods. Heterogeneity was low or absent for most outcomes, though (as noted above) there was moderate heterogeneity for one of the primary analyses.
Authors' conclusions:
SSRIs are effective in reducing the symptoms of PMS, whether taken in the luteal phase only or continuously. Adverse effects are relatively frequent, the most common being nausea and asthenia. Adverse effects are dose-dependent.
We systematically reviewed empirical studies that investigated the use of cognitive-behavioral therapy (CBT) for premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD). Our multi-database search identified seven published empirical reports. Three were identified as randomized controlled trials (RCTs). The methods utilized to investigate therapeutic efficacy of CBT in these studies varied widely from case reports to RCTs with pharmacotherapy comparison groups. Initially we provide a brief overview of CBT and justifications for its potential use to treat PMS/PMDD. Next, we provide critical evaluations of the analyses used in each study focusing on the detection of intervention effects assessed by statistically significant time by group interactions. When possible we calculate effect sizes to elucidate the clinical significance of results. Our review revealed a dearth of evidence providing statistically significant CBT intervention effects. Issues such as overall time investment, latency to treatment effects, and complementary and combined therapies are considered. We present a theoretical argument for applying mindfulness- and acceptance-based CBT interventions to PMS/PMDD and suggest future research in this area. In conclusion, to produce the necessary evidence-base support for PMS/PMDD given the limited empirical evidence reported here, researchers are called on to produce methodologically rigorous investigations of psychosocial interventions for PMS/PMDD.
The development of a Menstrual Distress Questionnaire (MDQ) is described. Each of 839 women rated their experience of 47 symptoms on a six-point scale separately for the menstrual, premenstrual, and intermenstrual phases of her most recent menstrual cycle and for her worst menstrual cycle. The 47 symptoms were intercorrelated and factor analyzed separately for each phase, and eight basically replicated factors were extracted from each of these analyses. These fac- tors, which represent separate but empirically intercorrelated clusters of symptoms, were labeled pain, concentration, behavioral change, autonomic reactions, water retention, negative affect, arousal, and control. Scores on these eight clusters of symptoms were slightly correlated with age and parity. The scores were not af- fected by the specific menstrual cycle phase a woman was in when filling out the questionnaire or by the length of time since the woman had experienced the symptoms. Menstrual cycle symptom-profiles graphically depicting a woman's menstrual symptomatology were constructed and illustrated. The need for and utility of standard methods with which to measure menstrual cycle symptomatology is discussed.
Serotonin reuptake inhibitors (SSRIs) have today become the first-line treatment of premenstrual dysphoric disorder (PMDD). However, the actual success rate of these agents in clinical practice also depends on factors such as adequate dosing, duration of therapy and patient compliance. The aim of the current study was to investigate compliance and reasons for discontinuing tricyclic antidepressant (TCA) or SSRI treatment which had been prescribed for premenstrual syndrome. All women who were given an SSRI or TCA prescription for premenstrual symptoms at three gynecologic practices between January 1994 and December 1997 received a written questionnaire. In all, 202 women received the questionnaire, of whom 84.2% replied. Thirteen per cent never started TCA or SSRI treatment and 54% continued the therapy for more than 6 months. Reasons for discontinuing SSRI or TCA were negative side-effects (43%), other reasons (29%), a wish to deal with the problems 'naturally' (23%), fear of dependence (19%), not wanting to take these drugs (20%) and a desire to find out if the premenstrual symptoms had ended (18%). The main reason for poor compliance was negative side-effects, most often sexual dysfunction. The results of this study suggest that the future challenge in this area for gynecologists will be to ensure adequate education of patients and adequate monitoring of the initial phase of treatment.
Throughout history, doctor-patient relationships have been acknowledged as having an important therapeutic effect, irrespective of any prescribed drug or treatment. We did a systematic review to determine whether there was any empirical evidence to support this theory.
A comprehensive search strategy was developed to include 11 medical, psychological, and sociological electronic databases. The quality of eligible trials was objectively assessed by two reviewers, and the type of non-treatment care given in each trial was categorised as cognitive or emotional. Cognitive care aims to influence patients' expectations about the illness or the treatment, whereas emotional care refers to the style of the consultation (eg, warm, empathic), and aims to reduce negative feelings such as anxiety and fear.
We identified 25 eligible randomised controlled trials. 19 examined the effects of influencing patients' expectations about treatment, half of which found significant effects. None of the studies examined the effects of emotional care alone, but four trials assessed a combination of both cognitive and emotional care. Three of these studies showed that enhancing patients' expectations through positive information about the treatment or the illness, while providing support or reassurance, significantly influenced health outcomes.
There is much inconsistency regarding emotional and cognitive care, although one relatively consistent finding is that physicians who adopt a warm, friendly, and reassuring manner are more effective than those who keep consultations formal and do not offer reassurance.
Homeopathic medicines are regarded as safe but practitioners report several types of healing or remedy reactions including aggravations, new symptoms and recurrence of old symptoms, some of which could be regarded as side effects or unwanted effects. Some remedy reactions may be regarded as adverse events. AUDIT QUESTIONS: Do such reactions occur within our unit, and if so, how frequently? Do patients regard these events as "adverse"?
The audit was carried out in the Bristol Homeopathic Hospital Outpatient Department. All patients were given a questionnaire to complete when at their first follow-up consultation approx 6-10 weeks after their first appointment. One hundred and sixteen patients were sampled over a 2-month period.
Reactions were frequent: 28 out of the 116 (24%) patients, experienced an aggravation. Thirteen patients (11%) reported an adverse event even though 5 of those were patients who also reported an aggravation followed by an overall improvement of their symptoms. Thirty-one patients described new symptoms (27%) and 21(18%), a return of old symptoms. Those experiencing the latter appeared to have better outcomes.
Remedy reactions are common in clinical practice; some patients experience them as adverse events. Systematically recording side effects would facilitate our understanding of these reactions and would enable standards to be set for audit of information and patient care.
Premenstrual syndrome (PMS) encompasses a variety of symptoms appearing during the luteal phase of the menstrual cycle. Although PMS is widely recognized, the etiology remains unclear and it lacks definitive, universally accepted diagnostic criteria. To address these issues an international multidisciplinary group of experts evaluated the current definitions and diagnostic criteria of PMS and premenstrual dysphoric disorder (PMDD). Following extensive correspondence, a consensus meeting was held with the aim of producing updated diagnostic criteria for PMS and guidelines for clinical and research applications. This report presents the conclusions and recommendations of the group. It is hoped that the criteria proposed by the group will become widely accepted and eventually be incorporated into the next edition of the World Health Organization's International Classification of Diseases (ICD-11). It is also hoped that the proposed guidelines for quantification of criteria will be used by clinicians and investigators to facilitate diagnostic uniformity in the field as well as adequate treatment modalities when warranted.
Systematic assessment of the in vitro research on high potency effects.
Publications of experiments were collected through databases, experts, previous reviews, citation tracking. Inclusion criteria: stepwise agitated dilutions <10(-23); cells or molecules from human or animal. Experiments were assessed with the modified SAPEH score.
From 75 publications, 67 experiments (1/3 of them replications) were evaluated. Nearly 3/4 of them found a high potency effect, and 2/3 of those 18 that scored 6 points or more and controlled contamination. Nearly 3/4 of all replications were positive. Design and experimental models of the reviewed experiments were inhomogenous, most were performed on basophiles.
Even experiments with a high methodological standard could demonstrate an effect of high potencies. No positive result was stable enough to be reproduced by all investigators. A general adoption of succussed controls, randomization and blinding would strengthen the evidence of future experiments.
Most women of reproductive age have some physical discomfort or dysphoria in the weeks before menstruation. Symptoms are often mild, but can be severe enough to substantially affect daily activities. About 5-8% of women thus suffer from severe premenstrual syndrome (PMS); most of these women also meet criteria for premenstrual dysphoric disorder (PMDD). Mood and behavioural symptoms, including irritability, tension, depressed mood, tearfulness, and mood swings, are the most distressing, but somatic complaints, such as breast tenderness and bloating, can also be problematic. We outline theories for the underlying causes of severe PMS, and describe two main methods of treating it: one targeting the hypothalamus-pituitary-ovary axis, and the other targeting brain serotonergic synapses. Fluctuations in gonadal hormone levels trigger the symptoms, and thus interventions that abolish ovarian cyclicity, including long-acting analogues of gonadotropin-releasing hormone (GnRH) or oestradiol (administered as patches or implants), effectively reduce the symptoms, as can some oral contraceptives. The effectiveness of serotonin reuptake inhibitors, taken throughout the cycle or during luteal phases only, is also well established.
Dutch translation 3rd edition by
- Homeotherapy
Homeotherapy, paragraph 24-25 and The Simile, paragraph 26-34. In: Hahnemann S. Organon der Heilkunst (1810). Dutch
translation 3rd edition by O.E.A. Goetze. Alkmaar, Homeovisie
1996:14-19
Evaluating Homeopathic medicine: Clinical and Social Research with Premenstrual Syndrome (PMS) as a Case Study
- M Yakir
Yakir M. Evaluating Homeopathic medicine: Clinical and Social
Research with Premenstrual Syndrome (PMS) as a Case Study
[PhD Dissertation, English version], Hebrew University, Jerusalem,
2002
The cognitive orientation of suggestibility. A tool for predicting who will respond to suggestion (unpublished)
- S Kreitler
- H Kreitler
Kreitler S, Kreitler H. The cognitive orientation of suggestibility.
A tool for predicting who will respond to suggestion (unpublished). Dept. of Psychology, Tel Aviv University; 1990
A qualitative study to determine the efficacy of the homeopathic simillimum in the treatment of premenstrual syndrome
- T Komar
- K S Peck
- J R Torline
- M Deroukakis
Komar T, Peck KS, Torline JR, Deroukakis M. A qualitative study to
determine the efficacy of the homeopathic simillimum in the
treatment of premenstrual syndrome. Am J Hom Med 2006;
99:196-204