Nocebo effect in multiple system atrophy: systematic review and meta-analysis of placebo-controlled clinical trials

Background Nocebo effect is prevalent among neurological diseases, resulting in low adherence and treatment outcome. We sought to examine the nocebo effect in randomized controlled trials (RCTs) in multiple system atrophy (MSA). Methods We searched RCTs in MSA from Medline since September, 2021. RCTs for drug treatment conducted in adult MSA patients with more than 5 cases in each treatment arm were included. We assessed the number of dropout due to placebo intolerance. We also did a symptomatic/disease-modifying subgroup analysis based on two different treatment purposes. The STATA software was used for statistical analysis. Overall heterogeneity was assessed using the Cochran Q and I2. Results Data were extracted from 11 RCTs fulfilling our search criteria. Of 540 placebo-treated patients, 64.2% reported at least one adverse event (AE) and 7.5% reported dropout because of AEs. The chance of dropping out because of an AE and experiencing at least one AE did not differ between placebo and active drug treatment arms. Besides, the pooled nocebo dropout rate in the symptomatic subgroup was similar to that of the disease-modifying subgroup. Conclusion In MSA RCTs, nocebo dropout rate was not at a low level among neurological disorders. Nocebo effect was an important reason of dropout because of AE in placebo and active drug treatment arms. Different treatment purposes may not influence nocebo effect.

Efficacy of open-label counterconditioning for reducing nocebo effects on pressure pain

Nocebo effects can adversely affect the experience of physical symptoms, such as pain and itch. Nocebo effects on itch and pain have shown to be induced by conditioning with thermal heat stimuli and reduced by counterconditioning. However, open-label counterconditioning, in which participants are informed about the placebo content of the treatment, has not been investigated, while this can be highly relevant for clinical practice. Furthermore, (open-label) conditioning and counterconditioning has not been investigated for pain modalities relevant to musculoskeletal disorders, such as pressure pain. In a randomized controlled trial, we investigated in 110 healthy female participants whether nocebo effects on pressure pain combined with open-label verbal suggestions can be 1) induced via conditioning and 2) reduced via counterconditioning. Participants were allocated to either a nocebo or sham conditioning group. Next, the nocebo group was allocated to either counterconditioning, extinction, or continued nocebo conditioning; sham conditioning was followed by placebo conditioning. Nocebo effects were significantly larger after nocebo conditioning than sham conditioning (d = 1.27). Subsequently, a larger reduction of the nocebo effect was found after counterconditioning than after extinction (d = .99) and continued nocebo conditioning (d = 1.63), with effects similar to placebo conditioning (following sham conditioning). These results show that (counter)conditioning combined with open-label suggestions can modulate nocebo effects on pressure pain, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders, particularly for musculoskeletal disorders.

Serenoa repens and its effects on male sexual function. A systematic review and meta-analysis of clinical trials

Background: Serenoa repens (SR) is a plant used to treat benign prostatic hyperplasia and prostatitis. We know that SR act as a 5α-reductase inhibitor, moreover, several studies have proved that SR has anti-inflammatory and antioxidant properties. There is some belief among patients that SR may negatively impact male sexual function. Such belief is circulating in non-medical social networks and is perhaps maintained by patients as a result of incorrect web surfing. However, it is also possible that SR may exert a “nocebo” effect thus negatively impacting on the general well-being of patients. Objective: The aim of this study is to investigate whether SR is causing negative effects on male sexual function. Methods: To ascertain the effect of SR on male sexual function, we conducted a systematic review and meta-analysis, by performing an electronic database search in accordance with the PRISMA guidelines. Results: Out of 20 included papers, 8 papers reported comparisons of SR with placebo, and 7 studies reported comparisons of SR with tamsulosin. The standardized mean difference of changes from baseline scores of sexual function was not significantly different between SR and placebo (SMD: 0.43, 95% CI: 0.18 to 1.05; I^2 = 95%). Similarly, no significant mean differences in the Male Sexual Function-4 (MSF-4) test scores were found between SR and tamsulosin (SMD: -0.31, 95% CI: -0.82 to 0.19; I^2 = 90%). Conclusions: We found no statistically significant differences between negative effects on sexual function in patients treated with SR compared to patients who received placebo. The results of our meta-analysis are similar to those of other systematic reviews. Studies are warranted to ascertain whether any such effects might occur as a result of a nocebo effect.

COVID-19 vaccination, from first dose to booster: New insights into the frequency of most common systemic adverse events and possible booster nocebo effects based on a systematic review

Background: Based on placebo data, it has been recently demonstrated that the frequencies of most common adverse events (AEs) of COVID-19 vaccination are overestimated due to negative expectation bias of vaccine recipients (nocebo effect). Since booster studies lack comparators, estimating the extent of the nocebo effect is difficult. We aimed to overcome this obstacle through a systematic comparison of most common AE frequencies across vaccine doses (first, second, booster), age groups, and vaccine vs. placebo arms. Methods: We systematically assessed systemic AEs in approved COVID-19 vaccines according to the PRISMA guidelines. All documents regarding COVID-19 vaccines with a booster dose authorized by the FDA (cutoff date 19 November 2021) were systematically searched on PubMed and the FDA website. Solicited systemic AEs from all documents supporting approval/authorization were collected. After standardization of doses and age groups, AE frequencies were compared between vaccine and placebo. Findings: Two trials were identified for BNT162b2 (n=21,785 participants), two for mRNA-1273 (n=22,324), and one for Ad26.COV2.S (n=4,085). Fever cases dropped to about half with the booster dose in all vaccines, whereas all other systemic AE frequencies were similar to the preceding dose. Almost no fever cases occurred with placebo (first/second dose); all other systemic AEs occurred at high frequencies. After subtracting placebo arm values from vaccine values, the frequencies for the various AEs were roughly comparable within each dose for each vaccine. Interpretation: Fever is the only solicited systemic AE that can be assessed objectively. It occurs about 50% less often with the booster than with the preceding dose. This may indirectly indicate a considerable overestimation of systemic AEs in the case of booster vaccinations and a pronounced nocebo effect. The nocebo effect appears to substantially contribute to the differences in the frequencies of the various systemic AEs.

Preventing Adverse Events of Chemotherapy for Gastrointestinal Cancer by Educating Patients about the Nocebo Effect: A Randomized-controlled Trial

Background: Adverse events of chemotherapy may be caused by pharmacodynamics or psychological factors such as negative expectations, which constitute nocebo effects. In a randomized controlled trial, we examined whether educating patients about the nocebo effect is efficacious in reducing the intensity of self-reported adverse events. Methods: N = 49 and n = 51 patients (mean age: 60.2 years, 65% male, 54% UICC tumour stage IV) with newly-diagnosed gastrointestinal cancer were allocated to a nocebo education and attention control group, respectively.Results: GLM with adjustments for tumour staging and distress indicated that intensity of adverse events differed at 12-weeks after onset of chemotherapy (mean difference: 4.04, 95% CI [0.72, 7.36], p = .02, d = 0.48), with lower levels in the nocebo education group. Of these,). This was attributable to less non-specific adverse events (mean difference: 0.39, 95% CI [0.04, 0.73], p = .03, d = 0.44) and a trend towards less specific adverse events in the nocebo education group (mean difference: 0.36, 95% CI [-0.02, 0.74], p = .07, d = 0.37). We found no difference in adverse events at 10-days follow-up, perceived control of adverse events, or tendency to misattribute non-specific symptoms to the chemotherapy. Conclusions: This study provides first proof-of-concept evidence for the efficacy of a brief information session in preventing adverse events of chemotherapy. However, results regarding patient-reported outcomes cannot rule out response biases. Informing patients about the nocebo effect may be an innovative and clinically feasible intervention for reducing the burden of adverse events.Trial registration: retrospectively registered on March 27, 2018 to the German Clinical Trial Register (ID: DRKS00009501).

Zsigeri fájdalom, nocebo-hatások, placebo-analgézia

Összefoglaló. A belső szervek működési zavarai gyakran származnak viselkedési, lelki vagy pszichoszociális okokból, amelyeknek nem mindig vagyunk tudatában. Minthogy ebben a folyamatban egy bonyolult neuronális hálózat játssza a fő szerepet, ezeknek a zavaroknak a diagnózisa és terápiája számos tényező manipulálását igényli. A funkcionális gyomor-bélhuzam rendellenességek (FGID), például az irritábilisbél-szindróma (IBS), jellemző példái ennek: olyan működési zavarokról van szó, amelyek mögött jól detektálható szervi vagy biokémiai elváltozásokat nem találnak. Ilyenkor szükségesnek tűnik a komplex megközelítés, amely többféle szakember együttműködését kívánja meg. Szerepe lehet a pszichés vagy életmód terápiának, a gyógyszeres és fizikai kezelésnek is, és – ahogy ebben a cikkben megmutatjuk – a placebo-terápiának is. Summary. Functional disorders of the internal organs frequently are results of behavioral, mental or psycho-social dysfunctions, although we are usually not conscious about it. A typical example isirritable bowel syndrome (IBS), a characteristic functional gastro-intestinal disorder (FGID), which is regularly accompanied by abdominal pain and irregular intestinal motility and defecation. It has been shown that this disorder cannot be due to a single factor, nor is it a result of a local cause. Recently researchers have proven that malfunction of a complicated neuronal network, including several brain sites, may be responsible for IBS. It is believed now that IBS is the consequence of several nocebo-effects. IBS is a typical source of visceral pain or discomfort, a source that is frequently difficult to identify. Main factors are stimuli originating from the gastro-intestinal tract, passing through the spinal cord and reaching several brain structures, including cortical and sub-cortical sites. It has been shown that some structures become thicker while others thinner as a result of lasting visceral pain, resulting in altered top-down effects on the visceral organs. Several hormones accompany these processes resulting in a complicated network activity. Recent research has revealed that IBS requires a complex approach, optimally provided by a therapeutic team of physicians, psychologist/psychiatrist, associates, and even the patient himself/herself. They may apply or suggest medicines, physiotherapy, lifestyle modifications, alimentary changes etc. An important feature is that the nocebo-effect plays an important role in the generation of IBS, thus one may think the opposite phenomenon, placebo-effect could be used in the therapeutic process. And really, placebo-analgesia is a method frequently used in the therapy of IBS. Placebo-analgesia affects brain processes, including pain processing, release of hormones, including endogenous opioids, the primary pain-decreasing factors. A top-down pain-modification system exists which can be affected and activated by the placebo-analgesia thus counteracting the nocebo-effects and improving the condition of the individual. The placebo phenomenon is interesting in itself, too. By now, the major question is not the existence of the placebo-effect but the mechanisms behind it. Recently, as brain-mapping techniques have gained their role in research, a lot of new information proves that the placebo-effect (as well as the nocebo-effect) is a complex phenomenon that involves several different brain sites, including the brain cortex and the limbic system, respectively.P The placebo-effect is widely used in clinical practice, first of all as a reference treatment when new drugs or medicines are tested for their effectivity. There are numerous ethical problems in this area, recently, for example, when testing Covid-19 vaccines. The main problem is whether it is legal to keep a non-treated population, whether the placebo-group should be treated immediately after the trial ends, whether the members of the placebo-group should get adequate information.

Monitoring the transition of patients on biologics in rheumatoid arthritis: Consensus guidance for pharmacists

Background: Recent approvals for novel agents such as the small molecule Janus kinase inhibitors (JAKi), combined with the advent of biosimilars has widened the gamut of available therapeutic options in the treatment of rheumatoid arthritis (RA). This combined with the introduction of mandatory non- medical switches to biosimilars in some jurisdictions by both public and private payors has led to a significant increase in the volume of therapeutic changes for patients. Pharmacists are well positioned to ensure effective and safe transitions, however there is a significant unmet need for objective and subjective clinical guidance around therapy as well disease state monitoring in RA that facilitates best practices throughout the patient journey. Objective: In this paper we aim to create a consensus derived monitoring algorithm for pharmacists to facilitate best practices throughout therapeutic transitions from originator biologic to other originator biologics, biosimilars, and Janus kinase inhibitors in RA. Methods: The Nominal Group Technique (NGT) was used to understand if consensus could be found among the participants. Clinically relevant questions were developed to capture solutions to the identified unmet need. The faculty considered the questions as individuals, and privately generated answers/ideas. After discussion and consideration, the participants ranked the ideas and established a consensus. Results: Based on the outcome of the consensus discussions, an algorithm was created to help guide pharmacists through therapeutic transitions in RA. The tool covers important topics such as pre-transition considerations, avoiding the nocebo effect for biosimilars, specific considerations for each drug or class, monitoring efficacy, and when to refer. Conclusions: New classes of anti-rheumatic drugs including JAKi, along with the introduction of biosimilars are presenting more opportunity for therapeutic changes and monitoring in patients with RA. We hope our evidence-based consensus derived guidance tool will assist frontline pharmacists in supporting their patients to a successful therapeutic transition in RA.