The Powerful Placebo Effect in Cough: Relevance to Treatment and Clinical Trials.

Interest in the placebo effect of medicines has developed from the use of placebo treatments as controls in clinical trials into a whole new area of research around how placebos fit into a psychosocial model of therapeutics. The large placebo effect associated with cough medicines is both a problem and an opportunity for researchers: a problem for clinical trials on new actives as the active must beat the large placebo effect, and an opportunity for harnessing the placebo effect to produce effective cough medicines without any pharmacologically active ingredient. This review discusses the mechanisms associated with the placebo effect of cough medicines and distinguishes between a 'perceived placebo effect' and a true 'placebo effect'. The efficacy of sweeteners in cough syrups is discussed as well as viscosity, mucoadhesion, and flavoring. The complexity of modern cough medicines is demonstrated by an example of a medicine which contains one active ingredient, and eighteen excipients which provide a complex and intense sensory experience to enhance the placebo effect and complement the pharmacological activity of the medicine.

Pain relief of sore throat with a new anti-inflammatory throat lozenge, ibuprofen 25 mg: A randomised, double-blind, placebo-controlled, international phase III study.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of a new oromucosal ibuprofen form, ibuprofen 25 mg lozenge, in single and repeat dosing for up to 4 days, to the matched placebo, in the treatment of acute sore throat pain in adults. METHODS: In this randomised, double-blind, placebo-controlled trial, adult patients with non-streptococcal sore throat and signs of moderate-to-severe associated pain (≥5 on the objective Tonsillo-Pharyngitis Assessment 21-point scale and ≥60 mm on the subjective 0-100 mm visual analogue Sore Throat Pain Intensity Scale [STPIS]) were assigned ibuprofen 25 mg (n=194) or matching placebo (n=191) lozenge treatment. Efficacy was assessed (at the investigating centre up to 2 hours after first dosing, then on an ambulatory basis) by parameters derived from patient's scores on scales of pain relief, pain intensity, and global efficacy assessment. The primary efficacy end-point was the time-weighted TOTal PAin Relief (TOTPAR) over 2 hours after first dosing using the Sore Throat Relief Scale (STRS). Safety and local tolerability were assessed. RESULTS: Ibuprofen 25 mg was superior to placebo on numerous pain relief parameters; TOTPAR was significantly higher with ibuprofen 25 mg over 2 hours after first dosing (P<.05), the effect being apparent from the first evaluation at 15 minutes (P<.05). The STPIS reduction in favour of ibuprofen 25 mg was not significant vs placebo. Mean STRS scores and patient's global efficacy assessment both reflected a higher efficacy of ibuprofen 25 mg over the 4-day treatment period with tests of statistical significance up to day 1 evening (P<.05), and, in patients with still clinically significant pain (n=128), after an average 4 days (P<.01). Ibuprofen 25 mg lozenge was well tolerated with a safety profile similar to placebo. CONCLUSION: Low-dose ibuprofen 25 mg lozenge in repeat dosing provides in adults more efficacious and rapid relief of sore throat pain and is as well tolerated as placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01785862.

Characterization of urge to cough and cough symptoms associated with the common cold: results of a US internet survey.

OBJECTIVES: Our knowledge of cough physiology is limited despite years of study. Even less is known about the sensation of urge to cough. Given that limited clinical data are available about urge to cough and cough attributes during a common cold, we sought to gain insights into experiences and perceptions related to these symptoms. METHODS: An internet survey consisting of 51 questions was fielded in the United States. Eligible survey participants included men and women aged 18 years and older who had suffered from a cold with cough within the three months preceding the survey. Participants who confirmed suffering from recurrent cough, asthma, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, or gastrointestinal reflux were excluded. RESULTS: Of 19,530 initial respondents, 8011 had a cold in the past three months. Of these, 6484 (81%) had experienced cough symptoms; 2708 respondents with cough due to cold and no exclusionary condition made up the analysis sample. Most respondents (62%) reported that cough developed one to two days after the onset of cold symptoms, and 45% felt that cough worsened their other cold symptoms. In 69% of respondents, cough outlasted other cold symptoms. Urge to cough was reported by 98% of respondents, and among these respondents, 64% described it as uncontrollable and 65% rated severity as moderate. More than half of respondents (57%) considered the sensation of urge to cough and the act of coughing as equally bothersome. Although urge to cough and inability to control cough were the most bothersome aspects of cough due to cold, few (<20%) respondents asked healthcare providers for treatment recommendations. CONCLUSION: Symptoms of urge to cough and cough are common and have a significant impact on cold sufferers. Understanding attributes of these symptoms may provide insights for effective management and the development of novel treatment strategies.

Aspirin in the 21st century-common mechanisms of disease and their modulation by aspirin: a report from the 2015 scientific conference of the international aspirin foundation, 28 August, London, UK.

Professor Peter Rothwell of Oxford University chaired the annual Scientific Conference of the International Aspirin Foundation in London on 28 August 2015. It took the form of four sessions. Aspirin has more than one action in its effects on disease. Its acetylation of cyclooxygenase 2 (COX-2) in platelets leads to the blockade of pro-inflammatory chemicals and generation of anti-inflammatory mediators and increase in nitrous oxide (NO) production, which helps to preserve arterial endothelium. But platelets are not its only target. There is now evidence that aspirin has a direct antitumour effect on intestinal mucosal cells that block their potential transformation into cancer cells. Randomised placebo-controlled trials (RCTs) in people with histories of colorectal neoplasia have shown that aspirin reduces the risk of recurrent adenomas and reduces long-term cancer incidence in patients with Lynch syndrome. Among women given aspirin for cardiovascular disease, there were fewer cancers than in those given placebo. Epidemiological evidence has suggested that aspirin treatment after cancer is diagnosed reduces the incidence of metastases and prolongs survival, and long-term studies of anticancer treatment with aspirin are under way to confirm this. Apart from cancer studies, aspirin use is now firmly established as treatment for antiphospholipid syndrome (Hughes syndrome) and is being used to prevent and treat the heightened risk of cardiovascular disease in diabetes mellitus and in patients with HIV.

Impact of cough and common cold on productivity, absenteeism, and daily life in the United States: ACHOO Survey.

BACKGROUND: Although the common cold is among the most frequent ailments encountered in clinical practice, little is known about its impact on productivity, absenteeism, and daily life. OBJECTIVE: The United States Attitudes of Consumers Toward Health, Cough, and Cold (ACHOO) survey was developed to inform healthcare providers on patients' experience of cough/cold. This analysis focuses on the impact of cough/cold on daily activity, productivity, and absenteeism; other results are reported elsewhere. DESIGN: ACHOO was a 36-question online survey. PARTICIPANTS: US adult Internet/mobile device users (N = 3333) were recruited in October 2012. Response quotas modeled on 2010 US Census data ensured a demographically representative sample; 75% of completed surveys were randomized as the primary analysis pool. MAIN MEASURES: Demographics and impact of cough/cold were reported using means, frequencies, and percentages. Weighted least squares regression or weighted paired t-test were used to identify factors associated with greater impact. KEY RESULTS: The analysis pool (N = 2505) included 1342 (53.6%) women and 1163 (46.4%) men (mean ages, 46.7 and 45.9 years). A majority (84.7%) had ≥1 cold in the past year. Fifty-two percent said cough/cold impacted daily life a fair amount to a lot. Productivity decreased by a mean 26.4%, and 44.5% of respondents reported work/school absenteeism (usually 1-2 days) during a cold. Overall, 93% of survey participants reported sleep difficulty (slight to extreme) during a cough/cold. Among all respondents, 57% reported cough or nasal congestion as the symptoms making sleep difficult. Higher frequency of colds, more cold symptoms, difficulty sleeping, and worse overall health status correlated with greater impact on productivity, absenteeism, and daily life. LIMITATIONS: Study limitations include the potential for recall bias given the retrospective nature of the self-reports. Furthermore, no attempt was made to distinguish treatment effects, if any, from those of the underlying cough/cold. CONCLUSIONS: To our knowledge, this is the first large national survey to quantify adverse effects of cough/cold on daily activity, productivity, and absenteeism. Cold- and patient-related characteristics influence the degree of impact.

Comparison of the classic and Broms methods of rhinomanometry using model noses.

Calculation of nasal airway resistance (NAR) using rhinomanometry can be obtained using different methods of analysis of the pressure-flow curve. The two commonest methods for measuring NAR in rhinomanometry are the classic method at 75 and 150 Pa and the Broms method at radius 200. The objective of this study was to compare the unilateral NAR values measured using both classic and Broms method over four artificial model noses (R1, R2, R3 and R4). The study found that at low resistances (R1 and R2), NAR measurements of Broms were not significantly different from measurements of classic method at 75 Pa but were significantly different from measurements of classic method at 150 Pa. At high resistances (R3 and R4), NAR measurements of Broms were not significantly different from measurements of classic method at 150 Pa but were significantly different from measurements of classic method at 75 Pa. The magnitude of any change in resistance due to surgery or medical intervention is therefore also dependent on the method used to analyze the pressure-flow curves, with bigger change observed in Broms method at certain level of nasal resistances compared to classic measurements in the same patient. In conclusion, nasal airway resistance is not a standardized measurement like blood pressure. Clinicians need to be careful when comparing unilateral measurements of resistance from the classic and Broms methods because the two methods can give either similar or different measurements depending on the level of nasal resistance.

Comparison of classic and 4-phase rhinomanometry methods, is there any difference?

BACKGROUND: There are various different parameters used to measure nasal airway resistance (NAR) in rhinomanometry, which include the classic method at fixed pressure of 150Pa or 75Pa and 4-phase rhinomanometry. This study aims to determine if there is any difference between the measurements of NAR obtained by the classic and 4-phase rhinomanometry methods. METHODOLOGY: In-vitro study with measurements of NAR using both methods when applied across four artificial nose models. RESULTS: No statistically significant differences were found between NAR values obtained from both methods. Strong, positive correlations were found between NAR measured with both methods, which were statistically significant. Bland-Altman method also showed good agreement between both methods with narrow limits of agreement. CONCLUSION: There is high level of conformity between the values of nasal airway resistance measured using both methods.

Efficacy and safety of an antiviral Iota-Carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold.

BACKGROUND: The common cold, the most prevalent contagious viral disease in humans still lacks a safe and effective antiviral treatment. Iota-Carrageenan is broadly active against respiratory viruses in-vitro and has an excellent safety profile. This study investigated the efficacy and safety of an Iota-Carrageenan nasal spray in patients with common cold symptoms. METHODS: In a randomized, double-blind, placebo-controlled exploratory trial, 35 human subjects suffering from early symptoms of common cold received Iota-Carrageenan (0.12%) in a saline solution three times daily for 4 days, compared to placebo. RESULTS: Administration of Iota-Carrageenan nasal spray reduced the symptoms of common cold (p = 0.046) and the viral load in nasal lavages (p = 0.009) in patients with early symptoms of common cold. Pro-inflammatory mediators FGF-2, Fractalkine, GRO, G-CSF, IL-8, IL-1alpha, IP-10, IL-10, and IFN-alpha2 were reduced in the Iota-Carrageenan group. CONCLUSIONS: Iota-Carrageenan nasal spray appears to be a promising treatment for safe and effective treatment of early symptoms of common cold. Larger trials are indicated to confirm the results.

Importance of placebo effect in cough clinical trials.

Cough is a unique symptom because, unlike sneeze and other symptoms, it can be under voluntary control and this complicates clinical trials on cough medicines. All over-the-counter cough medicines (OTC) are very effective treatments because of their placebo effect. The placebo effect is enhanced by expectancy related to advertising, brand, packaging, and formulation. This placebo effect creates a problem for the conduct of clinical trials on OTC cough medicines that attempt to demonstrate the efficacy of a pharmacological agent above that of any placebo effect. Up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect. The placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward mean, demulcent effect, effect of sweetness, voluntary control, and effects related to expectancy and meaning of the treatment. The placebo effect has been studied most in the pain model, and placebo analgesia is reported to depend on the activation of endogenous opioid systems in the brain; this model may be applicable to cough. A balanced placebo design may help to control for the placebo effect, but this trial design may not be acceptable due to deception of patients. The placebo effect in clinical trials may be controlled by use of a crossover design, where feasible, and the changes in the magnitude of the placebo effect in this study design are discussed.

The power of the placebo.

The placebo is much more than a control medicine in a clinical trial. The placebo response is the largest component of any allergy treatment and consists of two components: nonspecific effects (eg, natural recovery) and a "true placebo effect" that is the psychological therapeutic effect of the treatment. Belief in the beneficial nature of the treatment is a key component of the true placebo effect, and can be enhanced by factors such as interaction with the physician and the sensory impact of the treatment. Negative beliefs can generate a nocebo effect that may explain some psychogenic illnesses; this is the basis of much research in psychoneuroimmunology. An understanding of the placebo and nocebo effects is important for general allergy practice, and harnessing the power of the true placebo effect is a major challenge to modern medicine.

Supramedullary influences on cough.

The evidence for supramedullary influences on cough is largely indirect. Cough can be voluntarily induced or inhibited, functions usually thought to reside in the cerebral cortex. A sensation of 'urge-to-cough' usually precedes cough due to an airway irritant stimulus, and this may well involve the cerebral cortex. In conditions with interruption of the pathways between the cortex and the brainstem, such as strokes and Parkinson's disease, voluntary cough may be inhibited without disruption of reflex cough from the larynx or lower airways. 'Habit cough', like Tourette's syndrome, is assumed to be cortically mediated. Placebos and many treatments based on complementary medicine are effective in inhibiting clinical cough, and the site of action is likely to be the cerebral cortex. In sleep and in anaesthesia cough is depressed and, again, this seems likely to be at a cortical level. However there are few or no experimental or clinical observation as to the localization and functions of supramedullary areas responsible for cough. It is a field of research wide open for exploration.

Understanding the symptoms of the common cold and influenza.

The common cold and influenza (flu) are the most common syndromes of infection in human beings. These diseases are diagnosed on symptomatology, and treatments are mainly symptomatic, yet our understanding of the mechanisms that generate the familiar symptoms is poor compared with the amount of knowledge available on the molecular biology of the viruses involved. New knowledge of the effects of cytokines in human beings now helps to explain some of the symptoms of colds and flu that were previously in the realm of folklore rather than medicine-eg, fever, anorexia, malaise, chilliness, headache, and muscle aches and pains. The mechanisms of symptoms of sore throat, rhinorrhoea, sneezing, nasal congestion, cough, watery eyes, and sinus pain are discussed, since these mechanisms are not dealt with in any detail in standard medical textbooks.

The antitussive effect of placebo treatment on cough associated with acute upper respiratory infection.

OBJECTIVE: The objective of this study was to determine the effects of a placebo treatment on cough in patients with cough associated with acute upper respiratory tract infection (URTI). METHODS: Patients with dry or slightly productive cough associated with a history of URTI were recruited. Cough frequency (CF) over 15 minutes was recorded by means of a microphone connected to a pen recorder. Cough suppression time (CST) was recorded when patients were instructed by means of a red light to try not to cough. Patients received either a single dose of vitamin E (placebo treatment) or no treatment. CF and CST were recorded before and 15 minutes after treatment. RESULTS: Twenty-seven patients were randomized to placebo treatment and 27 to the no-treatment group (mean age 22.6 years). The median difference between post- and pretreatment CF was -3 in the no-treatment group and -18 in the placebo group (p = .0003). There was a significant increase in CST in the placebo group compared with no treatment (p = .027). CONCLUSIONS: The results demonstrate that placebo treatment has significant antitussive activity. This placebo effect may be related to generation of central neurotransmitters such as endogenous opioids.

Objective monitoring of nasal patency and nasal physiology in rhinitis.

Nasal obstruction can be monitored objectively by measurement of nasal airflow, as evaluated by nasal peak flow, or as airways resistance/conductance as evaluated by rhinomanometry. Peak flow can be measured during inspiration or expiration. Of these measurements, nasal inspiratory peak flow is the best validated technique for home monitoring in clinical trials. The equipment is portable, relatively inexpensive, and simple to use. One disadvantage, however, is that nasal inspiratory peak flow is influenced by lower airway as well as upper airway function. Rhinomanometry is a more sensitive technique that is specific for nasal measurements. The equipment, however, requires an operator, is more expensive, and is not portable. Thus, it is applicable only for clinic visit measures in clinical trials. Measurements require patient cooperation and coordination, and not all can achieve repeatable results. Thus, this objective measure is best suited to laboratory challenge studies involving smaller numbers of selected volunteers. A nonphysiological measure of nasal patency is acoustic rhinometry. This sonic echo technique measures internal nasal luminal volume and the minimum cross-sectional area. The derivation of these measures from the reflected sound waves requires complex mathematical transformation and makes several theoretical assumptions. Despite this, however, such measures correlate well with the nasal physiological measures, and the nasal volume measures have been shown to relate well to results obtained by imaging techniques such as computed tomography scanning or magnetic resonance imaging. Like rhinomanometry, acoustic rhinometry is not suitable for home monitoring and can be applied only to clinic visit measures or for laboratory nasal challenge monitoring. It has advantages in being easy to use, in requiring little patient cooperation, and in providing repeatable results. In addition to nasal obstruction, allergic rhinitis is recognized to be associated with impaired mucociliary clearance and altered nasal responsiveness. Measures exist for the monitoring of these aspects of nasal dysfunction. Although measures of mucociliary clearance are simple to perform, they have a poor record of reproducibility. Their incorporation into clinical trials is thus questionable, although positive outcomes from therapeutic intervention have been reported. Measures of nasal responsiveness are at present largely confined to research studies investigating disease mechanisms in allergic and nonallergic rhinitis. The techniques are insufficiently standardized to be applied to multicenter clinical trials but could be used in limited-center studies to gain insight into the regulatory effects of different therapeutic modalities.

Effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection.

OBJECTIVE: Acetylsalicylic acid (ASA) has been widely used for over a century to treat pain and fever associated with acute upper respiratory tract infection (URTI), but there is a lack of clinical data to support the efficacy of ASA in this disease state. The objective of this study was to investigate the efficacy and safety of ASA for the treatment of sore throat pain associated with URTI. DESIGN: A double-blinded, placebo-controlled, parallel group design. Two hundred seventy-two patients (mean age: 25 years) with sore throat pain associated with URTI were recruited at two centers. Pain scores were made during a 2-hour laboratory phase and continued for secondary objectives during a 4-hour home phase. Patients were treated with either two effervescent tablets of ASA 400 mg in water or matched placebo tablets. Patients took medication as required over a 3-day home phase. RESULTS: ASA was found to be superior to placebo for: The primary efficacy parameter predefined in the protocol, reduction in sore throat pain intensity over 2 hours (P < 0.001), and for secondary efficacy parameters, reduction in sore throat pain intensity over 4 and 6 hours, relief of sore throat pain over 2, 4, and 6 hours, reduction in intensity of pain associated with headache, and reduction in muscle aches and pains over a 2-hour time period (P < 0.01). No safety problems were encountered. CONCLUSIONS: Treatment with ASA was shown to provide relief from sore throat pain, headache, and muscle aches and pains associated with URTI.

A study to assess the usefulness of a portable spirometer to quantify the severity of nasal septal deviation.

INTRODUCTION: An objective measure of the severity of septal deviation would help the surgeon to select patients, and could also be used to assess the effectiveness of surgery. The aim of this study was to determine the usefulness of a portable spirometer to assess the severity of septal deviation. METHODS: Six healthy subjects and 26 patients awaiting nasal septal surgery for the treatment of chronic complaint of nasal obstruction were recruited. The severity of septal deviation was calculated as a nasal partitioning ratio (NPR) determined by rhinomanometry (NPRcon) and spirometry (NPRvol). NPR is expressed as a ratio scale, where -1 equals complete left side obstruction, zero equates to equal airfow on each side of the nose, and 1 equals complete right side obstruction. RESULTS: The spirometer proved to be useful in measuring the degree of septal deviation in terms of NPRvol (range from -0.21 to 0.20 in healthy subjects, and -0.66 to 1.0 in patients awaiting surgery). The correlation between NPRvol and NPRcon was good (r = 0.77, p = 0.01). In 20 out of 26 patients there was agreement on the side of septal deviation as determined by patient's subjective assessment and the objective assessment with spirometry. DISCUSSION: The results demonstrate that the severity of septal deviation may be quantified in terms of a nasal partitioning ratio determined by use of a portable spirometer (NPRvol). This new measure of septal deviation may prove to be useful to the surgeon in selecting patients for septal surgery and in measuring the success of septal surgery.