Placebo in the treatment of pain

Placebo is the use of the substance or procedure without specific activity for the condition that is trying to be healed. In medicine, benefits of placebo effect are used since 1985 and 1978 placebo effect was first scientifically confirmed. It was found that placebo induced analgesia depends on the release of endogenous opiates in the brain and that the placebo effect can be undone using the opiates antagonist naloxone. Functional magnetic resonance imaging of the brain showed that placebo analgesia was obtained regarding the activation and increased functional relationship between ant. cingulate, prefrontal, orbitofrontal, and insular cortex, nucleus accumlens, amygdala, periaqueduktalne gray matter and spinal cord. Placebo also facilitates descending inhibition of nociceptive reflexes through periacvaeductal gray substance. Placebo effect can be achieved in several ways: by using pharmacological preparations or simulation of operating or other procedures. This phenomenon is associated with perception and expectation of the patient. To achieve the effect of placebo it is essential degree of the suggestions of the person who prescribe a placebo, and the degree of belief of the person receiving the placebo. Expected effect of placebo is to achieve the same effect as the right remedy. Achieved placebo effect depends on the way of presentation. If a substance is presented as harmful, it may cause harmful effects, called 'nocebo" effect. Placebo effect is not equal in all patients, same as the real effect of the drug is not always equal in all patients. Application of placebo in terms of analgesia will cause a positive response in 35% of patients. Almost the same percentage (36%) of patients will respond to treatment with morphine in medium doses (6-8 mg). Therefore, one should remember that response to placebo does not mean that a person simulates the pain and then it is unethical to withhold the correct treatment especially in light of findings that the prefrontal cortex is activated expecting liberation of pain and how this action reduce activities in brain regions responsible for sensation of pain (thalamus, somatosensory cortex and other parts of the cortex). However, the use of placebos is ethically, legally and morally very dubious. The basis for the placebo effect is deception. It undermines honest relationship and trust between doctor and patient which is extremely important for successful treatment. Consciously giving placebos to patients for a condition that can be adequately treated, with prejudice the right of patients to the best care possible, opens up many bioethical issues. Despite all the current knowledge level, placebo effect remains still a scientific mystery.     

Antidepressant effects of combination of sleep deprivation and early evening treatment with melatonin or placebo for winter depression

Patients with winter depression (seasonal affective disorder) respond beneficially to sleep deprivation and bright light, but the mechanisms of these responses remain unknown. The study was designed to test whether afternoon/evening melatonin can prevent further relapse after sleep deprivation (presumably due to a pharmacologically induced advance shift of circadian phase). Compared to phase advancing by alteration of sleep - wake schedule or by bright light exposure, the melatonin intake is a more tolerated treatment procedure, and it provides a possibility of blind comparison between chronotherapeutic and placebo treatments. The depression was scored in 16 female patients with winter depression and 17 age-matched female controls before and after total night sleep deprivation and after subsequent six-day administration of melatonin (0.5 mg) or placebo under double blind conditions. The melatonin intake was scheduled at 17:00 in order to produce a phase advance of circadian rhythms. Sleep deprivation resulted in 38% reduction of depression score in patients, but it did not reduce depression score in controls. After subsequent treatment with placebo or melatonin, slight but significant improvement of mood was found in controls. These treatments also stabilized the antidepressant response to sleep deprivation in patients. However, neither differential effect of melatonin and placebo on depression score nor alteration of habitual sleep timing was found in patients and controls. Thus, the study results do not provide evidence for the antidepressant potential of melatonin in patients with winter depression under realistic clinical conditions. The finding of stabilization of mood in patients with placebo points to the contribution of psychological factors to the therapeutic action of this and other types of innovative treatments for winter depression. To include psychosocial aspects in the theoretical framework of seasonal depression, we conceptualized depression as an evolved feature of emotional response to psychosocial rather than physical environment. The seasonality of depression might be explained by cumulative effects of aperiodical psychosocial factors and periodical physical factors on one of the mechanisms of brain neurotransmission.     

REEXAMINATION OF THE ETHICS OF PLACEBO USE IN CLINICAL PRACTICE

A placebo is a substance or intervention believed to be inactive, but is administered by the healthcare professional as if it was an active medication. Unlike standard treatments, clinical use of placebo usually involves deception and is therefore ethically problematic. Our attitudes toward the clinical use of placebo, which inevitably includes deception or withholding information, have a tremendous effect on our practice regarding truth‐telling and informed consent. A casual attitude towards it weakens the current practice based on shared decision‐making and mutual trust between patients and healthcare professionals. Issues concerning the clinical use of placebo are thus intimately related to patient‐provider relationships, the public's trust in medicine, and medical education. A review of recent survey studies suggests that the clinical use of placebo appears to be fairly well accepted among healthcare professionals and is common in clinical settings in various countries. However, we think that an ethical discussion is urgently needed because of its controversial nature. If judged to be ethically wrong, the practice should end. In the present paper, we discuss the ethicality of the clinical use of placebo with deception and argue against it, concluding that it is unethical and should be banned. We will show that most arguments in favor of the clinical use of placebo can be refuted and are therefore incorrect or weak. These arguments will be presented and examined individually. Finally, we will briefly consider issues relevant to the clinical use of placebo without deception.     

Polymicrobial infections involving clinically relevant Gram‐negative bacteria and fungi

Interactions between fungi and bacteria and their relevance to human health and disease have recently attracted increased attention in biomedical fields. Emerging evidence shows that bacteria and fungi can have synergistic or antagonistic interactions, each with important implications for human colonization and disease. It is now appreciated that some of these interactions may be strategic and helps promote the survival of one or both microorganisms within the host. This review will shed light on clinically relevant interactions between fungi and Gram‐negative bacteria. Mechanism of interaction, host immune responses, and preventive measures will also be reviewed.     

New insights into the placebo and nocebo responses

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.     

Light sensitivity of the photoperiodic response system in higher vertebrates: wavelength and intensity effects

Most species use daily light in one way or the other in regulation of their short and/or long term activities. Light is perceived by pigment(s) present in the retinal (RP) and/or extra-retinal photoreceptors (ERPs). ERPs may be located at various sites in the body but in non-mammalian vertebrates they are found predominantly in the pineal body and hypothalamic region of the brain, Light radiations directly penetrate brain tissues to reach and stimulate the hypothalamic (deep-brain) photoreceptors. How does light information finally reach to the clock is not fully understood in many vertebrate groups? In mammals, however, the light information from the retina to the clock (the hypothalamic suprachiasmatic nuclei, SCN) is relayed through the retino-hypothalamic tract (RHT) which originates from the retinal ganglion cells, and through the geniculo-hypothalamic tract (GHT) which originates from the photically responsive cells of a portion of the lateral geniculate nucleus (LGN), called the intergeniculate leaflet (IGL). A response to light (the photoperiodic response) is the result of the interpretation of light information by the photoperiodic system. Apart from the duration, the animals use the gradual shifts in the intensity and wavelength of daily light to regulate their photoperiodic clock system. The wavelengths to which photoreceptors are maximally sensitive or the wavelengths which have greater access to the photoreceptors can induce a maximal response. There can also be differential effects of wavelength and intensity of light on circadian process(es) involved in the entrainment and induction of the photoperiodic clock. This may have some adaptive implications. Entrainment to daily light-dark (LD) cycle may be achieved at dawn or dusk, depending whether the animal is day- or night-active, when there is relatively low intensity of light. By contrast, photoperiodic induction in many species occurs during long days of spring and summer when plenty of daylight at higher intensity is available later in the day.     

The dynamics of human body weight change

An imbalance between energy intake and energy expenditure will lead to a change in body weight (mass) and body composition (fat and lean masses). A quantitative understanding of the processes involved, which currently remains lacking, will be useful in determining the etiology and treatment of obesity and other conditions resulting from prolonged energy imbalance. Here, we show that a mathematical model of the macronutrient flux balances can capture the long-term dynamics of human weight change; all previous models are special cases of this model. We show that the generic dynamic behavior of body composition for a clamped diet can be divided into two classes. In the first class, the body composition and mass are determined uniquely. In the second class, the body composition can exist at an infinite number of possible states. Surprisingly, perturbations of dietary energy intake or energy expenditure can give identical responses in both model classes, and existing data are insufficient to distinguish between these two possibilities. Nevertheless, this distinction has important implications for the efficacy of clinical interventions that alter body composition and mass.     

The effects of continuous prostacyclin infusion on regional blood flow and cerebral vasospasm following subarachnoid haemorrhage: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: One of the main causes of mortality and morbidity following subarachnoid haemorrhage (SAH) is the development of cerebral vasospasm, a frequent complication arising in the weeks after the initial bleeding. Despite extensive research, to date no effective treatment of vasospasm exists. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. In vitro models have shown a relaxing effect of prostacyclin after induced contraction in cerebral arteries and a recent pilot trial showed positive effect on cerebral vasospasm in a clinical setting. No randomised, clinical trials have been conducted, investigating the possible pharmacodynamic effects of prostacyclin on the human brain following SAH. METHODS: This trial is a single-center, randomised, placebo controlled, parallel group, blinded, clinical, pilot trial. A total of 90 patients with SAH will be randomised to one of 3 intervention arms; epoprostenol 1 ng/kg/min, epoprostenol 2 ng/kg/min or placebo in addition to standard treatment. Trial medication will start day 5 after SAH and continue to day 10. Primary outcome measure is changes in regional cerebral blood flow from baseline in the arterial territories of the anterior cerebral artery, medial cerebral artery and the posterior cerebral artery, measured by CT perfusion scan. The secondary outcomes will be vasospasm measured by CT angiography, ischaemic parameters measured by brain microdialysis, flow velocities in the medial cerebral artery, clinical parameters and outcome (Glasgow Outcome Scale) at 3 months. CONCLUSION: The trial is an explorative, pilot trial designed to investigate the feasibility and possible effects of low-dose prostacyclin on a primary outcome of regional blood flow and vasospasm in the human brain following SAH. Trial registration: Clinicaltrials.gov NCT01447095.     

Primate molar crown formation times and life history evolution revisited.

Comparative studies have convincingly demonstrated that the pattern and timing of tooth emergence are highly correlated with life-history variables and brain size. Conversely, a firm relationship between molar formation time and life-history variables has not yet been established. It seems counterintuitive that one aspect of dental development should be correlated with life-history variables, whereas the other should not. In order to shed light on this apparent discrepancy this study analyzed all data on primate molar crown formations available in the published literature in relation to life-history variables, brain size, and female body mass. Crown formation times were found to be particularly highly correlated with both female body mass and brain size. Species that depart from the overall brain/body allometry by being relatively large-bodied, e.g., Gorilla gorilla and later Theropithecus oswaldi, also have shorter molar crown formation times than expected. The reverse is not found for species that depart from the overall brain/body allometry due to their larger brains, i.e., Homo sapiens. This finding is interpreted within an evolutionary and ecological framework. Specifically, by focusing on ecological commonalities, a scenario is proposed which may allow predictions to be made about the evolutionary history of other extinct primates also. If confirmed in future studies, crown formation time may again become a powerful tool in evolutionary enquiry.     

Functional salutogenic mechanisms of the brain

Neuroscientists are typically interested in the brain in relation to disease, but much could also be learned by studying the brain in relation to health. The brain has processes, functional salutogenic mechanisms, that contribute to health by enabling one's outlook on life to benefit one's health. For example, the belief that things will work out as well as can reasonably be expected is a key aspect of the outlook of people who tend to stay well even when in potentially stressful situations. Believing in God, feeling happy, being mutually in love, and expecting things to change for the better are also outlooks that can be salutogenic. Beliefs need not even be rational or realistic in order for them to be salutogenic, as shown by phenomena such as faith healing and the placebo effect. Thus, the brain responds to stimuli and interprets them, mainly without one's awareness, in ways that can enhance one's well-being. Although little is presently known concerning neuropathways of functional salutogenic mechanisms, further research on relations between salutogenesis and brain function can be expected to provide new strategies for improving health worldwide.     

PISA. The effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute stroke: Protocol for a phase II double-blind randomised placebo-controlled trial [ISRCTN98608690]

Background

During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may improve their functional outcome. Previously, we studied the effect of high dose (6 g daily) and low dose (3 g daily) paracetamol (acetaminophen) in a randomised placebo-controlled trial of 75 patients with acute ischemic stroke. In the high-dose paracetamol group, mean body temperature at 12 and 24 hours after start of treatment was 0.4°C lower than in the placebo group. The effect of ibuprofen, another potent antipyretic drug, on body-core temperature in normothermic patients has not been studied.

Aim

The aim of the present trial is to study the effects of high-dose paracetamol and ibuprofen on body temperature in patients with acute ischaemic stroke, and to study the safety of these treatments.

Design

Seventy-five (3 × 25) patients with acute ischaemic stroke confined to the anterior circulation will be randomised to treatment with either: 400 mg ibuprofen, 1000 mg acetaminophen, or with placebo 6 times daily during 5 days. Body-temperatures will be measured with a rectal electronic thermometer at the start of treatment and after 24 hours. An infrared tympanic thermometer will be used to monitor body temperature at 2-hour intervals during the first 24 hours and at 12-hour intervals thereafter. The primary outcome measure will be rectal temperature at 24 hours after the start of treatment. The study results will be analysed on an intent-to-treat basis, but an on-treatment analysis will also be performed. No formal interim analysis will be carried out.     

A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo

Background

Cycloset? is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset? either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset? therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset? therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points.

Methods/Design

3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset? compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset? is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset? versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids.

Discussion

This study will extend the current data on Cycloset? safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens.

Trial registration

clinical trials.gov NCT00377676     

Comparative analysis of different impression techniques in relation to single tooth impression

It is of interest to compare the accuracy of three different impression techniques for a single tooth impression. We used 3 groups with 15 samples each in this study. Group 1: Putty and light body in a sectional stock tray; Group 2: Monophase and extra light body in a sectional stock tray; Group 3: Matrix impression technique. 15 impressions were taken of a prepared tooth on a typodont with each technique. The dimensions of the casts poured from these impression techniques were compared with the control typodont tooth. Data analysis shows that the matrix impression technique gave the best results in terms of dimensional study followed by monophase and extra light body impression technique and putty and light body impression technique gave the least accurate results. The results show that there is a statistically significant difference between the three impression techniques in terms of dimensional stability. Data analysis shows that the matrix impression technique gave the best results in terms of dimensional study followed by monophase and extra light body impression technique and putty and light body impression technique gave the least accurate results. The variations between the groups are within acceptable limits. Hence, it can be concluded that all the impression techniques will result in adequate dimensional stability and can be used in clinical scenarios.     

Effect of Omacor on HRV parameters in patients with recent uncomplicated myocardial infarction - A randomized, parallel group, double-blind, placebo-controlled trial: study design [ISRCTN75358739

BACKGROUND: A large body of data derived from animal, epidemiological and clinical studies indicate that n-3 polyunsaturated fatty acids have a favourable effect on the prognosis of patients with cardiovascular disease in general, and on reducing sudden death in particular.Depressed heart rate variability (HRV), an indicator of impairment of the autonomic nervous system, has been shown to be a powerful predictor of subsequent mortality in patients surviving an acute myocardial infarction. A multitude of studies have demonstrated this strong association, suggesting that the imbalance in the sympathic/parasympathetic system may facilitate emergence of ventricular arrhythmias.Heart rate variability parameters will be assessed in the present study, with the primary objective of evaluating the possible superiority of Omacor (a highly refined, concentrated omega-3 fatty acid) versus placebo in improving HRV from baseline to endpoint in patients with recent uncomplicated myocardial infarction. Both groups will receive optimal conventional treatment.The study will also explore and quantify improvement in time domain HRV indices and will assess the safety of administering Omacor to optimally treated post-infarction patients (conventional treatment). METHODS: This multi-centre study will evaluate the effect of Omacor 1 g, o.d. on time-domain HRV parameters in comparison to placebo o.d. in patients with recent uncomplicated transmural myocardial infarction.Patients will be screened during the first few days after the acute event as appropriate for the patient's condition, and after obtaining informed consent. Based on inclusion/exclusion criteria, a first 24-hour Holter recording will be performed. Two to five days later, screened patients still eligible for the study will undergo a second 24-hour Holter recording. After the second Holter recording, all patients will be randomly allocated to treatment with Omacor 1 g, o.d. or placebo o.d.One hundred patients will be followed in double-blind fashion for a six-month period after randomization. Visits, including 24-hour Holter recording and assessment of adverse events, will take place at one-month intervals +/- five days after randomization, i.e., six times in all.     

On confidence bounds for the ratio of net differences in the "gold standard" design with reference, experimental, and placebo treatment

The three-arm clinical study including a placebo has been recommended to be the preferred study design for the comparison of an experimental treatment relative to a reference treatment. In a confirmatory three-arm study multiplicity issues arise that are not present in two-arm studies. In the past a successful demonstration of superiority of the reference over placebo has been regarded a prerequisite validation step for the demonstration of superiority of the experimental treatment over placebo. However, for an investigator this last comparison is the most critical one. In a clinical study the demonstration of superiority of the experimental treatment over placebo is a result of its own value and this should therefore not be made dependent on tests that are of higher priority in a hierarchical test procedure. This can be achieved through a symmetrical formulation of Fieller's method for constructing confidence intervals for ratio of the expected values from normally distributed variables. In the symmetrical formulation the different meanings of nominator and denominator disappear, and simultaneous statements for comparisons between the experimental treatment and placebo, reference treatment and placebo, and reference and experimental treatment can be made. This is accomplished by moving the discussion on confidence sets from the line of real numbers to the unit circle which allows representing confidence sectors always as connected sets, gives always simple geometrical interpretations, and is easy to be transformed back to the real numbers if the traditional calculations behave well. The proposed procedures provides additional insight in existing methods but does obviously not answer the clinical question whether or not the demonstration of superiority of the reference treatment over placebo is a necessary validation step for further comparisons.     

Head organization and the head/trunk relationship in protochordates: problems and prospects

The fossil record has been an invaluable aid for reconstructing the major events of vertebrate evolution. There is no comparable record for protochordates, however, which severely limits our knowledge of their ancestral morphology, habits, and mode of life. The alternative is inference based on an interpretation of living protochordates but this is fraught with problems, not least being our own biases of what we think an ancestral chordate ought to look like. Relevant to the present symposium is the problem of head/trunk relationships and whether or not the myotomes of the trunk originally extended into the head in vertebrates. I will review what is currently known of patterns of innervation in tunicates and amphioxus in relation to Romer's somaticovisceral concept of the vertebrate body to show how little progress has been made in resolving this problem. There are, in contrast, surprisingly good prospects for solving some other puzzles concerning chordate origins. Dorsoventral inversion provides a good example. A consensus is now emerging, based largely on molecular data from hemichordates that casts new light on the asymmetry of the head in amphioxus. Specifically, the morphogenetic growth process that reestablishes symmetry in late-stage larvae can now be seen, at least in part, as a recapitulation of past evolutionary events, and this has important implications for the origin and basic organization of the brain.     

Bridging behavior and physiology: ion-channel perspective on mushroom body-dependent olfactory learning and memory in Drosophila

An important body of evidence documents the differential expression of ion channels in brains, suggesting they are essential to endow particular brain structures with specific physiological properties. Because of their role in correlating inputs and outputs in neurons, modulation of voltage-dependent ion channels (VDICs) can profoundly change neuronal network dynamics and performance, and may represent a fundamental mechanism for behavioral plasticity, one that has received less attention in learning and memory studies. Revisiting three paradigmatic mutations altering olfactory learning and memory in Drosophila (dunce, leonardo, amnesiac) a link was established between each mutation and the operation of VDICs in Kenyon cells, the intrinsic neurons of the mushroom bodies (MBs). In Drosophila, MBs are essential to the emergence of olfactory associative learning and retention. Abnormal ion channel operation might underlie failures in neuronal physiology, and be crucial to understand the abnormal associative learning and retention phenotypes the mutants display. We also discuss the only case in which a mutation in an ion channel gene (shaker) has been directly linked to olfactory learning deficits. We analyze such evidence in light of recent discoveries indicating an unusual ion current profile in shaker mutant MB intrinsic neurons. We anticipate that further studies of acquisition and retention mutants will further confirm a link between such mutations and malfunction of specific ion channel mechanisms in brain structures implicated in learning and memory.     

Determinants of the Clinical Outcomes of Gout During the First Year of Urate-Lowering Therapy

Clinical benefit early in urate-lowering treatment of gout is difficult to document. We examined data from 1,832 gouty subjects treated with either urate-lowering agents or placebo to identify determinants of gout flare incidence and tophus size during year 1 of treatment. Reductions from pretreatment serum urate levels influenced flare frequency and tophus size, but the effect of urate level on flare incidence was biphasic. Lower urate levels were associated with higher flare incidence early in treatment but lower incidence by one year. The complex relationship between urate-lowering and clinical outcome early in treatment has implications for both clinical and investigative approaches to urate-lowering management.