Relieving pain using dose-extending placebos

Placebos are often used by clinicians, usually deceptively and with little rationale or evidence of benefit, making their use ethically problematic. In contrast with their typical current use, a provocative line of research suggests that placebos can be intentionally exploited to extend analgesic therapeutic effects. Is it possible to extend the effects of drug treatments by interspersing placebos? We reviewed a database of placebo studies, searching for studies that indicate that placebos given after repeated administration of active treatments acquire medication-like effects. We found a total of 22studies in both animals and humans hinting of evidence that placebos may work as a sort of dose extender of active painkillers. Wherever effective in relieving clinical pain, such placebo use would offer several advantages. First, extending the effects of a painkiller through the use of placebos may reduce total drug intake and side effects. Second, dose-extending placebos may decrease patient dependence. Third, using placebos along with active medication, for part of the course of treatment, should limit dose escalation and lower costs. Importantly, provided that nondisclosure is pre-authorized in the informed consent process and that robust evidence indicates therapeutic benefit comparable to that of standard full-dose therapeutic regimens, introducing dose-extending placebos into the clinical arsenal should be considered. This novel prospect of placebo use has the potential to change our general thinking about painkiller treatments, the typical regimens of painkiller applications, and the ways in which treatments are evaluated

Does Sex/Gender Play a Role in Placebo and Nocebo Effects? Conflicting Evidence From Clinical Trials and Experimental Studies

Sex has been speculated to be a predictor of the placebo and nocebo effect for many years, but whether this holds true or not has rarely been investigated. We utilized a placebo literature database on various aspects of the genuine placebo/nocebo response. In 2015, we had extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine). These meta-analyses were screened for whether sex/gender differences had been noted to contribute to the placebo/nocebo effect: in only 3 such analyses female sex was associated with a higher placebo effect, indicating poor evidence for a contribution of sex to it in RCTs. This was updated with another set of meta-analyses for the current review, but did not change the overall conclusion. The same holds true for 18 meta-analyses investigating adverse event (nocebo) reporting in RCT in the placebo arm of trials. We also screened our database for papers referring to sex/gender and the placebo effect in experimental studies, and identified 28 papers reporting 29 experiments. Their results can be summarized as follows: (a) Despite higher sensitivity of pain in females, placebo analgesia is easier to elicit in males; (b) It appears that conditioning is effective specifically eliciting nocebo effects; (c) Conditioning works specifically well to elicit placebo and nocebo effects in females and with nausea; (d) Verbal suggestions are not sufficient to induce analgesia in women, but work in men. These results will be discussed with respect to the question why nausea and pain may be prone to be responsive to sex/gender differences, while other symptoms are less. Lastly, we will discuss the apparent discrepancy between RCT with low relevance of sex, and higher relevance of sex in specific experimental settings. We argue that the placebo response is predominantly the result of a conditioning (learning) response in females, while in males it predominantly may be generated via (verbal) manipulating of expectancies. In RCT therefore, the net outcome of the intervention may be the same despite different mechanisms generating the placebo effect between the sexes, while in experimental work when both pathways are separated and explicitly explored, such differences may surface

IKT az óvodában : kihívások és lehetőségek

We suggest a new placebo analgesia animal model and investigated the role of the dopamine and opioid systems in placebo analgesia. Before and after the conditioning, we conducted a conditioned place preference (CPP) test to measure preferences for the cues (Rooms 1 and 2), and a hot plate test (HPT) to measure the pain responses to high level-pain after the cues. In addition, we quantified the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and c-Fos in the anterior cingulate cortex (ACC) as a response to reward learning and pain response. We found an enhanced preference for the low level-pain paired cue and enhanced TH expression in the VTA of the Placebo and Placebo + Naloxone groups. Haloperidol, a dopamine antagonist, blocked these effects in the Placebo + Haloperidol group. An increased pain threshold to high-heat pain and reduced c-Fos expression in the ACC were observed in the Placebo group only. Haloperidol blocked the place preference effect, and naloxone and haloperidol blocked the placebo analgesia. Cue preference is mediated by reward learning via the dopamine system, whereas the expression of placebo analgesia is mediated by the dopamine and opioid systems.Funding Agencies|international cooperation program [2014K2A3A1000166]</p

Recurrent abdominal pain in children and adolescents – a survey among paediatricians

Objective: Little is known about prevalence and usual treatment of childhood and adolescent recurrent abdominal pain (RAP) in outpatient paediatricians’ practice. This study’s primary objective was to acquire insights into the usual paediatricians’ treatment and their estimation of prevalence, age and gender of RAP patients. Further objectives were to assess to which extent family members of patients report similar symptoms, how paediatricians rate the strain of parents of affected children and adolescents and how paediatricians estimate the demand for psychological support

Recurrent abdominal pain in children and adolescents – a survey among paediatricians

Objective: Little is known about prevalence and usual treatment of childhood and adolescent recurrent abdominal pain (RAP) in outpatient paediatricians’ practice. This study’s primary objective was to acquire insights into the usual paediatricians’ treatment and their estimation of prevalence, age and gender of RAP patients. Further objectives were to assess to which extent family members of patients report similar symptoms, how paediatricians rate the strain of parents of affected children and adolescents and how paediatricians estimate the demand for psychological support

Can a Brief Relaxation Exercise Modulate Placebo or Nocebo Effects in a Visceral Pain Model?

Translational research aiming to elucidate mediators and moderators of placebo and nocebo effects is highly relevant. This experimental study tested effects of a brief progressive muscle relaxation (PMR) exercise, designed to alter psychobiological stress parameters, on the magnitude of placebo and nocebo effects in a standardized psychosocial treatment context. In 120 healthy volunteers (60 men, 60 women), pain expectation, pain intensity, and pain unpleasantness in response to individually-calibrated rectal distensions were measured with visual analog scales during a baseline. Participants were then randomized to exercise PMR (relaxation group: N = 60) or a simple task (control group: N = 60), prior to receiving positive (placebo), negative (nocebo) or neutral suggestions regarding an intravenous administration that was in reality saline in all groups. Identical distensions were repeated (test). State anxiety, salivary cortisol, heart rate, and blood pressure were assessed repeatedly. Data were analyzed using analysis of covariance, planned Bonferroni-corrected group comparisons, as well as exploratory correlational and mediation analyses. Treatment suggestions induced group-specific changes in pain expectation, with significantly reduced expectation in placebo and increased expectation in nocebo groups. PMR had no discernable effect on pain expectation, state anxiety or cortisol, but led to significantly lower heart rate and systolic blood pressure. Relaxation significantly interacted with positive treatment suggestions, which only induced placebo analgesia in relaxed participants. No effects of negative suggestions were found in planned group comparisons, irrespective of relaxation. Exploratory correlation and mediation analyses revealed that pain expectation was a mediator to explain the association between treatment suggestions and pain-related outcomes. Clearly, visceral pain modulation is complex and involves many cognitive, emotional, and possibly neurobiological factors that remain to be fully understood. Our findings suggest that a brief relaxation exercise may facilitate the induction of placebo analgesia by positive when compared to neutral treatment suggestions. They underscore the contribution of relaxation and stress as psychobiological states within the psychosocial treatment context—factors which clearly deserve more attention in translational studies aiming to maximize positive expectancy effects in clinical settings

Six-year follow-up of patients with functional bowel disorders, with and without previous psychotherapy

Introduction: Long-term follow-up studies in patients with functional bowel disorders are rare

Somatic Comorbidity in Chronic Constipation: More Data from the GECCO Study

Background. Comorbidity in chronic constipation has rarely been investigated, despite the fact that constipation can occur as one symptom in a number of neurological, systemic, and other nonintestinal and intestinal disorders. Methods. Of 1037 individuals with constipation identified during a telephone survey, 589 returned a postal questionnaire with valid data, asking for sociographic data, clinical symptoms, comorbid conditions, medication intake, and health care behavior related to constipation. Among them, 245 reported some somatic diagnoses and another 120 regular medication intake. They were compared to individuals without comorbid condition and presumed functional constipation ( = 215). Results. Individuals reporting a somatic comorbid condition and/or regular medication were significantly older than those with functional constipation (63.8 ± 15.8 and 43.7 ± 15.5 years, resp., &lt; 0.001) and had lower health and social status (both &lt; 0.001), but similar general life satisfaction (n.s.). Their quality-of-life was lower for the physical ( &lt; 0.001) but not for the mental health domain (n.s.), while among those with functional constipation, the mental health domain distinguished IBS-C individuals from those with functional constipation but without pain ( &lt; 0.001). Conclusion. In an unselected population sample with constipated individuals, those with a somatic comorbid condition outnumber those with functional constipation alone and are distinctly different with respect to age and health status

Somatic Comorbidity in Chronic Constipation: More Data from the GECCO Study

Background. Comorbidity in chronic constipation has rarely been investigated, despite the fact that constipation can occur as one symptom in a number of neurological, systemic, and other nonintestinal and intestinal disorders. Methods. Of 1037 individuals with constipation identified during a telephone survey, 589 returned a postal questionnaire with valid data, asking for sociographic data, clinical symptoms, comorbid conditions, medication intake, and health care behavior related to constipation. Among them, 245 reported some somatic diagnoses and another 120 regular medication intake. They were compared to individuals without comorbid condition and presumed functional constipation (n=215). Results. Individuals reporting a somatic comorbid condition and/or regular medication were significantly older than those with functional constipation (63.8±15.8 and 43.7±15.5 years, resp., p<0.001) and had lower health and social status (both p<0.001), but similar general life satisfaction (n.s.). Their quality-of-life was lower for the physical (p<0.001) but not for the mental health domain (n.s.), while among those with functional constipation, the mental health domain distinguished IBS-C individuals from those with functional constipation but without pain (p<0.001). Conclusion. In an unselected population sample with constipated individuals, those with a somatic comorbid condition outnumber those with functional constipation alone and are distinctly different with respect to age and health status

The Effects of 5-Hydroxytryptophan in Combination with Different Fatty Acids on Gastrointestinal Functions: A Pilot Experiment

Background. Fat affects gastric emptying (GE). 5-Hydroxythryptophan (5-HTP) is involved in central and peripheral satiety mechanisms. Influence of 5-HTP in addition to saturated or monounsaturated fatty acids (FA) on GE and hormone release was investigated. Subjects/Methods. 24 healthy individuals (12f : 12m, 22-29 years, BMI 19-25.7 kg/m(2)) were tested on 4 days with either 5-HTP + short-chain saturated FA (butter), placebo + butter, 5-HTP + monounsaturated FA (olive oil), or placebo + olive oil in double-blinded randomized order. Two hours after FA/5-HTP or placebo intake, a C-13 octanoid acid test was conducted. Cortisol, serotonin, cholecystokinin (CCK), and ghrelin were measured, as were mood and GE. Results. GE was delayed with butter and was normal with olive (P < 0.05) but not affected by 5-HTP. 5-HTP supplementation did not affect serotonin levels. Food intake increased plasma CCK (F = 6.136; P < 0.05) irrespective of the FA. Ghrelin levels significantly decreased with oil/5-HTP (F = 9.166; P < 0.001). The diurnal cortisol profile was unaffected by FA or 5-HTP, as were ratings of mood, hunger, and stool urgency. Conclusion. Diverse FAs have different effects on GE and secretion of orexigenic and anorexigenic hormones. Supplementation of 5-HTP had no effect on plasma serotonin and central functions. Further studies are needed to explain the complex interplay