Cutoff criteria for the placebo response: a cluster and machine learning analysis of placebo analgesia.

Computations of placebo effects are essential in randomized controlled trials (RCTs) for separating the specific effects of treatments from unspecific effects associated with the therapeutic intervention. Thus, the identification of placebo responders is important for testing the efficacy of treatments and drugs. The present study uses data from an experimental study on placebo analgesia to suggest a statistical procedure to separate placebo responders from nonresponders and suggests cutoff values for when responses to placebo treatment are large enough to be separated from reported symptom changes in a no-treatment condition. Unsupervised cluster analysis was used to classify responders and nonresponders, and logistic regression implemented in machine learning was used to obtain cutoff values for placebo analgesic responses. The results showed that placebo responders can be statistically separated from nonresponders by cluster analysis and machine learning classification, and this procedure is potentially useful in other fields for the identification of responders to a treatment

Comparison of Two Multidisciplinary Occupational Rehabilitation Programs Based on Multimodal Cognitive Behavior Therapy on Self-Rated Health and Work Ability

Objective: Musculoskeletal pain and common mental disorders constitute the largest proportion of people who are on sick leave. This study investigated the efficacy of two multidisciplinary occupational rehabilitation programs on self-rated health and work-related outcomes. The interventions were identical in content but differed in length. It was hypothesized that a longer inpatient program would yield greater improvements than a shorter outpatient program. Methods: Patients were sick-listed workers referred to occupational rehabilitation by the Norwegian Labor and Welfare Administration. A non-randomized 2 Condition (20 days, n = 64 versus 12 days, n = 62) × 4 repeated measures (start, end, 3 months, 12 months) between-subject design was used. Both programs were based on multimodal cognitive behavior therapy with a return-to-work focus. Health-related questionnaires were the Subjective Health Complaints inventory, Hospital Anxiety and Depression Scale, and SF-36 Bodily Pain. Work-related questionnaires were the Work Ability Index, the Fear-Avoidance Beliefs Questionnaire, Return To Work Self-Efficacy, and Return To Work expectations. Intervention effects were estimated using linear mixed models and Cohen’s d. Results: The results revealed that both groups improved on the selected outcomes. Within-group contrasts and effect sizes showed that the inpatient group showed larger effect sizes at the end of rehabilitation and 12 months post-intervention for work-related outcomes than the outpatient group. Conclusion: Both programs were efficacious in improving health- and work-related outcomes during and after rehabilitation, but the inpatient group generally displayed stronger and more rapid improvements and was more stable at one-year postintervention

The Opioid Receptor Mu 1 (OPRM1) rs1799971 and Catechol-O-methyltransferase (COMT) rs4680 as genetic markers for placebo analgesia

This is the accepted manuscript version of the following article: Aslaksen, P.M., Forsberg, J.T. & Gjerstad, J. (2018). The Opioid Receptor Mu 1 (OPRM1) rs1799971 and Catechol-O-methyltransferase (COMT) rs4680 as genetic markers for placebo analgesia. Pain. https://doi.org/10.1097/j.pain.0000000000001370. Published version available at https://doi.org/10.1097/j.pain.0000000000001370.The placebo effect is considered the core example of mind-body interactions. However, individual differences produce large placebo response variability in both healthy volunteers and patients. The placebo response in pain, placebo analgesia, may be dependent on both the opioid system and the dopaminergic system. Previous studies suggest that genetic variability affects the function of these 2 systems. The aim of this study was therefore to address the interaction between the single nucleotide polymorphisms opioid receptor mu 1 (OPRM1) rs1799971 and catechol-O-methyltransferase (COMT) rs4680 on placebo analgesia. Two hundred ninety-six healthy volunteers participated in a repeated-measures experimental design where thermal heat pain stimuli were used as pain stimuli. Participants were randomized either to a placebo group receiving placebo cream together with information that the cream would reduce pain, or to a natural history group receiving the same pain stimuli as the placebo group without any application of cream or manipulation of expectation of pain levels. The results showed that the interaction between OPRM1 rs1799971 and COMT rs4680 was significantly associated with the placebo analgesic response. Participants with OPRM1 Asn/Asn combined with COMT Met/Met and Val/Met reported significant pain relief after placebo administration, whereas those with other combinations of the OPRM1 and COMT genotypes displayed no significant placebo effect. Neither OPRM1 nor COMT had any significant influence on affective changes after placebo administration. As shown in this study, genotyping with regard to OPRM1 and COMT may predict who will respond favorably to placebo analgesic treatment

A four-month home-based tDCS study on patients with Alzheimer’s disease

In the present open-label study, our first aim was to study the tolerability and feasibility of long-term treatment with transcranial direct current stimulation (tDCS) and the second aim was to measure whether the treatment led to cognitive improvement. Participants with AD used a tDCS home-treatment kit inducing a low current (2 mA) via two scalp electrodes 30 minutes daily for 4 months. A total of 8 participants were recruited. The treatment technique was manageable for the participants and their spouses, and no troublesome side effects were reported. No significant effects of treatment were found after 4 months

Blame it on the weather? The association between pain in fibromyalgia, relative humidity, temperature and barometric pressure

Source at https://doi.org/10.1371/journal.pone.0216902.Self-reported pain levels in patients with fibromyalgia may change according to weather conditions. Previous studies suggest that low barometric pressure (BMP) is significantly related to increased pain, but that the contribution of changes in BMP has limited clinical relevance. The present study examined whether BMP influenced variability in perceived stress, and if stress levels moderated or mediated the relationship between BMP and pain. Forty-eight patients with fibromyalgia enrolled in a randomized controlled trail (RCT) reported pain and emotional state three times daily with mobile phone messages for a 30-consecutive day period prior to the start of the treatment in the RCT. The patients were unaware that weather data were collected simultaneously with pain and emotional reports. The results showed that lower BMP and increased humidity were significantly associated with increased pain intensity and pain unpleasantness, but only BMP was associated with stress levels. Stress levels moderated the impact of lower BMP on pain intensity significantly, where higher stress was associated with higher pain. Significant individual differences were present shown by a sub-group of patients (n = 8) who reacted opposite compared to the majority of patients (n = 40) with increased pain reports to an increase in BMP. In sum, lower BMP was associated with increased pain and stress levels in the majority of the patients, and stress moderated the relationship between BMP and pain at the group-level. Significant individual differences in response to changes in BMP were present, and the relation between weather and pain may be of clinical relevance at the individual level

The Fear of Pain Questionnaire-III and the Fear of Pain Questionnaire-Short Form: a confirmatory factor analysis

Source at https://doi.org/10.2147/JPR.S133032 Background: The Fear of Pain Questionnaire-III (FPQ-III) is a widely used instrument to assess the fear of pain (FOP) in clinical and nonclinical samples. The FPQ-III has 30 items and is divided into three subscales: Severe Pain, Minor Pain and Medical Pain. Due to findings of poor fit of the original three-factor FPQ-III model, the Fear of Pain Questionnaire-Short Form (FPQ-SF) four-factor model has been suggested as an alternative. The FPQ-SF is a revised version of the FPQ-III, reduced to 20 items and subdivided into four subscales: Severe Pain, Minor Pain, Injection Pain and Dental Pain. Aims and methods: The purpose of the study was to investigate the model fit, reliability and validity of the FPQ-III and the FPQ-SF in a Norwegian nonclinical sample, using confirmatory factor analysis (CFA). The second aim was to explore the model fit of the two scales in male and female subgroups separately, since previous studies have uncovered differences in how well the questionnaires measure FOP across sex; thus, the questionnaires might not be sex neutral. It has been argued that the FPQ-SF model is better because of the higher fit to the data across sex. To explore model fit across sex within the questionnaires, the model fit, validity and reliability were compared across sex using CFA. Results: The results revealed that both models’ original factor structures had poor fit. However, the FPQ-SF had a better fit overall, compared to the FPQ-III. The model fit of the two models differed across sex, with better fit for males on the FPQ-III and for females on the FPQ-SF. Conclusion: The FPQ-SF is a better questionnaire than the FPQ-III for measurement of FOP in Norwegian samples and across sex subgroups. However, the FPQ-III is a better questionnaire for males than for females, whereas the FPQ-SF is a better questionnaire for females than for males. The findings are discussed and directions for future investigations outlined.<p

Døgnvariasjoner for innleggelser ved akuttpsykiatriske enheter

Akuttpsykiatriske enheter gir øyeblikkelig hjelp til pasienter med særlig vanskelige og kompliserte tilstander med behov utover det som kan ivaretas i kommunehelsetjenesten eller ved distriktspsykiatriske senter (DPS). Flere studier har de siste årene sett på antallet innleggelser og hyppigheten av tvangsbruk i akuttpsykiatriske enheter i Norge (Bjerke et al., 2019; Tøgersen et al., 2015; Wynn, 2018). Bjerke, Gjelstad og Ruud viser at antallet tvangsinnleggelser holdt seg stabilt i perioden 2010 til 2017 (Bjerke et al., 2019). Videre er det funnet at den gjennomsnittlige liggetiden i psykisk helsevern er redusert med 30 % i perioden fra 2009 til 2018 (Statistisk sentralbyrå, 2019). Noen studier har også sett på tidspunkt for innleggelser i akuttpsykiatrien, det vil si når på døgnet pasienter blir lagt inn. Dette har imidlertid ikke blitt undersøkt de siste 10 årene og etter at samhandlingsreformen trådte i kraft (St.meld. nr. 47, 2008). Innleggelser ved akuttpsykiatriske enheter viser noe ulike mønstre. En norsk multisenterstudie fra 2006 der 19 akuttpsykiatriske enheter deltok, viste at gjennomsnittlig 48 % av innleggelsene i akuttpsykiatrien fant sted på dagtid, mens 42 % på kveldstid og 10 % på natt (Gråwe, Hatling & Ruud, 2006). En annen norsk studie fant at 24 % av pasientene ble innlagt mellom klokken (kl.) 16:00 og 22:00, mens 19 % ble lagt inn mellom kl. 22:00 og kl. 08:00, og øvrige innleggelser fant sted på dagtid (Deraas et al., 2006). Videre viste en undersøkelse av 1323 psykiatriske akuttinnleggelser på Lovisenberg Sykehus at 52 % av innleggelsene fant sted på dagtid, altså mellom klokken 08:00 og 16:00 (Berg, 2007). Det ble funnet at 39 % ble innlagt mellom klokken 16:00 og 01:00 og 9 % i tidsrommet 01:00–08:00. Forskjellene mellom tidspunktene var imidlertid ikke signifikante. Hensikten med den nåværende studien er å undersøke hvordan innleggelser i akuttpsykiatriske enheter fordeler seg over døgnet. Vi forventet å finne at flertallet av innleggelsene skjedde på dagtid

Transcranial direct current stimulation as a memory enhancer in patients with Alzheimer’s disease: a randomized, placebo-controlled trial

Background: The purpose of this study was to assess the efficacy of transcranial direct current stimulation (tDCS) on verbal memory function in patients with Alzheimer’s disease. Methods: We conducted a randomized, placebo-controlled clinical trial in which tDCS was applied in six 30-minute sessions for 10 days. tDCS was delivered to the left temporal cortex with 2-mA intensity. A total of 25 patients with Alzheimer’s disease were enrolled in the study. All of the patients were diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association criteria. Twelve patients received active stimulation, and thirteen patients received placebo stimulation. The primary outcome measure was the change in two parallel versions of the California Verbal Learning Test–Second Edition, a standardized neuropsychological memory test normalized by age and gender. The secondary outcome measures were the Mini Mental State Examination, clock-drawing test, and Trail Making Test A and B. Results: Changes in the California Verbal Learning Test–Second Edition scores were not significantly different between the active and placebo stimulation groups for immediate recall (p = 0.270), delayed recall (p = 0.052), or recognition (p = 0.089). There were nonsignificant differences in score changes on the Mini Mental State Examination (p = 0.799), clock-drawing test (p = 0.378), and Trail Making Test A (p = 0.288) and B (p = 0.093). Adverse effects were not observed. Conclusions: Compared with placebo stimulation, active tDCS stimulation in this clinical trial did not significantly improve verbal memory function in Alzheimer’s disease. This study differs from previous studies in terms of the stimulation protocol, trial design, and application of standardized neuropsychological memory assessment. Trial registration: ClinicalTrials.gov identifier NCT02518412. Registered on 10 August 2015

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial

Background Intermittent theta burst stimulation (iTBS) when applied over the left dorsolateral prefrontal cortex (DLPFC) has been shown to be equally effective and safe to treat depression compared to traditional repetitive transcranial magnetic stimulation (rTMS) paradigms. This protocol describes a funded single-centre, double-blind, randomized placebo-controlled, clinical trial to investigate the antidepressive effects of iTBS and factors associated with an antidepressive response. Methods In this trial, outpatients (N=96, aged 22–65 years) meeting the diagnostic criteria for at least moderate depression (Montgomery and Aasberg Depression Rating Scale score≥20) will be enrolled prospectively and receive ten, once-a-day sessions of either active iTBS or sham iTBS to the left DLPFC, localized via a neuronavigation system. Participants may have any degree of treatment resistance. Prior to stimulation, participants will undergo a thorough safety screening and a brief diagnostic assessment, genetic analysis of brain-derived neurotropic factor, 5-HTTLPR and 5-HT1A, and cerebral MRI assessments. A selection of neuropsychological tests and questionnaires will be administered prior to stimulation and after ten stimulations. An additional follow-up will be conducted 4 weeks after the last stimulation. The frst participant was enrolled on June 4, 2022. Study completion will be in December 2027. The project is approved by the Regional Ethical Committee of Medicine and Health Sciences, Northern Norway, project number 228765. The trial will be conducted according to Good Clinical Practice and published safety guidelines on rTMS treatment. Discussion The aims of the present trial are to investigate the antidepressive effect of a 10-session iTBS protocol on moderately depressed outpatients and to explore the factors that can explain the reduction in depressive symptoms after iTBS but also a poorer response to the treatment. In separate, but related work packages, the trial will assess how clinical, cognitive, brain imaging and genetic measures at baseline relate to the variability in the antidepressive effects of iTBS

Failure to Find a Conditioned Placebo Analgesic Response

Background: Associative learning has, in several studies, been modulated by the sex of the participant. Consistent with this, a recent review found that conditioned nocebo effects are stronger in females than in males.Purpose: It has been suggested that conditioned placebo responses are stronger in females, and this hypothesis was investigated in the present study. Cortisol and measures of negative emotions were taken to investigate if these processes could mediate any conditioned placebo effects.Methods: Cold pain was applied to the volar forearm. The Conditioned group received inert capsules prior to two presentations of less painful stimulations, to associate intake of the capsules with reduced pain. The pain control group received the same painful stimulation as the Conditioned group, but no capsules. The Capsule control group received the capsules in the same way as the Conditioned group, but no decrease in the painful stimulation. Participant sex was crossed across groups. It was hypothesized that in the Conditioned group, an expectation of reduced pain should be induced after administration of the capsules, and this should generate placebo analgesia, and mostly so in females.Results: The Conditioned group reported lower pain during conditioning, and rated the capsules as more effective painkillers than the capsule control group. However, placebo analgesia was not reliably observed in the Conditioned group.Conclusion: The placebo capsules were rated as effective painkillers, but this did not translate into a placebo analgesic effect. This could be due to violation of response expectancies, too few conditioning trials, and differences in pain ratings in the pre-test that could be due to previous experience with painkillers