Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain: A Systematic Review and Meta-analysis.

Importance: Persistent pain is a common and disabling health problem that is often difficult to treat. There is an increasing interest in medicinal cannabis for treatment of persistent pain; however, the limited superiority of cannabinoids over placebo in clinical trials suggests that positive expectations may contribute to the improvements. Objective: To evaluate the size of placebo responses in randomized clinical trials in which cannabinoids were compared with placebo in the treatment of pain and to correlate these responses to objective estimates of media attention. Data Sources: A systematic literature search was conducted within the MEDLINE and Embase databases. Studies published until September 2021 were considered. Study Selection: Cannabinoid studies with a double-blind, placebo-controlled design with participants 18 years or older with clinical pain of any duration were included. Studies were excluded if they treated individuals with HIV/AIDS or severe skin disorders. Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Review and Meta-analyses reporting guideline. Data were extracted by independent reviewers. Quality assessment was performed using the Risk of Bias 2 tool. Attention and dissemination metrics for each trial were extracted from Altmetric and Crossref. Data were pooled and analyzed using a random-effects statistical model. Main Outcomes and Measures: Change in pain intensity from before to after treatment, measured as bias-corrected standardized mean difference (Hedges g). Results: Twenty studies, including 1459 individuals (mean [SD] age, 51 [7] years; age range, 33-62 years; 815 female [56%]), were included. Pain intensity was associated with a significant reduction in response to placebo, with a moderate to large effect size (mean [SE] Hedges g, 0.64 [0.13]; P < .001). Trials with low risk of bias had greater placebo responses (q1 = 5.47; I2 = 87.08; P = .02). The amount of media attention and dissemination linked to each trial was proportionally high, with a strong positive bias, but was not associated with the clinical outcomes. Conclusions and Relevance: Placebo contributes significantly to pain reduction seen in cannabinoid clinical trials. The positive media attention and wide dissemination may uphold high expectations and shape placebo responses in future trials, which has the potential to affect the outcome of clinical trials, regulatory decisions, clinical practice, and ultimately patient access to cannabinoids for pain relief.

Augmented pain inhibition and higher integration of pain modulatory brain networks in women with self-injury behavior.

Individuals who engage in nonsuicidal self-injury (NSSI) have demonstrated insensitivity to pain compared with individuals without NSSI. Yet, the neural mechanisms behind this difference are unknown. The objective of the present study was to determine which aspects of the pain regulatory system that account for this decreased sensitivity to pain. In a case-control design, 81 women, aged 18-35 (mean [SD] age, 23.4 [3.9]), were included (41 with NSSI and 40 healthy controls). A quantitative sensory testing protocol, including heat pain thresholds, heat pain tolerance, pressure pain thresholds, conditioned pain modulation (assessing central down-regulation of pain), and temporal summation (assessing facilitation of pain signals) was used. Pain-evoked brain responses were assessed by means of fMRI scanning during thermal pain. NSSI participants showed a more effective central down-regulation of pain, compared to controls, assessed with conditioned pain modulation. The neural responses to painful stimulation revealed a stronger relation between nociceptive and pain modulatory brain regions in NSSI compared to controls. In line with previous studies, pressure and heat pain thresholds were higher in participants with NSSI, however, there were no correlations between pain outcomes and NSSI clinical characteristics. The augmented pain inhibition and higher involvement of pain modulatory brain networks in NSSI may represent a pain insensitive endophenotype associated with a greater risk for developing self-injurious behavior.

Internet-Delivered Cognitive Behavior Therapy for Atopic Dermatitis: A Randomized Clinical Trial.

IMPORTANCE: Atopic dermatitis is a common and debilitating skin condition characterized by intense itching and chronic inflammation. Research on behavioral treatments with high accessibility is needed. OBJECTIVE: To investigate the efficacy of a highly scalable internet-delivered cognitive behavior therapy (CBT) for adults with atopic dermatitis. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial from a medical university in Stockholm, Sweden, included 102 adults with atopic dermatitis, recruited from across Sweden, who received 12 weeks of internet-delivered CBT (March 29, 2017, to February 16, 2018). The first participant provided screening data on November 27, 2016, and the last 1-year follow-up assessment was conducted on June 28, 2019. INTERVENTIONS: Participants were randomized in a 1:1 ratio to 12 weeks of therapist-guided internet-delivered CBT (n = 51) or a control condition (n = 51) that gave instructions about standard care. MAIN OUTCOMES AND MEASURES: The primary outcome was the between-group difference in mean reduction of atopic dermatitis symptoms as measured by the Patient-Oriented Eczema Measure and modeled intention to treat during the 12-week treatment period. RESULTS: A total of 102 participants (mean [SD] age, 37 [11] years; 83 [81%] female) were recruited and randomized. The primary analysis indicated that participants receiving internet-delivered CBT, relative to the controls, had a significantly larger mean weekly reduction in symptoms of atopic dermatitis as measured with the Patient-Oriented Eczema Measure (B = 0.32; 95% CI, 0.14-0.49; P < .001), with a moderate to large, controlled effect size after treatment (d = 0.75; 95% CI, 0.32-1.16). Secondary analyses indicated that internet-delivered CBT also produced significantly larger reductions in itch intensity, perceived stress, sleep problems, and depression. Gains were sustained at 12 months of follow-up. Treatment satisfaction was high, and therapists spent a mean (SD) of 39.7 (34.7) minutes per treated patient providing internet-delivered CBT. CONCLUSIONS AND RELEVANCE: Internet-delivered CBT appears to be efficacious for reducing symptoms of atopic dermatitis, despite requiring minimal therapist resources. Thus, internet-delivered CBT has the potential to increase access to effective adjunct behavioral treatment for patients with this common skin condition. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03051958.

Offset analgesia and onset hyperalgesia with different stimulus ranges.

INTRODUCTION: Offset analgesia (OA), a large reduction in pain after a brief increase in intensity of an otherwise stable painful stimulus, has been established by a large body of research. But the opposite effect, onset hyperalgesia (OH), a disproportional hyperalgesic response after a briefly decreased intensity of a painful stimulus, has only been investigated in one previous study. OBJECTIVES: The aim of this study was to induce OA and OH in healthy participants and explore the effects of different stimulus ranges (increase/decrease of temperature) on OA and OH. METHODS: A total of 62 participants were tested in 2 identical experiments. Offset analgesia and OH conditions included 2 different temperature deviations (±1°C/±2°C) from initial temperature and were compared with a constant temperature (control). RESULTS: Offset analgesia was successfully elicited in OA1°C in experiment 1, and in OA1°C and OA2°C in experiment 2. Results indicate a continuous stimulus-response relationship between the stimulus range and the resulting hypoalgesic response. Onset hyperalgesia was only elicited in OH2°C in experiment 1. Exploratory analysis showed that the lack of OH response in experiment 2 could be explained by sex differences, and that OA and OH responses were only weakly correlated. CONCLUSIONS: The asymmetry between pain responses after a brief temperature increase and decrease suggests that different mechanisms are involved in the pain responses to increasing and decreasing temperature. This asymmetry may also be explained by high temperatures in OA condition (+1°C/+2°C above baseline) that could be seen as salient "learning signals," which augment the response to following changes in temperature.

Predicting pain: differential pain thresholds during self-induced, externally induced, and imagined self-induced pressure pain.

ABSTRACT: During self-induced pain, a copy of the motor information from the body's own movement may help predict the painful sensation and cause downregulation of pain. This phenomenon, called sensory attenuation, enables the distinction between self-produced stimuli vs stimuli produced by others. Sensory attenuation has been shown to occur also during imagined self-produced movements, but this has not been investigated for painful sensations. In the current study, the pressure pain thresholds of 40 healthy participants aged 18 to 35 years were assessed when pain was induced by the experimenter (other), by themselves (self), or by the experimenter while imagining the pressure to be self-induced (imagery). The pressure pain was induced on the participants left lower thigh (quadriceps femoris) using a handheld algometer. Significant differences were found between all conditions: other and self (P < 0.001), other and imagery (P < 0.001), and self and imagery (P = 0.004). The mean pressure pain threshold for other was 521.49 kPa (SE = 38.48), for self 729.57 kPa (SE = 32.32), and for imagery 618.88 kPa (SE = 26.67). Thus, sensory attenuation did occur both in the self condition and the imagery condition. The results of this study may have clinical relevance for understanding the mechanisms involved in the elevated pain thresholds seen in patients with self-injury behavior and the low pain thresholds seen in patients with chronic pain conditions. Imagery of sensory attenuation might also be used to alleviate the pain experience for patients undergoing procedural pain.

Fluidity of gender identity induced by illusory body-sex change.

Gender identity is a collection of thoughts and feelings about one's own gender, which may or may not correspond to the sex assigned at birth. How this sense is linked to the perception of one's own masculine or feminine body remains unclear. Here, in a series of three behavioral experiments conducted on a large group of control volunteers (N = 140), we show that a perceptual illusion of having the opposite-sex body is associated with a shift toward a more balanced identification with both genders and less gender-stereotypical beliefs about own personality characteristics, as indicated by subjective reports and implicit behavioral measures. These findings demonstrate that the ongoing perception of one's own body affects the sense of one's own gender in a dynamic, robust, and automatic manner.

Naltrexone during pain conditioning: A double-blind placebo-controlled experimental trial.

Naltrexone reversibly blocks the effects of opioids and has been shown to decrease placebo analgesia. However, it is not clear (1) to what extent naltrexone affects pain modulation in a nontreatment context, for example, in response to pain cues or (2) how naltrexone given prior to pain-cue learning shapes pain responses. In a double-blind procedure prior to pain-cue conditioning, 30 healthy participants were randomized to receive an oral dose of naltrexone (50 mg) or inert pill. During functional magnetic resonance imaging, high and low pain pressures were paired with two different visual cues: a high pain cue and a low pain cue (learning sequence). During a test sequence, medium levels of pressure were used for both cues and the difference in subjective pain ratings following high and low pain cues was calculated. Results showed significant conditioned pain responses across groups (P < .001); however, no significant difference between participants receiving naltrexone or inert pill (P = .193). There was a significant correlation between the difference in high and low pain ratings during the learning sequence and the effect of high and low pain cues during the test sequence (r = .575, P = .002). Functional magnetic resonance imaging analyses revealed no significant difference in brain activation between groups. Here, we demonstrate comparable learning of pain responses in participants treated with naltrexone or inert pill. The results point to the possibility that associative learning, and conditional responding to pain cues, is not dependent on endogenous opioids. Our results, using pain-cue conditioning to create reduced pain responses, contrast previous studies where opioid antagonists significantly reduced the placebo effect in treatment of pain.

The pain alarm response - an example of how conscious awareness shapes pain perception.

Pain is subjective and largely shaped by context, yet, little is known about the boundaries for such influences, in particular in relation to conscious awareness. Here, we investigated processing of noxious stimuli during sleep. Four experiments were performed where participants (n = 114) were exposed to repetitions of noxious heat, either when awake or during sleep. A test-phase followed where participants were awake and exposed to painful stimuli and asked to rate pain. Two control experiments included only the test-phase, without any prior pain exposures. Participants in the awake condition rated all test-phase stimuli the same. Conversely, participants who had been sleeping, and thus unaware of getting noxious heat, displayed heightened pain during the first part of the test-phase. This heightened reaction to noxious stimuli-a pain alarm response-was further pronounced in the control conditions where participants were naïve to noxious heat. Results suggest that the pain alarm response is partly dependent on conscious awareness.

Cognitive behaviour therapy for depression in primary care: systematic review and meta-analysis.

Depression is common in primary care, and most patients prefer psychological treatment over pharmacotherapy. Cognitive behaviour therapy (CBT) is an effective treatment, but there are gaps in current knowledge about CBT in the primary care context, especially with regard to long-term effects and the efficacy of specific delivery formats. This is an obstacle to the integration of primary care and specialist psychiatry. We conducted a systematic review and meta-analysis of randomised controlled trials of CBT for primary care patients with depression to investigate the effect of CBT for patients with depression in primary care. A total of 34 studies, with 2543 patients in CBT and 2815 patients in control conditions, were included. CBT was more effective than the control conditions [g = 0.22 (95% confidence interval (CI) 0.15-0.30)], and the effect was sustained at follow-up [g = 0.17 (95% CI 0.10-0.24)]. CBT also led to a higher response rate [odds ratio (OR) = 2.47 (95% CI 1.60-3.80)] and remission rate [OR = 1.56 (95% CI 1.15-2.14)] than the control conditions. Heterogeneity was moderate. The controlled effect of CBT was significant regardless of whether patients met diagnostic criteria for depression, scored above a validated cut-off for depression, or merely had depressive symptoms. CBT also had a controlled effect regardless of whether the treatment was delivered as individual therapy, group therapy or therapist-guided self-help. We conclude that CBT appears to be effective for patients with depression in primary care, and recommend that patients with mild to moderate depression be offered CBT in primary care.