Efficacy of mecobalamin (vitamin B12) in the treatment of long-term pain in women diagnosed with fibromyalgia: protocol for a randomised, placebo-controlled trial.

INTRODUCTION: Fibromyalgia causes long-term pain. It affects at least 2% of the population, the majority being women. In addition, extended symptoms corresponding to vitamin B12 deficiency occur. Findings from several studies have indicated that vitamin B12 may be a possible treatment for pain in fibromyalgia. The aim of the proposed study is to evaluate whether vitamin B12 decreases pain sensitivity and the experience of pain (ie, hyperalgesia and allodynia) in women with fibromyalgia. METHODS AND ANALYSIS: The study is a randomised, placebo-controlled, single-blind, clinical trial with two parallel groups which are administered mecobalamin (vitamin B12) or placebo over 12 weeks. 40 Swedish women aged 20-70 years with an earlier recorded diagnosis of fibromyalgia are randomised into the placebo group or the treatment group, each consisting of 20 participants. Outcomes consist of questionnaires measured at baseline and after 12 weeks of treatment. A final re-evaluation will then follow 12 weeks after treatment ends. The primary outcome is tolerance time, maximised to 3 min, which is assessed using the cold pressor test. In order to broaden the understanding of the lived experience of participants, qualitative interviews will be conducted using a phenomenological approach on a lifeworld theoretical basis (reflective lifeworld research approach). ETHICS AND DISSEMINATION: The protocol for the study is approved by the local ethical committee at Linkoping (EPM; 2018/294-31, appendices 2019-00347 and 2020-04482). The principles of the Helsinki Declaration are followed regarding oral and written consent to participate, confidentiality and the possibility to withdraw participation from the study at any time. The results will primarily be communicated through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: NCT05008042.

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.

Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls.

The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5-HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5-HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5-HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5-HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5-HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.

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.

The Effects of Positive or Neutral Communication during Acupuncture for Relaxing Effects: A Sham-Controlled Randomized Trial.

Introduction. The link between patient-clinician communication and its effect on clinical outcomes is an important clinical issue that is yet to be elucidated. Objective. Investigating if communication type (positive or neutral) about the expected treatment outcome affected (i) participants' expectations and (ii) short-term relaxation effects in response to genuine or sham acupuncture and investigating if expectations were related to outcome. Methods. Healthy volunteers (n = 243, mean age of 42) were randomized to one treatment with genuine or sham acupuncture. Within groups, participants were randomized to positive or neutral communication, regarding expected treatment effects. Visual Analogue Scales (0-100 millimeters) were used to measure treatment expectations and relaxation, directly before and after treatment. Results. Participants in the positive communication group reported higher treatment expectancy, compared to the neutral communication group (md 12 versus 6 mm, p = 0.002). There was no difference in relaxation effects between acupuncture groups or between communication groups. Participants with high baseline expectancy perceived greater improvement in relaxation, compared to participants with low baseline levels (md 27 versus 15 mm, p = 0.022). Conclusion. Our data highlights the importance of expectations for treatment outcome and demonstrates that expectations can be effectively manipulated using a standardized protocol that in future research may be implemented in clinical trials.

A Neural Mechanism for Nonconscious Activation of Conditioned Placebo and Nocebo Responses.

Fundamental aspects of human behavior operate outside of conscious awareness. Yet, theories of conditioned responses in humans, such as placebo and nocebo effects on pain, have a strong emphasis on conscious recognition of contextual cues that trigger the response. Here, we investigated the neural pathways involved in nonconscious activation of conditioned pain responses, using functional magnetic resonance imaging in healthy participants. Nonconscious compared with conscious activation of conditioned placebo analgesia was associated with increased activation of the orbitofrontal cortex, a structure with direct connections to affective brain regions and basic reward processing. During nonconscious nocebo, there was increased activation of the thalamus, amygdala, and hippocampus. In contrast to previous assumptions about conditioning in humans, our results show that conditioned pain responses can be elicited independently of conscious awareness and our results suggest a hierarchical activation of neural pathways for nonconscious and conscious conditioned responses. Demonstrating that the human brain has a nonconscious mechanism for responding to conditioned cues has major implications for the role of associative learning in behavioral medicine and psychiatry. Our results may also open up for novel approaches to translational animal-to-human research since human consciousness and animal cognition is an inherent paradox in all behavioral science.

Well-loved music robustly relieves pain: a randomized, controlled trial.

Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly preferred music. A two-session experiment was performed with 48 healthy, pain experiment-naïve participants. In a first cohort, 36 were randomized into 3 treatment groups, including music enhanced with positive expectancy, non-musical sound enhanced with positive expectancy, and no expectancy enhancement. A separate replication cohort of 12 participants received only expectancy-enhanced music following the main experiment to verify the results of expectancy-manipulation on music. Primary outcome measures included the change in subjective pain ratings to calibrated experimental noxious heat stimuli, as well as changes in treatment expectations. Without conditioning, expectations were strongly in favor of music compared to non-musical sound. While measured expectations were enhanced by conditioning, this failed to affect either music or sound analgesia significantly. Strongly preferred music on its own was as pain relieving as conditioning-enhanced strongly preferred music, and more analgesic than enhanced sound. Our results demonstrate the pain-relieving power of personal music even over enhanced expectations. TRIAL INFORMATION: Clinicaltrials.gov NCT01835275.

Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma.

Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biologic outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multikinase inhibitor with activity against RAF, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MAP-ERK kinase inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of COX and mitogen-activated protein kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Cotreatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving extracellular signal-regulated kinase, cellular phospholipase A2, and COX. Genome-wide expression profiling shows synergy-specific downregulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially, depending on unexplored components of the cell genotype.

The use of functional neuroimaging to evaluate psychological and other non-pharmacological treatments for clinical pain.

A large number of studies have provided evidence for the efficacy of psychological and other non-pharmacological interventions in the treatment of chronic pain. While these methods are increasingly used to treat pain, remarkably few studies focused on the exploration of their neural correlates. The aim of this article was to review the findings from neuroimaging studies that evaluated the neural response to distraction-based techniques, cognitive behavioral therapy (CBT), clinical hypnosis, mental imagery, physical therapy/exercise, biofeedback, and mirror therapy. To date, the results from studies that used neuroimaging to evaluate these methods have not been conclusive and the experimental methods have been suboptimal for assessing clinical pain. Still, several different psychological and non-pharmacological treatment modalities were associated with increased pain-related activations of executive cognitive brain regions, such as the ventral- and dorsolateral prefrontal cortex. There was also evidence for decreased pain-related activations in afferent pain regions and limbic structures. If future studies will address the technical and methodological challenges of today's experiments, neuroimaging might have the potential of segregating the neural mechanisms of different treatment interventions and elucidate predictive and mediating factors for successful treatment outcomes. Evaluations of treatment-related brain changes (functional and structural) might also allow for sub-grouping of patients and help to develop individualized treatments.

The effect of dietary fatty acids on post-operative inflammatory response in a porcine model.

The potential anti-inflammatory effects of dietary fish oil (FO) have been studied in numerous clinical trials. However, variation in lifestyle and morbidity among patients can be difficult to control. In the present study, the impact of a 3-week dietary pre-treatment with 10% (w/w) FO (n 28), sunflower oil (SO, n 28), or animal fat (AF, n 28) was evaluated with respect to post-operative responses in inflammatory markers in a porcine model on aortic vascular prosthetic graft infection. In the early post-operative period (0 < day ≤ 3), FO suppressed whole blood IL-8 and tumor necrosis factor-α responsiveness to LPS stimulation, decreased peripheral leukocyte IL-8 mRNA abundance, reinforced an increase in total leukocyte count, and counteracted a decrease in mononuclear leukocyte count compared with SO. In the late post-operative period (3 < day ≤ 14), FO increased total leukocyte count and showed higher maximum CRP and haptoglobin concentrations compared with SO. Compared with AF, FO decreased peripheral leukocyte IL-8 mRNA abundance in the early post-operative period, and increased total leukocyte count and maximum CRP concentration in the late post-operative period. In conclusion, the post-operative response in a number of inflammatory markers was affected by FO, and this was most apparent compared with SO.

Effects of dietary n-3 and n-6 fatty acids on clinical outcome in a porcine model on post-operative infection.

The present study was performed to evaluate the effects of dietary n-3 and n-6 long-chain PUFA (LC-PUFA) on clinical outcome in a porcine model on early aortic vascular prosthetic graft infection (AVPGI). A total of eighty-four pigs were randomised to a 35 d dietary treatment with 10 % (w/w) fish oil (rich in n-3 LC-PUFA), sunflower oil (rich in n-6 LC-PUFA) or animal fat. After 3 weeks of dietary treatment, the pigs had an aortic vascular prosthetic graft inserted, and it was inoculated with Staphylococcus aureus (106 colony-forming units). Changes in selected plasma and erythrocyte n-3 and n-6 LC-PUFA concentrations and in plasma PGE2 metabolite concentration were determined in the 3-week preoperative period. Clinical signs of infection, i.e. rectal temperature, hindquarter function, general appearance and feed intake, were monitored daily in the 14 d post-operative period, and, finally, daily body-weight gain was determined in both periods. The preoperative changes in plasma and erythrocyte n-3 and n-6 LC-PUFA concentrations reflected the fatty acid compositions of the dietary treatments given, and plasma PGE2 metabolite concentration decreased in the fish oil treatment (P < 0·001). In the post-operative period, feed intake (P = 0·004) and body-weight gain (P = 0·038) were higher in the fish oil treatment compared with the sunflower oil treatment. The dietary treatments did not affect the number of days pigs were showing fever, weakness in the hindquarters or impaired general appearance. In conclusion, preoperative treatment with dietary fish oil compared with sunflower oil improved clinical outcome in pigs with AVPGI by improving feed intake and body-weight gain post-operatively.

Imaging the functional connectivity of the Periaqueductal Gray during genuine and sham electroacupuncture treatment.

BACKGROUND: Electroacupuncture (EA) is currently one of the most popular acupuncture modalities. However, the continuous stimulation characteristic of EA treatment presents challenges to the use of conventional functional Magnetic Resonance Imaging (fMRI) approaches for the investigation of neural mechanisms mediating treatment response because of the requirement for brief and intermittent stimuli in event related or block designed task paradigms. A relatively new analysis method, functional connectivity fMRI (fcMRI), has great potential for studying continuous treatment modalities such as EA. In a previous study, we found that, compared with sham acupuncture, EA can significantly reduce Periaqueductal Gray (PAG) activity when subsequently evoked by experimental pain. Given the PAG's important role in mediating acupuncture analgesia, in this study we investigated functional connectivity with the area of the PAG we previously identified and how that connectivity was affected by genuine and sham EA. RESULTS: Forty-eight subjects, who were randomly assigned to receive either genuine or sham EA paired with either a high or low expectancy manipulation, completed the study. Direct comparison of each treatment mode's functional connectivity revealed: significantly greater connectivity between the PAG, left posterior cingulate cortex (PCC), and precuneus for the contrast of genuine minus sham; significantly greater connectivity between the PAG and right anterior insula for the contrast of sham minus genuine; no significant differences in connectivity between different contrasts of the two expectancy levels. CONCLUSIONS: Our findings indicate the intrinsic functional connectivity changes among key brain regions in the pain matrix and default mode network during genuine EA compared with sham EA. We speculate that continuous genuine EA stimulation can modify the coupling of spontaneous activity in brain regions that play a role in modulating pain perception.

Retropharyngeal tendinitis may be more common than we think: a report on 45 cases seen in Danish chiropractic clinics.

OBJECTIVE: This study presents information from 45 cases of retropharyngeal tendinitis that were collected in Danish chiropractic clinics. METHODS: A practicing Danish chiropractor collected cases of retropharyngeal tendinitis from colleagues who were members of the Danish Society of Chiropractic and Clinical Biomechanics. Only cases where a patient history of acute severe neck pain, cervical stiffness, and dysphagia were considered, and these were supplemented with imaging in the form of x-rays, computed tomography, or magnetic resonance imaging scans. All cases were reviewed independently by the chiropractor and a medical radiologist with a specialty in musculoskeletal disorders before acceptance into this case series. RESULTS: Forty-five cases fulfilled the inclusion criteria and were included in this review. Sixteen of these were recruited from a single chiropractic practice. Nineteen were males and 26 were females with an average age of 48 years. All but 2 patients had the characteristic depositions of calcium hydroxyapatite in the tendon of the longus colli muscle, and the average diameter of the retropharyngeal space was 8.1 mm. CONCLUSIONS: Patients presenting with a triad of acute severe neck pan, stiff neck, and dysphagia may have retropharyngeal tendinitis. This condition may be a more common than previously thought among patients presenting with acute neck pain in the primary health care sector.

Escherichia coli post-weaning diarrhoea occurrence in piglets with monitored exposure to creep feed.

The objective of the study was to investigate the effect of offering supplementary creep feed to piglets during the suckling period on the faecal shedding of haemolytic Escherichia coli bacteria and occurrence of spontaneous post-weaning diarrhoea 0-5 days after weaning. Supplementary creep feed was offered to half of the piglets in 12 litters, from 2 weeks of age until weaning at 4 weeks, and the individual feed contact was recorded by direct observations. It was found that diarrhoea occurrence was associated with faecal shedding of haemolytic E. coli bacteria (p=0.003), specifically E. coli O149 (p=0.004). Occurrence of diarrhoea and faecal shedding of haemolytic E. coli was not associated with creep feeding per se. However, the faecal E. coli O149 shedding occurred significantly less often in piglets that were offered creep feed in the suckling period but only showed limited interest in the feed (i.e. contacted the feed less than or equal to the median level of contact) compared to piglets that had frequent creep feed contact or piglets that had not had access to creep feed at all (p=0.015). Correspondingly, the diarrhoea occurrence tended to be lower in these piglets (p=0.081). Piglets with low creep feed contact during the suckling period ate the same total amount of feed during the 5 days after weaning, however, they ate less feed on days 0-2 after weaning compared to the piglets with frequent creep feed contact and non-creep fed piglets. It is suggested that intestinal function associated with a voluntary low creep feed contact during the suckling period leads to decreased feed intake just after weaning, and thus reduces the intestinal proliferation of E. coli O149 in these piglets.