Human Studies

Fibromyalgia is a common chronic pain pathology with an incidence of 4.3 per 1000 person-years. An open, randomized clinical trial of patients with fibromyalgia comparing an immediate vs. delayed 18-day spa therapy in five spa therapy care facilities in France enrolled 220 patients. Randomization was in blocks of four, stratified by center, severity of fibromyalgia and previous spa therapy. Patients continued usual treatment. The main endpoint was the number of patients achieving minimal clinically important difference (MCID) at 6 months, defined as 14% change in their baseline fibromyalgia impact questionnaire (FIQ) score. The intention-to-treat analysis included 100 and 106 patients in the intervention and control groups, respectively. At 6 months, 45/100 (45.0%) and 30/106 (28.3%) patients in the intervention and control groups, respectively, achieved a MCID (p=0.013). There was also a significant improvement in pain, fatigue, and symptom severity (secondary outcomes) in the intervention group but not for generic quality of life (QOL), sleep or physical activity. None of the 33 serious adverse events reported by 25 patients were related to the spa therapy. Our results demonstrate the benefit of spa treatment in patients with fibromyalgia. PERSPECTIVE: A 12-month, open, randomized clinical trial of 220 patients with fibromyalgia compared an immediate vs. delayed (i.e. after 6 months) 18-day spa therapy. The results showed a clinically significant improvement at 6 months for those who received immediate therapy which was maintained up to 12 months. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02265029.

: Chronic low back pain (CLBP) is a major cause of disability globally. Stratified care has been proposed as a means to improve prognosis and treatment but is generally based on limited aspects of pain, including biopsychosocial drivers. : Following Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations, the present study explored pain phenotypes with a sample of workers with CLBP, a population for which no pain phenotypes have been derived to date. : A cross-sectional design was used with a sample of 154 workers with CLBP attending a rehabilitation clinic, recruited in person and from social media. Latent class analysis was used to identify subgroups of patients with different pain profiles based on ten pain indicators (pain variability, pain intensity, pain quality, somatization, sleep quality, depression, fatigue, pain catastrophizing, neuropathic pain, and central sensitization). : The majority of the sample (85%) were recruited through social media. Both the two-class and three-class solutions were found to be satisfactory in distinguishing phenotypes of workers with CLBP. Three variables proved particularly important in distinguishing between the pain phenotypes-pain quality, fatigue, and central sensitization-with higher scores on these indicators associated with pain phenotypes with higher pain burden. Increased chronic pain self-efficacy, work-related support, and perceived work abilities were protective risk factors for being in a higher pain burden class. : The present study is the first to explore IMMPACT recommendations for pain phenotyping with workers with CLBP. Future prospective research will be needed to validate the proposed pain phenotypes.

Chronic low back pain (CLBP) is highly disabling, but often without identifiable source. Focus has been on impaired anti-nociceptive mechanisms contributing to pain maintenance, though methods of targeting this impairment remain limited. This randomised-controlled cross-over pilot trial used active versus sham medial prefrontal cortex (mPFC) high-definition transcranial direct current stimulation (HD-tDCS) for three-consecutive days to improve descending pain inhibitory function. Twelve CLBP patients were included with an average visual analogue scale (VAS) pain intensity of 3.0±1.5 and pain duration of 5.3±2.6 years. Pressure pain thresholds (PPTs), conditioned pain modulation (CPM), and temporal summation of pain (TSP) assessed by cuff algometry, as well as pain symptomatology (intensity, unpleasantness, quality, disability) and related psychological features (pain catastrophizing, anxiety, affect), were assessed on Day1 before three consecutive days of HD-tDCS sessions (each 20 min), at 24-hours (Day4) and 2-weeks (Day21) following final HD-tDCS. Blinding was successful. No significant differences in psychophysical (PPT, CPM, TSP), symptomatology or psychological outcomes were observed between active and sham HD-tDCS on Day4 and Day21. CPM-effects at Day1 negatively correlated with change in CPM-effect at Day4 following active HD-tDCS (P=0.002). Lack of efficacy was attributed to several factors, not least that patients did not display impaired CPM at baseline. TRIAL REGISTRATION: : ClinicalTrials.gov (NCT03864822) PERSPECTIVE: Medial prefrontal HD-tDCS did not alter pain, psychological nor psychophysical outcomes, though correlational analysis suggested response may depend on baseline pain inhibitory efficacy, with best potential effects in patients with severe impairments in descending pain inhibitory mechanisms. Future work should focus on appropriate patient selection and optimising stimulation targeting.

Chronic postoperative pain is common after breast cancer surgery. Peri-operative lidocaine infusion may prevent the development of chronic postoperative pain, but a large-scale trial is required to test this hypothesis. It is unclear whether a pragmatic, multicentre trial design that is consistent with expert guidance, addresses the limitations of previous studies, and overcomes existing translational barriers is safe, effective and feasible. We conducted a double-blind, randomised controlled pilot study in 150 patients undergoing breast cancer surgery across three hospitals in Western Australia. Patients received lidocaine, or equivalent volumes of saline, as an intravenous bolus (1.5 mg.kg ) and infusion (2 mg.kg .h ) intra-operatively, and a subcutaneous infusion (1.33 mg.kg .h ) postoperatively for up to 12 h on a standard surgical ward, with novel safety monitoring tools in place. The co-primary outcomes were: in-hospital safety events; serum levels of lidocaine during intravenous and subcutaneous infusion; and annualised enrolment rates per site with long-term data capture. In-hospital safety events were rare, and similar in the placebo and lidocaine arms (3% vs. 1%). Median (IQR [range]) serum lidocaine levels during intravenous (2.16 (1.74-2.83 [1.12-6.06]) µg.ml , n = 41) and subcutaneous (1.52 (1.28-1.83 [0.64-2.85]) µg.ml , n = 48) infusion were comparable with previous trials reporting improved pain outcomes. Annualised enrolment approximated 50 patients per site per year, with high levels of protocol adherence and ≥ 99% capture of outcomes at 3 and 6 months. The adjusted odds ratio (95%CI) for postoperative pain at 6 months in the lidocaine arm was 0.790 (0.370-1.684). We conclude that this trial, as designed, is safe, effective and feasible in patients undergoing breast cancer surgery, and a larger-scale trial is planned.

Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in the brain levels of the glial marker 18 kDa translocator protein (TSPO), and changes in functional connectivity. 25 cLBP patients (42.4 ± 13 years old; 13F, 12M) with chronic low back pain (cLBP) and 27 healthy control subjects (48.9 ± 13 years old; 14F, 13M) received an integrated (i.e., simultaneous) positron emission tomography (PET)/magnetic resonance imaging (MRI) brain scan with the second-generation TSPO ligand [C]PBR28. The relationship between [C]PBR28 signal and NA was assessed first with regression analyses against Beck Depression Inventory (BDI) scores in patients, and then by comparing cLBP patients with little-to-no, or mild-to-moderate depression against healthy controls. Further, the relationship between PET signal, BDI and frontolimbic functional connectivity was evaluated in patients with mediation models. PET signal was positively associated with BDI scores in patients, and significantly elevated in patients with mild-to-moderate (but not low) depression compared with controls, in anterior middle and pregenual anterior cingulate cortices (aMCC, pgACC). In the pgACC, PET signal was also associated with this region's functional connectivity to the dorsolateral PFC (pgACC-dlPFC), and mediated of the association between pgACC-dlPFC connectivity and BDI. These observations support a role for glial activation in pain-comorbid NA, identifying in neuroinflammation a potential therapeutic target for this condition.