Oral cannabidiol (CBD) as add-on to paracetamol for painful chronic osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial.

Background: Painful knee osteoarthritis (KOA) is common, pharmacological treatment, however, is often hampered by limited tolerability. Cannabidiol, which preclinically showed anti-inflammatory, analgesic activity, could supplement established analgesics, but robust clinical trials are lacking. The aim of our study was to investigate the effects of oral high-dose CBD administered over 8 weeks on pain, function and patient global assessment as an add-on to continued paracetamol in chronic symptomatic KOA. Methods: Prospective, randomized, placebo-controlled, double-blind, parallel-group study. Single center, Outpatient Clinic, Department of Special Anaesthesia and Pain Therapy at Medical University of Vienna, Austria. Eligibility criteria included: age: 18-98 years; painful KOA; score ≥5 on the pain subscale of the Western Ontario and McMasters Universities Osteoarthritis (WOMAC) Index; KOA confirmed by imaging. Participants were on continued dosage of paracetamol 3 g/d and randomly assigned by web-based software 1:1 to oral cannabidiol 600 mg/d (n = 43) or placebo (n = 43). Study period: 8 weeks. Primary outcome: Change in WOMAC pain subscale scores (0 = no pain, 10 = worst possible pain) from baseline to week 8 of treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04607603. Trial is completed. Findings: The trial was conducted from October 1, 2020 to March 29, 2022. 159 patients screened, 86 randomized. Among 86 participants (mean age, 62.8 [SD 20.3] years; 60 females [69.8%]), 58 (67.4%) completed the trial. Mean baseline WOMAC pain subscale was 6.0 ± 1.1. Analysis: Intention-to-treat principal. Mean reduction in WOMAC pain subscale was 2.5 (95% CI: 1.8-3.3) in the cannabidiol group and 2.4 (95% CI: 1.7-3.2) in the placebo group with no significant group difference (p = 0.80). Adverse events were significantly more frequent with cannabidiol (cannabidiol: 135 [56%]; placebo: 105 [44%]) (p = 0.008). Rise above baseline of liver aminotransferases and gamma-glutamyltransferase was significantly more common in the cannabidiol (n = 15) than the placebo group (n = 5) (p = 0.02). Interpretation: In KOA patients, oral high-dose add-on cannabidiol had no additional analgesic effect compared to adding placebo to continued paracetamol. Our results do not support the use of cannabidiol as an analgesic supplement in KOA. Funding: Trigal Pharma GmbH.

Effect of Regular Electrotherapy on Spinal Flexibility and Pain Sensitivity in Patients with Chronic Non-Specific Neck Pain and Low Back Pain: A Randomized Controlled Double-Blinded Pilot Trial.

Background and Objectives: Chronic neck pain and low back pain are common conditions in high-income countries leading to social and medical problems such as invalidity and decreased quality of life. The aim of this study was to investigate the effect of supra-threshold electrotherapy on pain level, subjective feeling of disability, and spinal mobility in patients with chronic pain in the spinal cord. Materials and Methods: 11 men and 24 women with a mean age of 49 years were randomly divided into three groups: group 1, "therapy": supra-threshold electrotherapy was applied on the whole back after electrical calibration; group 2, "control": electrical calibration without successive electrotherapy; group 3, "control of control": no stimulation. Sessions were performed once a week and six times in total, each lasting 30 min. The numeric pain rating scale (NRS), cervical and lumbar range of motion (ROM), as well as disability in daily live were investigated before and after the sessions using questionnaires (Neck Disability Index, Roland Morris Questionnaire, Short-form Mc Gill Pain Questionnaire (SF-MPQ)). Results: Spinal mobility improved significantly in the lumbar anteflexion (baseline mean, 20.34 ± SD 1.46; post session mean, 21.43 ± SD 1.95; p = 0.003) and retroflexion (baseline mean, 13.68 ± SD 1.46; post session mean, 12.05 ± SD 1.37; p = 0.006) in the group receiving electrotherapy. Pain levels measured by the NRS and disability-questionnaire scores did not differ significantly before and after treatment in any of the groups. Conclusions: Our data indicate that regular supra-threshold electrotherapy for six times has a positive effect on lumbar flexibility in chronic neck pain and low back pain patients, whereas pain sensation or subjective feeling of disability remained unchanged.

Correlation between the Neuropathic PainDETECT Screening Questionnaire and Pain Intensity in Chronic Pain Patients.

Background and Objectives: Pain is a multidimensional phenomenon with a wide range regarding the location, intensity and quality. Patients with chronic pain, in particular those suffering from mixed pain, often present a special challenge. The PainDETECT questionnaire (PD-Q) is a screening instrument designed to classify whether a patient has neuropathic pain (NP), often rated as more distressing compared to nociceptive pain. The objective of this study was to investigate whether the PD-Q score correlates with pain intensity, measured with the numeric rating scale (NRS), in chronic pain patients in an outpatient setting. Materials and Methods: A questionnaire-based study was conducted to identify the associations between the unidimensional NRS scale for pain intensity and the PD-Q score for screening of an NP component in an outpatient setting. Participants were asked to fill in the questionnaire themselves. Results: One hundred seventy-six participants completed the PD-Q questionnaire and rated pain on the NRS scale at the baseline visit. The PD-Q and NRS scores significantly correlated at the baseline visit and the 1-month follow-up visit in chronic pain patients. The identification of a neuropathic component in chronic pain may permit more targeted and effective pain management. Conclusions: The findings of our questionnaire suggest that a significant proportion of chronic pain patients had manifested features of NP at the first visit to the outpatient clinic. The PD-Q is a useful screening tool to alert clinicians of NP that may need further diagnostic evaluation or therapeutic intervention and may also help to predict treatment response. Further research is needed to investigate if a correlation is predictive of treatment response when pain therapy targets NP.

Brief High Oxygen Concentration Induces Oxidative Stress in Leukocytes and Platelets: A Randomized Cross-over Pilot Study in Healthy Male Volunteers.

BACKGROUND: Supplemental oxygen is administered routinely in the clinical setting to relieve or prevent tissue hypoxia, but excessive exposure may induce oxidative damage or disrupt essential homeostatic functions. It is speculated that oxidative stress in leukocytes and platelets may contribute to vascular diseases by promoting inflammation and cell aggregation. METHODS: In this pilot study 30 healthy male volunteers (18-65 years) were exposed to high oxygen concentration (non-rebreather mask, 8 L/min, 100% O2) and synthetic air (non-rebreather mask, 8 L/min, 21% O2) in a cross-over design for 20 min at a 3-week interval. Venous blood samples were obtained at baseline and 1, 3, and 6 h postintervention. Primary outcome was generation of reactive oxygen species in leukocytes as measured by the redox-sensitive fluorescent dye dihydrorhodamine 123. Additional outcomes were oxidative stress in platelets and platelet aggregation as measured by thromboelastography (ROTEM) and Multiplate analyses. FINDINGS: High oxygen exposure induced oxidative stress in leukocytes as evidenced by significantly higher mean fluorescence intensity (MFI) compared with synthetic air at 3 h postintervention (47% higher, P = 0.015) and 6 h postintervention (37% higher, P = 0.133). Oxidative stress was also detectable in platelets (33% higher MFI in comparison with synthetic air at 6 h, P = 0.024; MFI 20% above baseline at 3 h, P  = 0.036; 37% above baseline at 6 h, P = 0.002). ROTEM analyses demonstrated reduced mean clotting time 1 h postintervention compared with baseline (-4%, P = 0.049), whereas there were no significant effects on other surrogate coagulation parameters. CONCLUSION: Clinically relevant oxygen exposure induces oxidative stress in leukocytes and platelets, which may influence the immune and clotting functions of these cells.

Efficacy of Duloxetine in Chronic Low Back Pain with a Neuropathic Component: A Randomized, Double-blind, Placebo-controlled Crossover Trial.

BACKGROUND: Among patients with chronic low back pain (CLBP), approximately 37% show signs of a neuropathic pain component (radicular pain). Treatment of this condition remains challenging. Therefore, the current study aimed to investigate the efficacy of duloxetine in the treatment of CLBP patients with neuropathic leg pain. METHODS: The study was conducted as a prospective, randomized, placebo-controlled, double-blind crossover trial. CLBP with a visual analog scale (VAS) score greater than 5 and a neuropathic component that was assessed clinically and by the painDETECT questionnaire (score > 12) were required for inclusion. Patients were randomly assigned to either duloxetine or placebo for 4 weeks followed by a 2-week washout period before they crossed over to the alternate phase that lasted another 4 weeks. Duloxetine was titrated up to 120 mg/day. The primary outcome parameter was mean VAS score during the last week of treatment in each phase (VAS(week4)). RESULTS: Of 41 patients, 21 patients completed both treatment phases. In the intention-to-treat analysis (n = 25), VAS(week4) was significantly lower in the duloxetine phase compared with placebo (4.1 ± 2.9 vs. 6.0 ± 2.7; P = 0.001), corresponding to an average pain reduction of 32%. The painDETECT score at the end of each treatment phase was significantly lower in the duloxetine phase compared with placebo (17.7 ± 5.7 vs. 21.3 ± 3.6 points; P = 0.0023). Adverse events were distributed equally between the duloxetine (65%) and placebo phases (62%) (P = 0.5). CONCLUSION: In this crossover study, duloxetine proved to be superior to placebo for the treatment of CLBP with a neuropathic leg pain.

Expression of telomeres in astrocytoma WHO grade 2 to 4: TERRA level correlates with telomere length, telomerase activity, and advanced clinical grade.

Cancer cells bypass replicative senescence, the major barrier to tumor progression, by using telomerase or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms (TMMs). Correlation between ALT and patient survival was demonstrated for high-grade astrocytomas. Transcription from subtelomeres produces telomeric repeat-containing RNA (TERRA), a natural inhibitor of telomerase activity (TA). This led us to evaluate correlations of TERRA and TMM with tumor grade and outcome in astrocytoma patients. SYBR Green real-time reverse transcription-polymerase chain reaction assays for quantitation of total and chromosome 2p and 18p specific TERRA levels were developed. Tumor samples from 46 patients with astrocytoma grade 2 to 4, tissue controls, and cell lines were assessed. TMMs were evaluated by measuring TA and by detecting long telomeres due to ALT. In glioblastoma multiforme (GBM) grade 4, total TERRA levels were similar to cell lines but 14-, 31-, and 313-fold lower compared with grade 3, grade 2, and nonmalignant tissue, respectively. Total TERRA levels differed from chromosomal levels. Low 2p TERRA levels correlated with dense promoter methylation of subtelomeric CpG islands, indicating that TERRA expression in gliomas may be chromosome specific and epigenetically regulated. Total TERRA levels correlated with diagnosis, with low or absent TA and the presence of ALT, and were tentatively associated with favorable patient prognosis in our cohort (P = .06). TA and short telomeres identified a subset of GBM with a median survival of only 14.8 months. TERRA and TA may be prognostic in astrocytic tumors.

Sex-specific prevalence of adenomas, advanced adenomas, and colorectal cancer in individuals undergoing screening colonoscopy.

CONTEXT: Although some studies have shown that men are at greater age-specific risk for advanced colorectal neoplasia than women, the age for referring patients to screening colonoscopy is independent of sex and usually recommended to be 50 years. OBJECTIVE: To determine and compare the prevalence and number needed to screen (NNS) for adenomas, advanced adenomas (AAs), and colorectal carcinomas (CRCs) for different age groups in men and women. DESIGN, SETTING, AND PATIENTS: Cohort study of 44,350 participants in a national screening colonoscopy program over a 4-year period (2007 to 2010) in Austria. MAIN OUTCOME MEASURES: Prevalence and NNS of adenomas, AAs, and CRCs in different age groups for men and women. RESULTS: The median ages were 60.7 years (interquartile range [IQR], 54.5-67.5 years) for women and 60.6 years (IQR, 54.3-67.6 years) for men, and the sex ratio was nearly identical (51.0% [22,598] vs 49.0% [21,572]). Adenomas were found in 19.7% of individuals screened (95% CI, 19.3%-20.1%; n = 8743), AAs in 6.3% (95% CI, 6.1%-6.5%; n = 2781), and CRCs in 1.1% (95% CI, 1.0%-1.2%; n = 491); NNS were 5.1 (95% CI, 5.0-5.2), 15.9 (95% CI, 15.4-16.5), and 90.9 (95% CI, 83.3-100.0), respectively. Male sex was significantly associated with a higher prevalence of adenomas (24.9% [95% CI, 24.3%-25.4%] vs 14.8% [95% CI, 14.3%-15.2%]; P < .001; unadjusted odds ratio [OR], 1.9 [95% CI, 1.8-2.0]), AAs (8.0% [95% CI, 7.6%-8.3%] vs 4.7% [95% CI, 4.4%-4.9%]; P < .001; unadjusted OR, 1.8 [95% CI, 1.6-1.9]), and CRCs (1.5% [95% CI, 1.3%-1.7%] vs 0.7% [95% CI, 0.6%-0.9%]; P < .001; unadjusted OR, 2.1 [95% CI, 1.7-2.5]). The prevalence of AAs in 50- to 54-year-old individuals was 5.0% (95% CI, 4.4%-5.6%) in men but 2.9% (95% CI, 2.5%-3.4%) in women (adjusted P = .001); the NNS in men was 20 (95% CI, 17.8-22.6) vs 34 in women (95% CI, 29.1-40; adjusted P = .001). There was no statistical significance between the prevalence and NNS of AAs in men aged 45 to 49 years compared with women aged 55 to 59 years (3.8% [95% CI, 2.3%-6.1%] vs 3.9% [95% CI, 3.3%-4.5%] and 26.1 [95% CI, 16.5-44.4] vs 26 [95% CI, 22.5-30.2]; P = .99). CONCLUSION: Among a cohort of Austrian individuals undergoing screening colonoscopy, the prevalence and NNS of AAs were comparable between men aged 45 to 49 years and women aged 55 to 59 years.

von Willebrand factor antigen: a novel on-treatment predictor of response to antiviral therapy in chronic hepatitis C genotypes 1 and 4.

BACKGROUND: Levels of von Willebrand factor antigen (vWF-Ag) increase during combination antiviral therapy of chronic hepatitis C (CHC). The present study investigates the association between these changes in vWF-Ag levels and response to treatment. METHODS: Changes in levels of vWF-Ag on antiviral combination treatment in 184 patients with CHC genotype 1 or 4 infections were measured prospectively and effect on response was studied. RESULTS: High on-treatment levels of vWF-Ag were associated with relapse (P<0.01) and low on-treatment levels with sustained virological response (SVR). Receiver operating characteristic curve analysis showed that vWF-Ag levels of <300% at week 12 of therapy have a positive predictive value (PPV) of 78% for SVR. In early virological response (EVR) patients, the PPV of vWF-Ag levels <300% at week 12 was 74%. An even higher PPV of 88% in complete EVRs (undetectable HCV RNA at week 12) was observed for the same cutoff value at week 12. CONCLUSIONS: On-treatment levels of vWF-Ag can be utilized as an additional predictive marker for response to antiviral therapy. This is especially relevant in EVR patients because EVR alone only has a PPV of 58-72% on SVR, which increased to 74%, when factoring in vWF-Ag levels <300% at week 12, and to 88% in complete EVRs; therefore, measurement of vWF-Ag levels at week 12 is helpful. EVR patients that are above the cutoff values for vWF-Ag that make SVR very probable might profit from an extension of therapy to 72 weeks.