PSYCHO-EMOTIONAL ASPECTS IN THE FORMATION OF PAIN SYNDROME CHARACTERISTICS IN PATIENTS WITH MULTIPLE SCLEROSIS

Introduction: Pain syndromes, anxiety, and depression are common syndromes in multiple sclerosis (MS). Comorbidity of pain and depression or pain and anxiety exists in up to one-third of MS patients. Based on the biopsychosocial model of pain, given the high prevalence of these symptoms and their frequent combination in MS, which is significantly higher than in the general population, we can hypothesize the relationship between the characteristics of pain and anxiety and depression in patients with MS. Objectives: To assess the prevalence of anxiety and depression among MS patients with pain syndromes and analyze the relationship between anxiety and depression with pain syndromes' characteristics in patients with MS. Methods: Data were collected prospectively at Lviv Regional Multiple Sclerosis Center. 120 randomly selected patients with a confirmed diagnosis of multiple sclerosis were examined. 104 of them had pain syndromes during the last month. Complaints and medical history, analysis of medical records, neurological and general medical examination of the patients were collected. Depressive symptoms and anxiety were assessed in all patients using the Hospital Anxiety and Depression Scale (HADS) questionnaire. In patients with pain syndromes, the Visual analogue scale (VAS), Short-form McGill Pain Questionnaire 2 (SF-MPQ-2), Pain Detect were used to assess pain characteristics. Results: The levels of anxiety and depression were higher in the group of MS patients with pain. The level of anxiety was 9.0 [6,0; 12,75] in the group with pain and 7.0 [4,0; 9,25] in the group without pain (p=0.04). The level of depression was 7.0 [4,0; 10,0] in the group with pain and 4.0 [1,75; 6,0] in the group without pain (p<0,01). It was found that part of MS patients with pain syndromes with anxiety was 36.5%, and 29.8% had a subclinical level of anxiety; part of MS patients with pain syndromes with depression was 19.23%. The proportion of patients with anxiety was highest in patients with neuropathic pain: 56.3% ± 8.8% vs. 22.4% ± 6.0% with nociceptive, p<0.01. A similar situation is observed in patients with depression. The share of patients with depression was higher in the group with neuropathic pain 37.5% ± 8.6%, compared to 14.3% ± 5.0% with nociceptive, p=0.02. The proportion of patients with MS without signs of anxiety and depression is significantly higher among patients with nociceptive pain (p<0,05). Also, the correlational relationship between the level of anxiety and depression with the level of the neuropathic type of pain manifestation was found (r=0,40; p<0,01 and r=0,30; p<0,01). Levels of anxiety and depression correlated with the average pain intensity per month (r = 0,21; p=0,03) and did not have a statistically significant relationship with pain intensity at the time of examination and the strongest pain for the last month. The anxiety and depression had correlations with all components of the structure of pain syndromes (according to sfMPQ-2), but the most pronounced direct correlation was found between anxiety and the affective component of pain (r=0,57; p<0,01). It was also found that the level of anxiety was proved to be higher in patients who have 2-3 pain syndromes, than in patients with one pain syndrome: 12.0 [8,0; 14,0] points against 8.0 [5,0; 11,0] points, p<0.01. Besides, this localization of pain in the arms, shoulders and back was related to higher levels of anxiety (r=0.22; p=0.03). Conclusion: Pain syndromes, anxiety, and depression are widespread among patients with MS and there is a relationship between them. MS patients with pain have higher levels of anxiety and depression than MS patients without pain. It is also noteworthy that among MS patients with pain syndromes, high levels of anxiety are detected. Anxiety and depression also have a pronounced relationship with a neuropathic component of pain in patients with MS. Besides this, the presence of more than one pain syndrome, high average pain intensity per month is associated with higher levels of anxiety and depression. The localization of pain in the arms, shoulders and back is related to higher anxiety levels. These discoveries, combined with modern neuroimaging technologies used in the next step of our study, will provide a better understanding of both pain and its structure, as well as anxiety and depression

Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial

Background Low-dose naltrexone (LDN) is used widely as an off-label treatment for pain despite limited evidence for its effectiveness. A few small trials with a high risk of bias have investigated the effect of LDN on pain associated with fibromyalgia in women, but larger and more methodologically robust studies are needed. The primary aim of this randomized controlled trial is to investigate if 12 weeks of LDN treatment is superior to placebo in reducing the average pain intensity during the last 7 days in women with fibromyalgia. Methods A single-center, permuted block randomized, double-blind, placebo-controlled, parallel-group trial will be performed in Denmark. Randomization comprises 100 women aged 18–64 years diagnosed with fibromyalgia who will be treated with either LDN or placebo for 12 weeks including a 4-week titration phase. The primary outcome is change in average pain intensity (during the last 7 days) from baseline to 12 weeks. Secondary outcomes are other fibromyalgia-related symptoms, i.e., tenderness, fatigue, sleep disturbance, stiffness, memory problems, depression, anxiety and measures of global assessment, physical function, impact of fibromyalgia, pain distribution, and health-related quality of life. Intention-to-treat analysis will be performed, and the number of responders with a more than 15%, 30%, and 50% improvement of pain after 12 weeks will be calculated for the LDN and placebo groups. Exploratory outcomes include measures of pain sensitivity, muscle performance, and biomarkers. Discussion This study will contribute with high-level evidence on the efficacy of low-dose naltrexone for the treatment of pain in women with fibromyalgia. Secondary outcomes include both disease-specific and generic components investigating whether LDN influences other symptoms than pain. Explorative outcomes are included to provide greater insight into the mechanism of action of LDN and possibly a better understanding of the underlying pathology in fibromyalgia. Trial registration EudraCT 2019-000702-30. Registered on 12 July 2019. ClinicalTrials.gov NCT04270877. Registered on 17 February 2020

Capsaicin 8% Patch and Chronic Postsurgical Neuropathic Pain

(1) Background: Surgery is a frequent cause of persistent pain, defined chronic post-surgical pain (CPSP). The capsaicin 8% patch (Qutenza®) is approved for the treatment of postherpetic neuralgia (PHN) and for diabetic peripheral neuropathy (DPN) of the feet. We propose a review of the literature on use of the capsaicin 8% patch to treat neuropathic pain associated with surgery; (2) Methods: We identified the articles by searching electronic databases using a combination of such terms as “capsaicin 8% patch”, “Qutenza®”, and “chronic postsurgical pain”; (3) Results: We identified 14 selected studies reporting on a total of 632 CPSP cases treated with capsaicin 8% patch. Treatment with the capsaicin 8% patch significantly reduced the average pain intensity. Only 5 studies reported adverse events (AEs) after the patch application. The most common AEs were erythema, burning sensation and pain; (4) Conclusions: Our review indicate that capsaicin 8% patch treatment for CPSP is effective, safe and well tolerated, but randomized controlled trials on efficacy, safety and tolerability should be conducted.

Structural and functional biomarkers of efficacy of navigated repetitive transcranial magnetic stimulation in therapy for trigeminal neuralgia

Repetitive transcranial magnetic stimulation (rTMS) is an alternative treatment option for patients with drug-resistant trigeminal neuralgia (TN). However, the effect of rTMS is variable. The aim of this study was to find neuroimaging biomarkers of clinical efficacy of navigated rTMS. Seventeen patients with TN (14 women and 3 men, median age 56 years) received 10 sessions of high-frequency rTMS of the motor cortex contralateral to pain side. The data were analyzed for correlations between functional connectivity (FC), the grey matter (GM) volume and the reduction in pain intensity. Positive correlations were established between the reduction in average pain intensity and GM volume in caudate nuclei in both hemispheres (p(unc) = 0.03), both cerebellar hemispheres (p(unc) = 0.002) and the postcentral gyrus contralateral to pain side (p(unc) = 0.005); between the reduction in peak pain intensity and GM volume in the caudate nucleus contralateral to pain side (p(unc) = 0.04) and the cerebellar hemisphere ipsilateral to pain (p(unc) = 0.03). Significant positive correlations were discovered between the reduction in average pain intensity and FC between the thalamus contralateral to pain side, the postcentral gyrus and the insular operculum (both ipsilateral to pain side; (p(FWE) = 0.018), as well as between the cingulate cortex and the anterior cingulate cortex ipsilateral to pain (p(FWE) = 0.017), between the contralateral subcallosal gyrus and the cerebellar hemisphere ipsilateral to pain (p(FWE) = 0.018). A negative correlation was established for FC between the contralateral putamen and the occipital lobes in both hemispheres (p(FWE) = 0.001). Our findings may spur the development of individual predictors of rTMS efficacy in patients with chronic pain.

Impact of treatment dose on patient outcomes after Interdisciplinary Multimodal Pain Therapy

Objectives The impact of duration and intensity on outcomes after Interdisciplinary Multimodal Pain Therapy (IMPT) is poorly researched. The aim of this study was to compare the effects of low dose (LD, avg. 25 hours) and high dose IMPT (HD, avg. 110 hours).Methods Patients completed pain-related questionnaires at the beginning (T1), at the end of therapy (T2) and at 3-month follow-up (T3) and were matched according to age, sex, presence of back-pain and pain-related disability at T1, resulting in 32 patients per group. Primary endpoint was the difference in pain-related disability and average pain intensity at T3 between both groups. In addition, early treatment effects and group differences at T2 were analyzed.Results Both groups showed significant improvements in pain-related disability and average pain intensity between T1 and T2. These positive effects persisted in the HD group until the 3-month follow-up, whereas outcomes in the LD group patients deteriorated and were significantly poorer compared to HD at T3.Discussion Within a widely comparable therapeutic setting, high-dose IMPT was associated with longer lasting improvements compared to low-dose IMPT in chronic pain patients, indicating that the “dose” of therapy is a relevant factor for clinical outcomes and should be further investigated.

Leriche Syndrome Misdiagnosed as Complex Regional Pain Syndrome in a Patient with Neuropathic Pain Caused by a Chip Fracture: A Case Report

Introduction: Leriche syndrome is an aortoiliac occlusive disease caused by atherosclerotic occlusion. We report a case of Leriche syndrome with a fracture that was suspected as complex regional pain syndrome (CRPS), as the post-traumatic pain gradually worsened in the form of excruciating neuropathic pain. Case Report: A 52-year-old woman with a history of hypertension was referred to the Department of Pain Medicine from a local orthopedic clinic because of suspected CRPS for excruciating neuropathic pain for one month. She complained of gait dysfunction and severe pain in the right foot following an incident of trauma with the right first toe. The average pain intensity assessed using the visual analog scale (VAS) was 90 (0: no pain, 100: the worst pain imaginable), and the neuropathic pain was evident as a score of 6/10 on Douleur neuropathique 4. Allodynia, hyperalgesia, blue discoloration of the skin, asymmetric temperature change (1.38 °C), and edematous soft tissue changes were observed. Ultrasonography showed a chip fracture in the first distal phalanx of the right first toe. The diagnosis was most probably CRPS type I according to the Budapest research criteria for CRPS. However, multiple pain management techniques were insufficient in controlling the symptoms. A month and a half later, an ankle-brachial index score of less than 0.4 suggested severe peripheral artery disease. Computed tomography angiography showed total occlusion between the infrarenal abdominal aorta and the bilateral common iliac arteries. Therefore, she underwent aortic-bifemoral bypass surgery with a diagnosis of Leriche syndrome. Three months after the surgery, the average pain intensity was graded as 10 on the VAS (0–100), the color of the skin of the right first toe improved and no gait dysfunction was observed. Conclusion: A chip fracture in a region with insufficient blood flow could manifest as excruciating neuropathic pain in Leriche syndrome.

Progressive Response to Repeat Application of Capsaicin 179 mg (8% w/w) Cutaneous Patch in Peripheral Neuropathic Pain: Comprehensive New Analysis and Clinical Implications

Objective To investigate efficacy of repeated application of capsaicin 179 mg cutaneous patch in non-responders to the first application. Design Post hoc, as-treated analysis of two prospective trials (STRIDE and PACE) with 52-week follow-up. Blinding Open-label. Setting Multicenter clinical trial. Subjects STRIDE: non-diabetic neuropathic pain; PACE: painful diabetic peripheral neuropathy. Methods Patients were divided according to number of applications needed before ≥30% response on average pain intensity (question 5 of the Brief Pain Inventory [BPI-Q5]). We assessed change from baseline in average pain intensity (BPI-Q5), mean ‘interference with sleep’ score, Patient Global Impression of Change, quality of life (QOL) using EuroQol 5-dimension, and Self-Assessment of Treatment. Results In STRIDE and PACE, respectively, n = 306/313 received capsaicin patch; n = 60/96 had a response after the first application, n = 33/68 after the second, n = 11/43 after the third. Among patients without a ≥ 30% reduction in pain intensity at 3 months, 23.3%/28.1% achieved a ≥ 30% reduction at 6 months, increasing to 33.9%/45.7% at 12 months. Similar results were obtained using a decrease of ≥ 50% as responder definition. Progressive improvements in pain intensity in slower responders reached similar levels as those in early responders at month 12 and were accompanied by improvements in sleep, QOL, and patient satisfaction. Conclusions While some patients with peripheral neuropathic pain experience rapid improvements with a single treatment of capsaicin 179 mg patch, some may require two or three treatments before an initial response is observed. Similar benefits on pain, sleep, and QOL can be achieved in early and late responders.

Low dose naltrexone for the treatment of fibromyalgia: Protocol for a double-blind, randomized, placebo-controlled trial

Background Low dose naltrexone (LDN) is used widely as off-label treatment for pain despite limited evidence for its effectiveness. A few small trials with high risk of bias have investigated the effect of LDN on pain associated with fibromyalgia in women, but larger and more methodologically robust studies are needed. The primary aim of this randomized controlled trial is to investigate if 12 weeks of LDN treatment is superior to placebo in reducing the average pain intensity during the last seven days in women with fibromyalgia.Methods A single-center, permuted block randomized, double-blind, placebo-controlled, parallel-group trial will be performed in Denmark. Randomization comprises 100 women aged 18–64 years and diagnosed with fibromyalgia who will be treated with either LDN or placebo for 12 weeks including a four-week titration phase. The primary outcome is change in average pain intensity (during the last seven days) from baseline to 12 weeks. Secondary outcomes are other fibromyalgia-related symptoms, i.e. tenderness, fatigue, sleep disturbance, stiffness, memory problems, depression, anxiety and measures of global assessment, physical function, impact of fibromyalgia, pain distribution, and health-related quality of life. Intention-to-treat analysis will be performed, and the number of responders with a more than 15%, 30%, and 50% improvement of pain after 12 weeks will be calculated for the LDN and placebo groups. Exploratory outcomes include measures of pain sensitivity, muscle performance, and biomarkers.Discussion This study will contribute with high-level evidence on the efficacy of low dose naltrexone for the treatment of pain in women with fibromyalgia. Secondary outcomes include both disease-specific and generic components investigating whether LDN influences other symptoms than pain. Explorative outcomes are included to provide greater insight into the mechanism of action of LDN and possibly a better understanding of the underlying pathology in fibromyalgia.Trial registration: EudraCT number 2019-000702-30 (registered on 2019-07-12). ClincalTrials.gov Identifier: NCT04270877 (registered on 2020-02-17).

A prospective cohort register-based study of chronic postsurgical pain and long-term use of pain medication after otorhinolaryngological surgery

Data on chronic postsurgical pain (CPSP) after otorhinolaryngological surgery are sparse. Adult in-patients treated in 2017 were included into the prospective PAIN OUT registry. Patients’ pain on the first postoperative day (D1), after six months (M6) and 12 months (M12) were evaluated. Determining factor for CPSP was an average pain intensity ≥ 3 (numeric rating scale 0–10) at M6. Risk factors associated with CPSP were evaluated by univariate and multivariate analyses. 10% of 191 included patients (60% male, median age: 52 years; maximal pain at D1: 3.5 ± 2.7), had CPSP. Average pain at M6 was 0.1 ± 0.5 for patients without CPSP and 4.2 ± 1.2 with CPSP. Average pain with CPSP still was 3.7 ± 1.1 at M12. Higher ASA status (Odds ratio [OR] = 4.052; 95% confidence interval [CI] = 1.453–11.189; p = 0.007), and higher minimal pain at D1 (OR = 1.721; CI = 1.189–2.492; p = 0.004) were independent predictors of CPSP at M6. Minimal pain at D1 (OR = 1.443; CI = 1.008–2.064; p = 0.045) and maximal pain at M6 (OR = 1.665; CI = 1.340–2.069; p < 0.001) were independent predictors for CPSP at M12. CPSP is an important issue after otorhinolaryngological surgery. Better instrument for perioperative assessment should be defined to identify patients at risk for CPSP.

An 8-Week Self-Administered At-Home Behavioral Skills-Based Virtual Reality Program for Chronic Low Back Pain: Double-Blind, Randomized, Placebo-Controlled Trial Conducted During COVID-19

Background Chronic low back pain is the most prevalent chronic pain condition worldwide and access to behavioral pain treatment is limited. Virtual reality (VR) is an immersive technology that may provide effective behavioral therapeutics for chronic pain. Objective We aimed to conduct a double-blind, parallel-arm, single-cohort, remote, randomized placebo-controlled trial for a self-administered behavioral skills-based VR program in community-based individuals with self-reported chronic low back pain during the COVID-19 pandemic. Methods A national online convenience sample of individuals with self-reported nonmalignant low back pain with duration of 6 months or more and with average pain intensity of 4 or more/10 was enrolled and randomized 1:1 to 1 of 2 daily (56-day) VR programs: (1) EaseVRx (immersive pain relief skills VR program); or (2) Sham VR (2D nature content delivered in a VR headset). Objective device use data and self-reported data were collected. The primary outcomes were the between-group effect of EaseVRx versus Sham VR across time points, and the between–within interaction effect representing the change in average pain intensity and pain-related interference with activity, stress, mood, and sleep over time (baseline to end-of-treatment at day 56). Secondary outcomes were global impression of change and change in physical function, sleep disturbance, pain self-efficacy, pain catastrophizing, pain acceptance, pain medication use, and user satisfaction. Analytic methods included intention-to-treat and a mixed-model framework. Results The study sample was 179 adults (female: 76.5%, 137/179; Caucasian: 90.5%, 162/179; at least some college education: 91.1%, 163/179; mean age: 51.5 years [SD 13.1]; average pain intensity: 5/10 [SD 1.2]; back pain duration ≥5 years: 67%, 120/179). No group differences were found for any baseline variable or treatment engagement. User satisfaction ratings were higher for EaseVRx versus Sham VR (P<.001). For the between-groups factor, EaseVRx was superior to Sham VR for all primary outcomes (highest P value=.009), and between-groups Cohen d effect sizes ranged from 0.40 to 0.49, indicating superiority was moderately clinically meaningful. For EaseVRx, large pre–post effect sizes ranged from 1.17 to 1.3 and met moderate to substantial clinical importance for reduced pain intensity and pain-related interference with activity, mood, and stress. Between-group comparisons for Physical Function and Sleep Disturbance showed superiority for the EaseVRx group versus the Sham VR group (P=.022 and .013, respectively). Pain catastrophizing, pain self-efficacy, pain acceptance, prescription opioid use (morphine milligram equivalent) did not reach statistical significance for either group. Use of over-the-counter analgesic use was reduced for EaseVRx (P<.01) but not for Sham VR. Conclusions EaseVRx had high user satisfaction and superior and clinically meaningful symptom reduction for average pain intensity and pain-related interference with activity, mood, and stress compared to sham VR. Additional research is needed to determine durability of treatment effects and to characterize mechanisms of treatment effects. Home-based VR may expand access to effective and on-demand nonpharmacologic treatment for chronic low back pain. Trial Registration ClinicalTrials.gov NCT04415177; https://clinicaltrials.gov/ct2/show/NCT04415177 International Registered Report Identifier (IRRID) RR2-10.2196/25291