The duration is 12 weeks, and mechanical heterogeneity index, pressure pain threshold (PPT), and pain intensity are measured at baseline, immediately after, 48 h after, and one week after treatment. Results: Statistically significant changes were immediately observed between the two groups: PPT decreased in the DN group (p = 0.05), while it increased in the IC group. At 48 h and one week after treatment, these values increased in the DN group and remained higher than in the IC group. The heterogeneity index improved in both groups but more significantly in the DN group than in the IC group. Conclusions: In subjects with CNP who had latent plus hyperalgesic MTrPs in the LS muscle, DN outperformed IC in PPT, pain intensity, and mechanical heterogeneity index at 48 h and one week after initiating therapy.Background: Chronic neck pain (CNP) may be associated with latent myofascial trigger points (MTrPs) in the levator scapulae (LS), which can be treated with ischemic compression (IC) and dry needling (DN). Variables and elastography changes are evaluated to compare the short-term efficacy of two treatments with DN. Methods: A randomized clinical trial is conducted with 80 participants in two groups: the DN group ( Chronic neck pain (CNP) is defined as localized pain that runs from the base of the skull to the first dorsal vertebra and is absent from the upper extremities . A totalTypically, 90% of cases are nonspecific, and the cause of the pathology is unknown in most populations . TherefoDue to its anatomical arrangement and design, the LS muscle may be the cause of chronic pain, as it has been proved that this muscle is constantly activated in many of the most common actions of daily life and can generate discomfort locally and even at a distance. This vital muscle in cervical statics also has an active role in the active component, as it must perform constant contraction in many movements since it can take a fixed point in the origin and its insertion; hence, it is a muscle responsible for CNP .MTrPs are the most sensitive points within a tight band of muscle fibers (“taut band”) that hurt when compressed and may also be accompanied by local and/or referred pain. MTrPs are not known as myofascial pain syndrome; instead, they are the cause of myofascial pain syndrome when active and are thought to cause a variety of sensory, motor, and autonomic symptoms ,4,5. TheAccording to recent studies, MTrPs are the initial indicator of muscular overload. However, in addition to affecting the musculoskeletal system, this disorder also interacts with the visceral somatic system, affects the central and peripheral neurological systems, overproduces inflammatory mediators, and alters microcirculation ,12,13,14Currently, the efficacy of IC and DN as MTrP treatments have been established ,16,17,18Gunn intramuscular stimulation technique .The most commonly used technique is Hong’s quick input–output method. REL has been demonstrated to disrupt motor endplate noise, producing an analgesic effect  and a faIn contrast to invasive techniques, noninvasive IC is one of the most recently used manual therapy techniques and is considered one of the most effective treatments for MPS . A theraThe imaging technique known as ultrasound elastography was initially introduced in the 1990s [After DN, the mechanical heterogeneity index measures changes in the characteristics of muscle tissue that correspond to modifications in the state of MTrPs.The aim was to measure several variables, assess changes at the elastography level, and compare the effectiveness of two potential short-term therapies for CNP.In order to determine the short- and medium-term effectiveness of DN and IC therapy sessions for the treatment of LS muscle MTrPs in patients with CNP, a single-blind, randomized, two-group, assessor-blinded clinical trial was conducted. The four variables under investigation were: range of motion (ROM), pressure pain threshold (PPT), quality of life, and pain intensity. Measurements were taken before, immediately after, 48 h, and one week after the therapy session. Only the quality-of-life survey was administered before and after treatment. Each participant read, comprehended, and signed an informed consent form before taking part in the study. The results’ publication was also approved by the authors.www.sergas.es) (accessed on 1 September 2023), each subject was randomized to either DN or CI. Because he or she was not the one giving the intervention to the patients, the researcher collecting the study data was likewise blinded.To achieve proper blinding, all study participants were randomly assigned before the session. Using the Epidat 3.1 program  the presence of a hypersensitive or hyperirritable point in the tension band; (II) patient reporting local or referred pain in the area of the latent MTrPs after mechanical stimulation; (III) the presence of a palpable tight band nodule in the LS muscle; (IV) patient reporting CNP for more than six weeks; and (V) signed informed consent forms.-Exclusion criteria were as follows: (I) cervical surgery; (II) patient with neurological disorder; (III) age under 18 years; (IV) systemic or local infection in the cervical herniated disc’s cervical region; (VI) cervical herniated discs; (VI) intake or injection of anticoagulant or antiplatelet medication; (VII) the presence of needle phobia (belonephobia); or (VIII) pregnancy.A two-group, randomized, single-blind clinical trial was conducted. This study examined the effectiveness of IC and DN therapies for latent MTrPs in the LS muscle in patients with CNP in conjunction with a sonoelastography examination. Additionally, the effectiveness of both treatments was hidden by the assessor.First, latent MTrPs were found in the LS muscle in both groups. The four assessments performed on the participants during the intervention were before, after, 48 h after the intervention, and one week later. Each group received four measurements for each intervention: PPT, ROM, quality of life, and pain intensity.Without being aware of the treatment assignment, the same physiotherapist found latent MTrPs in the LS muscle when measurements were taken before and after the intervention. The researcher who executed both interventions attested to the presence of latent MTrPs. Latent MTrPs from the LS that were the most hyperalgesic were chosen and permanently marked with a cross ,18. A hyIn order to introduce a 0.25 × 60 mm stainless-steel needle, the patient was first positioned in a prone position by a physiotherapist in a sterile environment . In order to evaluate and treat the most hyperalgesic latent MTrPs of the LS, which were defined as hyperirritable nodules of a taut band that were activated or produced pain upon palpation by digital compression and resulted in limitation of joint range upon stretching ,23,24, tA physiotherapist located the MTrPs of the LS muscle that were the most hyperalgesic before putting the patients in the prone position. His dominant hand’s thumb was then used to apply pressure until the patient’s pain threshold shifted from pressure feeling to pain for 90 s, and then he repeated the process three times .Primary measures: The Visual Analogue Scale (VAS) was created to measure the severity of pain. It is made up of a 10 cm long horizontal line with a number 10 at the right end (signifying the worst pain) and a number 0 at the left . Each peSecondary measures:Before and after each intervention, a CNP administered the Neck Disability Index (NDI) to each individual in order to gauge their level of disability . This scMinimal limitation or impairment ranges from 0 to 20%;Moderate limitation or disability is 21–40%;Severe limitation or disability is 41–60%;61–80% indicates disability.More than 81% of the patients had the maximum functional limitations.According to studies, DN and IC are both effective strategies for decreasing acute pain and improving ROM in MPS patients . A cerviPPT stands for the lowest pressure or stimulation level at which a patient feels pain . This met-test for independent samples was used for quantitative variables having a normal distribution (p > 0.05). The nominal variable sample’s homogeneity prior to the intervention was examined using the chi-squared test. The nonparametric Mann–Whitney U test was applied for quantitative variables without a normal distribution (p = 0.05).A statistical application called IBM SPSS  was used to conduct the analysis. To determine if a normal distribution existed, the Shapiro–Wilk test was initially employed to perform descriptive statistics on the control or independent variables. A descriptive statistical analysis was also used to test for the existence of a normal distribution. The homogeneity of the samples was evaluated. The parametric Student’s The numerous measurements taken before, during, after, and 48 h and one week after treatment in each group were examined using repeated measures analysis. Data collection pre-intervention, postintervention, 48 h after, and one week after made up the four stages of the within-subject component. The group variable, which had two levels (DN Group or IC Group), made up the second intrasubject component.p > 0.05). The Greenhouse–Geisser correction was applied when a variable violated the Mauchly assumption of sphericity (p > 0.05).The Bonferroni method was used in a post hoc analysis to examine the variations in the groups’ measurements at different points in time. It was assessed whether the variables satisfied the sphericity requirement using Mauchly’s test  between the groups.p > 0.05) between the two groups at the pre-intervention time.p > 0.05) between the two groups when the measurements between the two groups were compared using the chi-squared test during the pre-intervention period. Furthermore, at one week, there were no statistically significant differences in ROM between the two groups (p > 0.05).The flexion–extension range-of-motion test descriptive statistics are shown in p > 0.05). At one week after therapy, the quality-of-life measure showed improvements in both groups, while the DN group’s mean score was lower.The descriptive statistics from the Oswestry quality-of-life survey are shown in In addition, after 1 week, LE muscle stiffness at rest was lower in individuals who received DN than in those who received IC, as measured by the mechanical heterogeneity index . All othIn terms of pain intensity, ROM, PPT, and quality of life in the short term and one week after treatment in each intervention, this study is the first clinical trial to examine the efficacy of DN and IC on latent trigger points of the LS in patients with CNP. Because they instantly lessen pain and increase the range of motion, recent investigations have shown that IC and DN are successful therapies for patients with upper trapezius trigger points and CNP pain ,33,34. ADN has been demonstrated to relieve pain right away after treatment in patients with musculoskeletal issues and is beneficial in treating CNP patients’ pain ,34,35,36Dry needling involves some degree of discomfort for patients. This could be especially problematic when trigger points are treated in patients with comorbid conditions, such as fibromyalgia, characterized by a generalized increased sensitivity to pain. This may be caused by anomalous depolarization of the postsynaptic membrane of the motor plate, resulting in a localized hypoxic energetic crisis that is associated with sensory and autonomic reflex arcs maintained by complex sensitization mechanisms. For this reason, it is also possible to explain how certain disorders with hyperalgesia  may benefit in the long term even though they generate high pain after the intervention. Thanks to the theory of McPartland et al., these complex sensitization mechanisms can be interpreted .These findings validate and complement research that demonstrated that all patients experience pain and hyperalgesia following the DN of a latent MTrP, which typically lasts less than 72 h . It was Studies revealed that two sessions of DN and IC had equivalent effects on pain, ROM, and disability at the cervical level, with the DN group displaying better outcomes . In a diThe measures most frequently endorsed and used to gauge the severity of CNP-related disability worldwide are the Roland–Morris scale and the Oswestry CNP disability scale . The latEven though certain studies ,48 have According to research, MTrPs in the thoracic, lumbar, and trapezius muscles immediately see a reduction in PPT following a single DN treatment session ,50,51,52The PPT rose after 48 h and remained the same after one week in our experiment with a single DN session. According to the studies cited above, the more local spasm responses that are obtained while taking the patient’s tolerance into account, the more potent and long-lasting the consequence. Llamas et al.’s research  on partiAccording to our IC approach, which was used in earlier experiments , we admiIn contrast to IC, DN successfully raised the quality of life, PPT, and pain intensity in patients with CNP on the most hyperalgesic latent MTrP locations of the LS muscle.Immediately after the treatment, IC raised PPT, pain level, and quality of life. No statistically significant differences existed in ROM between the DN and IC groups.


The primary end-point was the mean pain intensity assessed weekly with a visual numerical scale during the month prior to treatment (baseline), the 5-month stimulation period and 1 month after the treatment. The weekly visual numerical scale pain score was significantly reduced at all time points compared to baseline in the transcutaneous spinal direct current stimulation group, at the last two time points in the repetitive transcranial magnetic stimulation group (end of the 5-month stimulation period and 1 month later), but at no time point in the transcranial direct current stimulation group. A significant pain relief was observed at the end of induction phase using transcutaneous spinal direct current stimulation compared to repetitive transcranial magnetic stimulation (P = 0.008) and to transcranial direct current stimulation (P = 0.003). In this trial, transcutaneous spinal direct current stimulation was more efficient to relieve pain in patients with complex regional pain syndrome compared to motor cortex stimulation techniques . This efficacy was found during the induction phase and was maintained thereafter. This study warrants further investigation to confirm the potentiality of transcutaneous spinal direct current stimulation as a therapeutic option in complex regional pain syndrome.The aim of the present study was to compare the analgesic effect of motor cortex stimulation using high-frequency repetitive transcranial magnetic stimulation or transcranial direct current stimulation and transcutaneous spinal direct current stimulation in patients with complex regional pain syndrome. Thirty-three patients with complex regional pain syndrome were randomized to one of the three treatment groups  for a scientific commentary on this article.See Bocci and Priori (  CRPS Type I develops without evidence of nerve damage in the affected limb, through pathophysiological mechanisms that are partly unknown. However, these mechanisms likely involve maladaptive neuroplasticity in the somatosensory and autonomic (sympathetic) central nervous system.1 Pharmacotherapy includes a wide variety of drugs, such as steroids, non-steroidal anti-inflammatory drugs, calcitonin, bisphosphonates, anticonvulsants, antidepressants, N-methyl-D-aspartate receptor antagonists or anti-hypertensives. The level of evidence depends on their use in the early or late phase of the disease. Topics can also be used, as well as locoregional ‘blocks’, in particular sympathetic nerve blocks or intravenous regional anaesthetic techniques. Non-pharmacological approaches include physiotherapy or psychotherapy, for example.The treatment of CRPS is based on various pharmacological or non-pharmacological approaches.2 The efficacy of surgically implanted electrical motor cortex stimulation has also been reported.3 Following the beneficial effects obtained in the treatment of CRPS by invasive cortical neuromodulation,4 non-invasive techniques of cortical stimulation have been developed, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS).5 The value of these techniques as alternatives for the treatment of refractory chronic pain has been demonstrated for 20 years.6Finally, usually at the last line of the therapeutic algorithm, interventional neuromodulation, mainly based on spinal cord stimulation (SCS), can be an effective solution in chronic refractory cases.7 In the French recommendations for the management of chronic neuropathic pain, rTMS is recommended as a third-line treatment.8 As for the use of rTMS in the treatment of chronic CRPS specifically, a recent analysis of the literature found only three controlled and short-term studies .9The analgesic efficacy of rTMS delivered to the motor cortex seems particularly well established. European experts have retained a level of evidence A concerning the analgesic effect of high-frequency rTMS (≥5 Hz) of the motor cortex in chronic neuropathic pain.10 The use of anodal tDCS delivered to the motor cortex as an analgesic therapy has provided encouraging results in patients with chronic pain.11-13 However, the current data in the literature do not allow to affirm, with a satisfactory level of evidence, the efficacy of tDCS in this context.15It is important to emphasize that rTMS requires heavy equipment with significant cost  and the constraint for the patient to come to the hospital (clinic) to be stimulated. On the contrary, tDCS, because of its low cost and ease of use , appears in such a context as a potential and interesting alternative. Low-intensity electrical current delivered transcranially to the cerebral cortex by tDCS electrodes placed on the scalp, usually with a bipolar montage using an anode and a cathode, can modulate neural activity and induce neuroplasticity.17 In the somatosensory domain, studies were mainly performed in healthy subjects, showing that tsDCS is able to interfere with spinal cord structures and to modulate conduction in the lemniscal and spinothalamic sensory pathways.19 In contrast, clinical studies concerning the impact of tsDCS on pain are few. In fact, we found only two therapeutic studies reporting the analgesic effect of repeated sessions in tsDCS in series of patients suffering from various chronic pain syndromes affecting the limbs, notably related to multiple sclerosis.21 In these studies, the anode was placed over the tenth thoracic vertebra and the cathode over the right shoulder20 or the somatosensory cortical area.21More recently, a non-invasive neuromodulation approach to the spinal cord, transcutaneous spinal direct current stimulation (tsDCS), has been developed.In the present study, our objective was to evaluate for the first time in CRPS patients the analgesic effect of tsDCS using a bipolar montage with both anode and cathode electrodes placed along the cervical or lumbar spine and to compare this effect to that of high-frequency rTMS and anodal tDCS delivered to the motor cortex, which are more established non-invasive neuromodulation therapies for chronic pain.Beyond the impact of these treatments on clinical questionnaires, we also assessed the possible modulation of the autonomic nervous system by recording the sympathetic-driven electrochemical skin conductance (ESC) measured with the Sudoscan® device.This study was a bi-centric clinical trial randomized in three parallel arms: rTMS, tDCS and tsDCS. The study was conducted at the Pain Centre of Grenoble Alps University Hospital  and the Clinical Neurophysiology Unit of Henri Mondor University Hospital  between 25 July 2016 (first visit of the first patient), and 10 September 2021 (last visit of the last patient).The study consisted of three periods : (i) a 1The neuromodulation protocol of rTMS, tDCS or tsDCS consisted of an ‘induction phase’ of one stimulation session per day for 5 consecutive days during 2 weeks (Weeks 1 and 2), then 2 sessions in the next week (Week 3) for a total of 12 sessions, and a ‘maintenance phase’ consisting of one session in Week 4 and then bi-monthly sessions for 4 months, for a total of 11 sessions. The interventions have been performed for the three types of stimulation by the same experimenters, in the same environment and during the same time period of inclusion.The Institutional Review Board of Sud-Est V, Grenoble, France (No. 6705), approved the study on November 13, 2015. Written informed consent was obtained from all patients prior to enrolment. The study was registered in clinicaltrials.gov (NCT02817880).Patients with CRPS Type I were included if they met the following criteria: age between 18 and 80 years, disease duration for more than 1 year, a diagnosis confirmed by bone scintigraphy, pain intensity >3/10 at screening, no change in drug treatments during the last month and lack of response to conventional treatments. Patients were not included if they were pregnant or breastfeeding women, or if they had a CRPS diagnosis with presence of a neurological lesion, an intracranial ferromagnetic material or implanted device, a history of drug addiction, epilepsy, severe traumatic brain injury or neuropsychiatric comorbidities that could interfere with the assessment of outcomes.After the baseline period, treatment allocation was made by the physician responsible for conducting the study at each centre using a secure Web-based random number generator (Research Electronic Data Capture system). Patients were randomly assigned to one of the three groups in a ratio of 1:1:1, with a random block size and stratified by two centres and affected limb (upper or lower limb).22 and stimulates deeper the motor cortex corresponding to lower limbs due to its angle of 150°.23Stimulation was performed using a MagPro stimulator  and either a flat B65 coil (MagVenture) in patients with upper limb pain or an angled B70 figure-of-eight coil (MagVenture) in patients with lower limb. Compared to flat figure-of-eight coils, the B70 coil is more powerful, leading to lower the resting motor threshold by 10–33%25The motor cortical representation of the painful region was targeted using a TMS Navigator system, integrating individual brain MRI data . Stimulation was performed at 10 Hz with an intensity set at 80% of the rest motor threshold  and the coil held in posteroanterior orientation. Each rTMS session consisted of 40 trains of 5-s duration with inter-train interval of 25 s for a total of 2000 pulses in 20 min. This protocol is in line with the expert recommendations for safety.Stimulation was performed using a Starstim neurostimulator  with saline-soaked surface sponge electrodes (35 cm²). The site of stimulation was determined according to the International 10–20 EEG System. The anode was placed over the motor cortex contralateral to pain, on C3/C4 in patients with upper limb pain and on C1/C2 in patients with lower limb. The cathode was placed over the supraorbital area ipsilateral to pain, on Fp1/Fp2. A constant current of 2 mA intensity was applied for 20 min.26 In patients with upper limb pain, the anode was placed on the spinous processes of the C4–C5 vertebrae and the cathode along the column, spaced 8 cm below. In patients with lower limb pain, the anode was placed over the spinous processes of the L1–L2 vertebrae and the cathode along the column, spaced 8 cm below.Stimulation was performed using the Starstim neurostimulator  and the same parameters as for the tDCS protocol, except for the placement of the stimulation electrodes. These electrodes were placed longitudinally on the cervical or lumbar spine, according to a model study which demonstrated that this configuration had a relevant impact on the distribution of the induced electric field (EF) for the efficacy of tsDCS.28 a possible reduction of −2/10 at the end of the induction phase (Week 4) and of −1/10 at the end of the maintenance phase (Week 25) and a correlation of 0.7 or more between repeated measures, the expected sample size was 20 patients for each group, providing 80% power for a two-tailed test with significance level of 0.01 (adjusting for multiple comparisons) to demonstrate differences between pairs of groups (NQuery Advisor® 7.0). Finally, only 36 patients were enrolled before recruitment stopped after a 5-year inclusion period due to a recruitment challenge and the Covid-19 pandemia.Assuming a mean pain intensity measured on a 0–10 visual numerical scale (VNS) of 7 ± 1/10 in CRPS patients at baseline,From the screening period (Week 4) to the end of follow-up (Week 25), patients filled a diary at home to measure their daily pain intensity on a VNS ranging from 0 (no pain) to 10 (the worst pain imaginable) and also to record the use of medication.The primary end-point was the mean pain intensity during the week (weekly VNS pain score) measured over time (from Week 4 to Week 25).Secondary end-points were the following clinical scores assessed on self-administered questionnaires completed by patients at Week 0 (pre-intervention visit), Week 13 (third month of treatment) and Week 25 (1-month post-treatment):(1)29the 12-item Short-Form Health Survey questionnaire (SF-12 questionnaire) to assess the health-related quality of life across two dimensions  with scores ranging from 0 to 100, a higher score indicating a better quality of life;(2)30the hospital anxiety and depression scale (HADS) questionnaire to assess symptoms of anxiety and depression, with scores ranging from 0 to 21 for each subscale, a higher score indicating worse symptoms;(3)31the Neuropathic Pain Symptom Inventory (NPSI) to assess the characteristics and impact of neuropathic pain, with total intensity score ranging from 0 to 100 and five sub-scores corresponding to various dimensions of pain  ranging from 0 to 10, a higher score indicating greater symptom severity;(4)32the Quick Disabilities of Arm, Shoulder and Hand (Q-DASH) scale to assess disability and symptoms affecting the upper limb, with a total intensity score ranging from 0 to 100, a higher score indicating more severe disability;(5)33the Western Ontario and McMaster Universities Osteoarthritis Index for knee and hip (WOMAC) to assess disability and symptoms affecting the lower limb, with a total intensity score ranging from 0 to 100 , a higher score indicating more severe disability.Of course, only patients with upper limb CRPS were required to complete the Q-DASH, and likewise only patients with lower limb CRPS were required to complete the WOMAC.34 Illness improvement rate was calculated as the percentage of patients improved. We also evaluated the responder rate at the end of follow-up (3-month post-treatment), according to a reduction of ≥30% from baseline regarding the mean intensity of pain on VNS.The overall effect of the stimulation was estimated by the patients according to the seven-point Clinical Global Impression—global Improvement (CGI-I) scale, from 1 (very much improved) to 7 (very much worsened) compared to the pre-treatment baseline period.et al.35) was completed to assess the various potential side-effects that occurred during or after the stimulation sessions .Finally, at the last visit (post-treatment), the self-administered Comfort Rating Questionnaire . Palmar and plantar ESC values were measured  at W0 (pre- treatment), W 13 (third month of treatment) and W25 (1-month post treatment). Sudoscan technology provides a quantitative assessment of small fibre neuropathy. During the test, patients were asked to stand for 2 min, with their palms and soles placed on large stainless steel electrode plates. A low direct current voltage (<4 V) was applied incrementally to the electrodes, generating a current proportional to the chloride ion flow extracted from the sweat glands innervated by small fibres. The ESC value was acquired for each foot and hand. The ESC was used to assess the skin conductance of affected limb, with higher measures indicating better conductance.Continuous data are expressed as mean and standard deviation (SD) or median and interquartile range , according to the normal or non-normal distribution, respectively, assessed by the Shapiro–Wilk test. Categorical data are expressed in numbers and percentages. One-way ANOVA, Kruskal–Wallis Test and Fisher’s exact test were used to compare outcomes at baseline across the three treatment groups.Efficacy analyses were conducted on an intention-to-treat basis with missing data imputed as last-observation carried forward. All patients who received at least one session of treatment and completed at least one post-baseline weekly pain measurement were included in the intent-to-treat analysis. In addition, sensitivity analyses were conducted to explore the impact of missing values by performing a secondary analysis following the per-protocol principle that concerns only patients who completed each phase of study and had measurements for all pre-specified key times . We consThe primary end-point of the study (effects of treatments on pain) was examined by the use of two-way repeated measures ANOVA (rmANOVA) with treatment group  as the between-subject factor, time  as the within-subject factor and the calculation of time-by-group interaction. Change from baseline over the time was also tested for each motor cortex neurostimulation group (rTMS and tDCS) compared with tsDCS group sequentially at a significance level of 0.017 (Bonferroni correction for three groups’ pairwise comparisons). The pairwise comparisons were tested only when the time-by-group interaction of the three groups over time was considered statistically significant. A significant time-by-group interaction would indicate that the change in pain intensity over time from baseline differed among groups. Sphericity was examined for all statistical analyses, and in case of non-sphericity, results were corrected according to the Greenhouse–Geisser method.t-test. Between-group differences from the baseline period to each follow-up period were compared between the three groups using one-way ANOVA test. Bonferroni’s post hoc tests for comparisons to baseline were performed for significant main effects or interaction. Effect size was determined using Cohen’s d  to compare the effects of the treatment group on the dependent variables. In addition, an analysis of covariance was implemented as a sensitivity analysis to compare groups at key time points, with baseline values used as covariates (Within-group differences from the baseline (Week 1) to the follow-up periods  at each group were analysed using paired variates . In ordeThe same analyses were used for pre-specified secondary end points  with the factor time as a three-level variable : baselinThe statistical significance level (α) for the comparison of three groups was set to 0.05, and the significance level (α) after Bonferroni’s correction for three groups was thus at 0.017. Analysis was conducted under blinded conditions using STATA 16.0 software .n = 11; tDCS, n = 12; tsDCS, n = 13)  . Three pP > 0.05)  . The meaThe primary outcome was the change in weekly VNS pain score over time from baseline  to 1-month post treatment (Week 25). = 2.39, P = 0.0004] and tsDCS group  but not for tDCS group . Post hoc tests of rmANOVA showed a significant reduction in the weekly VNS pain score at all time points compared to baseline in the tsDCS group , at the last two time points in the rTMS group , but at no time point in the tDCS group  = 1.52, P = 0.014] and the two-group analyses regarding tsDCS versus rTMS  and tsDCS versus tDCS . Post hoc pairwise comparisons showed a significant decrease from baseline of the VNS pain score at Week 3 (end of induction phase) regarding tsDCS versus rTMS  and tsDCS versus tDCS  (P = 0.063) and Week 13   . A tende= 0.043) .P = 0.019 and difference versus tDCS: −1.7; 95% CI: −2.9 to −0.5; P = 0.004), at Week 5  and at Week 13 .In addition, the differences between groups when the means were adjusted from baseline values were in favour of tsDCS at Week 3 .P = 0.010). On the other hand, this proportion was significantly higher in the rTMS group (54%) than in the tsDCS (27%) and tDCS (0%) groups at the end of follow-up (Week 25) (P = 0.035).Similarly, the proportion of patients with at least 30% reduction in weekly VNS pain score from baseline (responders) was significantly higher in the tsDCS group (73%) compared to the rTMS (18%) and tDCS (11%) groups at Week 13  = 6.05, P = 0.012] and not for rTMS group  or tDCS group . Post hoc tests of rmANOVA showed a significant improvement only at Week 25 compared to baseline in the tsDCS group  but at no time points in the other groups.For the SF-12 Mental Component score, the two-way rmANOVA analysis revealed significant time effect only for the tsDCS group  and tDCS group  but not for rTMS group . Post hoc tests of rmANOVA showed a significant reduction only at Week 25 compared to baseline in the tsDCS group (P = 0.007) and in the tDCS group (P = 0.006) but at no time points in the rTMS group.For the HADS-anxiety score, the two-way rmANOVA analysis revealed significant time effect for the tsDCS group  and not for rTMS group  or tDCS group . Post hoc tests of rmANOVA showed a significant improvement at all-time points compared to baseline in the tsDCS group  but at no time points in the other groups.For the HADS-depression score, the two-way rmANOVA analysis revealed significant time effect only for the tsDCS group  and rTMS group  but not for tDCS group . Post hoc tests of rmANOVA showed a significant reduction only at Week 25 compared to baseline in the tsDCS group (P = 0.002) and in the rTMS group (P = 0.003) but at no time points in the tDCS group.For the NPSI score, the two-way rmANOVA analysis revealed significant time effect for the tsDCS group  and not for rTMS group  or tDCS group . Post hoc tests of rmANOVA showed a significant improvement only at Week 25 compared to baseline in the tsDCS group (P = 0.050) but at no time points in the other groups.For the Q-DASH/WOMAC score, the two-way rmANOVA analysis revealed significant time effect only for the tsDCS group   and a tendency at Week 25   and versus tDCS regarding HADS-depression score  , although a tendency towards a significant interaction was observed for SF-12 Mental Component score [F= 0.083] . Moreove= 0.081) . For the= 0.072) .P = 0.049) but not at Week 25 (P = 0.139). The rate of patients with at least minimal improvement was higher in the tsDCS versus tDCS group at Week 13 (P = 0.024), but not at Week 25 (P = 0.124)  . No diffNo significant difference in CRQ sum scores or any specific CRQ item was found between treatment groups (data not shown). No adverse effects were reported during or following any of the three interventions.P = 0.015]. In addition, the patients with at least 30% reduction in weekly VNS pain score at Day 90/Week 13 from baseline (responders) had lower ESC values at the affected limb compared to the other patients (non-responders) at baseline  and also a significant ESC increase at Day 90/Week 13 .On the ESC at the limb affected, no significant change was observed over time at Week 13 or Week 25 in any treatment groups, and no difference between the groups was neither observed (data not shown). However, at baseline, ESC was reduced at the limb affected by CRPS compared to the non-affected limb [mean (µS) ± SD: 72.3 ± 16.8 versus 75.0 ± 15.5, 15Overall, this study shows a better efficacy of spinal stimulation by means of tsDCS compared to motor cortex stimulation techniques  to produce an analgesic effect in patients with chronic refractory CRPS. This improved efficacy was also observed more rapidly, during the induction phase. In the longer term, rTMS also showed significant efficacy, but not tDCS. This is one of the first studies to show the efficacy of tsDCS in a chronic pain syndrome, which is also a recognized indication for implanted SCS.37 Regarding rTMS, beyond a proof-of-principle trial based on a single session,38 only two studies showed some analgesic effects of 10Hz-rTMS applied to the motor cortex in patients with CRPS.39 First, in a sham-controlled study, Picarelli et al.28 applied rTMS as an add-on intervention to standard pharmacological and rehabilitation therapy for 10 consecutive sessions in 23 patients with CRPS Type I . Not only pain intensity but also functional and affective scores were reduced during the rTMS protocol, but the effects vanished soon (<1 week) after the stimulation period. However, there was a large inter-individual variation in the response duration, and one patient was completely relieved up to 3 months after rTMS. Second, in an open-label study, Gaertner et al.39 investigated the effects of five daily rTMS sessions primed by a sequence of intermittent theta burst stimulation in 12 patients with CRPS of Type I or II. Pain intensity score was decreased by more than 30% in 58% of the patients (7/12) at the end of the stimulation protocol. Among these seven patients, three remained improved for 3–4 weeks and two for 3–4 months beyond the rTMS protocol.Only a few studies have been reported to date on the use of non-invasive neuromodulation in patients with CRPS, as recently reviewed.41 only one randomized sham-controlled study was reported.42 In a series of 22 patients with CRPS Type I , Lagueux et al.42 applied anodal tDCS over the motor cortex for five consecutive days during the first 2 weeks of a therapy based on a technique of graded motor imagery and once a week during 4 subsequent weeks of graded motor imagery therapy. No significantly greater pain reduction was observed in the group of patients receiving active tDCS versus sham tDCS, while some differences were observed between the two groups in terms of pain catastrophizing and anxiety, but not at a clinically meaningful level.42 However, the effect of a protocol of tDCS performed alone has never been assessed in the context of CRPS.Regarding tDCS, beyond two single case reports,37), but not on spinal structures. In particular, the analgesic effect of tsDCS has never been evaluated in patients with CRPS. Anodal tsDCS has mainly been applied to modulate experimentally induced pain in healthy subjects. For example, anodal tsDCS has been shown to modulate pain ratings or thresholds in response to pressure,43 heavy mechanical pinprick44 or other types of nociceptive stimuli,45 but without affecting hyperalgesia induced by electrical high-frequency stimulation.46 Neurophysiological correlates of these analgesic effects were also investigated, either at the segmental level of spinal nociceptive integration by assessing changes induced by tsDCS in the nociceptive withdrawal flexion reflex (NWFR)48 or along the spinothalamic nociceptive pathways by recording laser-evoked cortical potentials.49Regarding non-invasive stimulation performed on non-brain structures in patients with CRPS, there are various published studies using repetitive peripheral magnetic stimulation or transcutaneous electrical nerve stimulation (TENS) on neuromuscular structures  in 16 patients with chronic pain of different aetiology for five daily sessions within a week. The anode was placed over the tenth thoracic vertebra and the cathode over the somatosensory cortex. The pain condition was related to lumbosacral radiculopathy in nine patients, herpes zoster in two patients, diabetes in two patients or multiple sclerosis in one patient. The design of the study was a randomized, sham-controlled crossover trial. Compared to sham, anodal tsDCS decreased pain intensity and NPSI scores at 1 month after the week of stimulation, in correlation with a reduction of NWFR area. Second, Berra et al.20 applied anodal tsDCS (2 mA) in 33 patients with chronic neuropathic pain related to multiple sclerosis for 10 daily sessions within 2 weeks. The anode was placed over the tenth thoracic vertebra and the cathode over the right shoulder. The design of the study was a randomized, sham-controlled parallel-arm trial . Compared to sham, anodal tsDCS decreased NPSI score from the end of the stimulation period up to 1 month after, while the NWFR tended to be also reduced.On the other hand, as mentioned in the introduction, we found only two clinical studies reporting the analgesic effect of repeated sessions of tsDCS in patients with chronic pain.51 The rare studies reporting long-term analgesic efficacy of rTMS52-59 and tDCS61 have been not performed in the context of CRPS.Our results are consistent with these precedents, but extend the findings over the long term according to a 5-month stimulation protocol based on 23 tsDCS sessions. This point is of importance, since most rTMS and tDCS studies are of short duration, in particular the very few studies that compared the analgesic effects of rTMS versus tDCS in patients.62 Indeed, the maximum EF magnitude resulting from this montage is predicted to lie in the spinal segment comprised between the anode and the cathode in human models.On the other hand, there was a striking methodological difference in our study compared to previous ones, which was the montage including the placement of both anode and cathode along the spine. Such a ‘spinal montage’ is most relevant for focusing the induced EF in the spinal cord as recently modelled.64 There is further evidence that tsDCS can induce persistent changes in the trans-synaptic properties of spinal neurons.64 In the context of nociceptive information processing, the neuromodulatory effect of tsDCS is primarily segmental and most likely associated with changes in the synaptic efficiency of input pathways at the level of the dorsal horn.49 Also, long-term synaptic changes (depression or potentiation) can occur in the spinal cord in a manner dependent on the polarity of stimulation, anodal or cathodal.65 Like tDCS,66 tsDCS is likely to modify glutamatergic neurotransmission, notably involving N-methyl-D-aspartate receptors, which may have an important role in prolonging segmental changes in spinal neuronal activity in the long term. For example, it was found that the perception of provoked pain was already reduced during the application of tsDCS but became more pronounced during the 30 min following its discontinuation, although inter-individual variation was large.47Even though the dorsal horns are probably the site most strongly modulated by tsDCS, the diffusion of EF in the transverse  plane and the nature of the neuronal structures affected remain speculative. Modelling studies have, however, improved the understanding of the spatial distribution of the current density generated by tsDCS.67-69 or fMRI of brain connectivity.70 In particular, fMRI showed that anodal tsDCS resulted in a decreased connectivity between the somatosensory cortex and the posterior insula and between the thalamus and the anterior cingulate cortex, while cortico-thalamic connectivity was increased.70 Regarding TMS variables, tsDCS was found to modulate resting motor cortex threshold,68 short-interval intracortical inhibition (SICI)68 and interhemispheric functional connection 69 in a polarity-specific manner: resting motor threshold, SICI and TCT are increased by anodal tsDCS, while cathodal tsDCS produces rather opposite effects.However, the mechanisms of action might not be strictly segmental and spinal, as tsDCS can also modulate various neural structures and neurotransmitter systems through ascending spinal pathways to the brain, including brainstem or thalamo-cortical networks. Indeed, there is evidence that the changes in excitability properties of neurons induced by tsDCS extent to corticospinal tracts or even intracortical circuits, as revealed by TMS excitability studies71), especially a reduced SICI. These literature data therefore offer a pathophysiological rationale for the efficacy of anodal tsDCS, which would be to restore a deficient SICI in patients with chronic pain related to CRPS. Restoration of SICI has been the subject of several publications regarding the analgesic efficacy of neuromodulation techniques, with a proven correlation between SICI improvement and pain relief following motor cortex rTMS,72 anodal tDCS73 or even repetitive peripheral magnetic stimulation.74 This hypothesis merits specific investigation in future work on the analgesic role of tsDCS in patients with chronic pain.On the other hand, CRPS is characterized by various alterations in TMS parameters of cortico-spinal excitability (reviewed in75 At least a subset of patients had evidence of sympathetic deficit (reduced ESC) in the affected limb and cortical or spinal neuromodulation may have corrected this central sympathetic dysfunction in association with pain relief. However, this finding was not specific to the effect of tsDCS.Another interesting end-point is the measurement of ESC, the reduction of which for the affected limb at baseline seeming to be predictive of good pain relief under treatment. Moreover, successful neuromodulation therapy was associated with a significant increase  of initially reduced ESC. This result illustrates the involvement of the sympathetic nervous system in CRPS and its ‘cross-talk’ with somatosensory processing.76 Through the application of tsDCS, segmental modulation of inflammatory response and healing or regeneration of neural tissue may have beneficial impact on the activity and plasticity of spinal neurons. Therefore, using repeated sessions of tsDCS, pain reduction and clinical improvement may be related to various molecular or cellular interactions beyond involving a segmental or bottom-up modulation of synaptic plasticity and neural network activities, as suggested by a recent experimental study in a rat model of chronic pain.77 All of these changes can contribute to a progressive positive outcome in the long term beyond the stimulation period, as also illustrated by the impact of tsDCS procedure in the rehabilitation of motor control disorders, for example.78Other mechanisms of action may be involved in the analgesic effect of tsDCS. Depending on the orientation and intensity of the induced EFs, a steady direct current delivered by repeated daily sessions of tDCS over 20-min duration may guide and stimulate the migration or proliferation of inflammatory or glial cells or the outgrowth of neurites by specific actions on various cytokines or neurotrophins.79 The mechanisms of action of SCS are multiple,80 probably as for tsDCS, and SCS parameters of stimulation are currently diversifying, with new modes, including broadly covering or highly focused high-frequency, burst or paraesthesia-free stimulation.81 Like conventional SCS, these new modes may also be effective in treating CRPS.82 On the other hand, implanted dorsal root ganglion stimulation (DRGS) has recently been shown to work even better and longer than implanted SCS to improve patients with CRPS.84 It is unclear from modelling studies whether tsDCS can act on dorsal roots as it does on dorsal horns. However, at least for the lower limbs, with the anode at the level of the L1–L2 vertebrae and the cathode 8 cm below, our tsDCS montage is more suitable for stimulating the cauda equina, but also the dorsal root ganglia, than the lumbar spinal cord corresponding to the painful territory of the lower limb. Whatever the exact target, our study shows that a non-invasive approach to spinal stimulation could be an alternative solution to invasive SCS for the treatment of chronic pain. This is already the case for rTMS which has replaced epidural stimulation of the motor cortex in clinical practice for the treatment of neuropathic pain.6 However, while rTMS and epidural MCS most likely share the same mechanisms of action for producing pain relief,85 it is certain that the pulsed electrical stimuli delivered by implanted SCS or DRGS have a markedly different impact at the neuronal level compared to the constant current delivered by tsDCS. This is notably due to the fact that SCS or DRGS generate action potentials and not tsDCS.10As mentioned above, the potential benefit of tsDCS in CRPS echoes the fact that CRPS is a classic indication for invasive SCS.86As a non-invasive neuromodulation technique, the advantage of tsDCS, like TENS, is that it can be performed at home, without any requirement for surgically implantable devices, unlike SCS or DRGS. An intermediate solution could be the use of percutaneous direct current stimulation, currently under development.88 which is capable of defining a clinically relevant change in CRPS symptomatology, was not used, as well as objective neurophysiological methods to assess sensory and autonomic symptoms.This pioneering study has various limitations, especially the absence of sham control, the relatively small sample size and the fact that the CRPS severity score,90) or cerebellar91 targets.Regarding tDCS, this study showed the inefficacy of tDCS with a conventional bipolar montage in relieving chronic pain associated with CRPS. However, the conventional bipolar montage used here is not at all focal and probably led to various changes in axonal excitability in a large region of the cortex and not strictly limited to the region of M1 corresponding to the painful limb, unlike rTMS using a focal coil and neuronavigated targeting. Also, differences in spatial interactions with the cerebral neural networks related to the geometry of the induced current, even beyond the differences in mechanisms of action inherent in these neuromodulation techniques, could explain the difference in efficacy between the two cortical stimulation methods used in this study. Thus, these results do not rule out a potential value of tDCS with other montages (high definition or multisite) or on other cortical (e.g. somatosensory or dorsolateral prefrontal cortexAnyway, these results pave the way for the use of cervical or lumbar anodal tsDCS as a therapeutic technique for providing pain relief in patients with CRPS. This is especially possible to consider given the improvement obtained in the absence of side-effects and the ease of performing the technique. A future controlled study is awaited to confirm the drastic effect observed here compared to placebo stimulation. Other evaluation methods, both clinical and neurophysiological ones, should also be added to better determine the mechanisms of action of tsDCS. These mechanisms could be segmental or supraspinal, related to modulations of sensory, nociceptive or sympathetic neuronal circuits, to neuroplasticity or to molecular or cellular neurotrophic effects associated with longer-term improvement.fcad191_Supplementary_DataClick here for additional data file.


After adjusting for sociodemographic, disease-related characteristics, depression, sleep duration, and morphine milligram equivalent, patient reports of cancer-related pain were significantly associated with poorer survival  compared to those with non-cancer-related pain, which was not associated with survival . Cytokines did not significantly mediate the link between pain and survival. Conclusion: While nearly half of the pain reported was cancer-related, both types of pain resulted in greater symptom burden, but only cancer-related pain was associated with survival.Objectives: The aims of the study were to (1) describe types of pain in cancer patients, (2) examine the predictors and consequences of pain, (3) investigate the association between type of pain and survival, and (4) examine potential biological mediators of pain and survival. Methods: This was a secondary analysis of baseline data from patients diagnosed with cancer. Patients answered questionnaires that assessed sociodemographic characteristics, pain, depression, sleep, and fatigue. Blood was collected and cytokine assays were performed. Analysis of variance, Kaplan–Meier, and Cox regression survival analyses were used to test the aims. Results: Of the 779 patients diagnosed with cancer, the mean age was 63.5 years, 57.8% male, and 90.6% White. Of those who reported pain , 46.5% stated their pain was cancer-related while 53.5% stated their pain was non-cancer-related. While both cancer and non-cancer-related pain was associated with depressive symptoms, fatigue, and sleep duration, those with cancer-related pain had significantly higher rates of depressive symptoms  = 21.217,  Palliative care may be defined as enhancing the medical care and quality of life for people with serious, complex, or terminal medical conditions, such as cancer, through targeted symptom management . The AmeCancer-related pain may be associated with the diagnosis of cancer itself, tests, and/or treatments. Pain associated with the cancer can be chronic , acute , or transient . It is critical to understand the type of pain to develop appropriate interventions for the pain targeted  . DepressIn the last decade, not only has the type of pain been differentiated in those with cancer  but pain interference, which is not always correlated with pain intensity, has begun to receive greater attention ,14. FurtAdditionally, chronic and cancer-related pain has been linked to survival outcomes, but not consistently, and they have not been studied together in the same cohort of patients ,18. InflThe objectives of this study were to (1) describe pain quality, intensity, and interference in patients diagnosed with cancer; (2) investigate the sociodemographic predictors and psychological and behavioral consequences of non-cancer and cancer-related pain; (3) examine the association between pain and survival; and (4) investigate circulating cytokines as potential mediators of survival while covarying for sociodemographic, disease-specific, morphine milligram equivalent (MME), and comorbid psychological and behavioral factors associated with inflammation . We hypothesized that patients who report that their pain is due to cancer will have (1) more pain intensity and interference, (2) more predictors and consequences of pain, (3) poorer survival rates, and (4) common underlying cytokines as mediators of survival than those who report their pain is due to other causes.This cross-sectional study was a secondary analysis of baseline data from prospective studies performed between 2008–2023. The prospective studies were clinical trials . Participants, who were referred by their medical team, were enrolled at a tertiary cancer center in the USA and followed for up to seven years, from diagnosis until death or last follow-up. Patients were explained the risks and benefits of the study and given time to consider participation and ask questions. If the patient was interested in participating in the study, written informed consent was obtained. Inclusion criteria for all studies were (1) cancer diagnosis as determined by radiography or biopsy, (2) 21 years of age or older, and (3) fluency in English. Fluency in English was determined by the study coordinator consenting the patient. If the patient was able to understand English without an interpreter during their medical visit as well as was able to repeat back an understanding of the different components of the consent form, they were considered fluent in English. Exclusion criteria included (1) evidence of a thought disorder, hallucinations, delusions, or suicidal ideation. Data were managed using Research Electronic Data Capture (REDCap) software  ,25,26.For the purposes of the study, patients were assessed at least 8 weeks from their last treatment  so as not to assess symptoms like acute pain associated with treatment.Sociodemographic data, such as a patient’s sex, age, marital status, income, educational level, and race, were collected using a 13-item questionnaire designed specifically for the prospective studies. The 13-item questionnaire also included information such as height, weight, zip code, and employment status. Disease-specific information, such as diagnosis, number of lesions, largest tumor size, and morphine equivalent were obtained from patients’ electronic medical records.Participants filled out questionnaires for the Brief Pain Inventory (BPI), a valid and reliable instrument that measures pain intensity, interference, quality, location, and management with medications . AdditioThe Center for Epidemiologic Studies-Depression (CES-D) assessment is a 20-item questionnaire that involves a 4-point scale, in which participants report the weekly frequency of depressive symptoms ; it is known to be reliable and valid in a population of patients with cancer ,31. A suThe FACIT quality of life assessment system includes a 20-item anemia (FACT-An) module that contains a 13-item questionnaire Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale . FACT-F The Pittsburgh Sleep Quality Index (PSQI) is a validated and reliable self-reported questionnaire that assesses sleep quality and disturbances in individuals . SpecifiSerum levels of cytokines IL-10, IL-1β, IL-2, TNF-α, IFN-γ, and IL-1α were measured. IL-10 is anti-inflammatory while IL-1β, TNF-α, IFN-γ, and IL-1α are pro-inflammatory, and IL-2 is a master regulator type cytokine. Blood draws were performed between 8 a.m. and 12 p.m. when possible. To obtain serum, red-top vacutainer tubes were filled with drawn blood without anticoagulant. Serum aliquots were stored in −80 °C freezers. The samples were thawed only once before testing using Luminex™ . Milliplex Analyst 5.1 software was utilized to calculate standard curve concentrations and minimal detectable concentrations (MDC) for all measured cytokines in pg/mL.The study protocol was first approved by the University of Pittsburgh’s Institutional Review Board. Patients were then referred to the project manager by their medical team. Patients who agreed to speak to a study team member were explained the risks and benefits of the study. Written informed consent was obtained from patients prior to the commencement of study activities, which included completing questionnaires or having their blood drawn. Study data were collected and managed using REDCap electronic data capture tools hosted at the University of Pittsburgh ,25,26.2) analyses were performed to test differences between patient groups (patients who reported pain and patients who did not report pain). Linear regression analyses were used to determine significant predictors of pain intensity and interference as well as to determine whether pain was associated with serum levels of cytokines after covarying for sociodemographic, disease-specific, and psychosocial factors. Listwise deletion and imputation were used to handle missing data in all models. Kaplan–Meier and Cox regression analyses were performed to test patient survival in months from diagnosis to death or last follow-up.Patient data were entered, verified, and analyzed in IBM SPSS Statistics 25 . Binary variables were coded for analysis, including education level , sex , endorsement of affective pain component , clinical level cutoffs for depression , and race , which was included to examine potential racial health inequities. Cytokines were log-transformed for parametric analysis. Descriptive statistics including mean, standard deviation, distribution, and percentages were computed for each sociodemographic variable. Analyses of variance (ANOVA) and chi-square  followed by patients diagnosed with neuroendocrine carcinoma with liver metastases ; patients other primaries and liver metastases ; and finally, patients with gallbladder, pancreatic, stomach, and appendiceal cancers .A total of 779 patients diagnosed with cancer were included in the study. The majority of patients identified as male (57.8%) and White (90.6%). The mean age of participants was 63.5 years (SD = 11.02). Descriptive statistics for other sociodemographic and disease-specific factors are reported in p = 0.07), gender , marital status , number of lesions , and largest tumor size  = 2.305, p = 0.13). However, there were significant differences between patients who reported pain versus patients who did not with regard to race as those from a racially minoritized group reported pain in the past week (78.1%) compared to White patients (65.9%) . A greater proportion of patients who did not complete high school reported pain (72.3%) compared to those who completed high school (62.5%) . A greater proportion of patients whose household income did not meet their basic needs reported pain (80.0%) compared to patients whose household income did meet their basic needs .There was no difference between patients who reported pain in the last week versus those who did not report pain with regard to age  = 3.401, p < 0.001) and fatigue  = 46.166, p < 0.001) but no differences in sleep duration  = 0.171, p = 0.68); see Patients who described the quality of their pain in affective terms, compared to those patients who did not use these terms, reported higher levels of depressive symptoms  = 20.926, p = 0.002). Using Cox regression and after adjusting for sociodemographic and disease-related characteristics, depression, sleep duration, and MME; cancer-related pain remained significantly associated with poorer survival . See p = 0.395).Using Kaplan–Meier analyses, the median survival for those who reported pain due to cancer was poorer  when compared to patients who reported that their pain was non-cancer-related , IL-1α , TNF-α , IFN-γ , IL-2 , or IL-10 .We examined the association between pain and inflammation as a potential mediator between pain and survival. For patients with non-cancer-related pain, after adjusting for sociodemographic, disease-specific, MME, and psychiatric variables as well as patients’ daily morphine equivalent, the PEG was not significantly associated with circulating cytokine levels for IL-1β , IL-1α , TNF-α , IFN-γ , IL-2 , or IL-10 .Similarly, for patients with cancer-related pain, the PEG score was not significantly associated with circulating cytokine levels for IL-1β  and diagnosis . None of the other sociodemographic or disease-specific variables significantly predicted PEG scores. The predictors included in this model only accounted for 6.4% of the variance in pain scores. When examining cancer-related pain, the only significant predictor of their PEG score was solely the number of years of education . None of the other sociodemographic or disease-specific variables significantly predicted PEG scores , fatigue , and significantly fewer hours of sleep per night . The predictors in the models account for 24.1% of the variance for depression, 30.7% for fatigue, and 6.3% for sleep duration. For patients with cancer-related pain, after adjusting for significant sociodemographic and disease-specific variables as well as daily morphine equivalent, the PEG predicted significantly higher levels of depressive symptoms, higher levels of fatigue, and significantly fewer hours of sleep per night. The predictors in the models account for 16.0% of the variance for depression, 37.8% for fatigue, and 5.5% for sleep duration; see For patients with non-cancer-related pain, after adjusting for significant sociodemographic and disease-specific variables as well as daily morphine equivalent (MME), the PEG predicted significantly higher levels of depressive symptoms  and fatigue  = 30.973, p < 0.001; mean = 26.20, SD = 11.32 versus 31.71, SD = 11.59) but not shorter sleep duration  = 0.597, p = 0.440).While both cancer and non-cancer-related pain was associated with depressive symptoms, fatigue, and sleep duration, those with cancer-related pain had significantly higher rates of depressive symptoms  = 21.217, Given the severity of a disease like cancer as well as the American Society of Clinical Oncology’s recommendations that all patients with advanced cancer receive palliative care, understanding pain in a population of cancer patients is important to providing key symptomatic management . While aWhile some studies have found a link between pain and cytokines, our study did not observe an association between cancer-related or non-cancer-related pain and inflammation as measured by circulating cytokines . The lacOnly two sociodemographic and disease-specific variables significantly predicted overall pain intensity and interference: educational attainment and type of cancer diagnosis. Specifically, patients with less than a high school education as well as those diagnosed with hepatobiliary cancers (hepatocellular carcinoma or cholangiocarcinoma) tended to report greater non-cancer-related pain intensity and interference, which is consistent with previous findings . Lower hIt is known that patients with cancer, as well as the general population, who report clinical levels of depressive symptoms along with those who sleep less than 6 h or more than 10 h per night tend to have poorer survival ,47. WhilThis study has several strengths, including its large sample size and validated measures of pain, fatigue, sleep, and depression as well as the inclusion of several biomarkers of inflammation. To our knowledge, this is the first study to differentiate between non-cancer-related and cancer-related pain in patients diagnosed with cancer while covarying for sociodemographic, psychological, and behavioral factors and MME to examine the relationships between pain, inflammatory biomarkers, and survival in patients diagnosed with cancer. It is also the first study to our knowledge to examine the quality of pain and psychological and behavioral outcomes in patients diagnosed with cancer.In terms of the limitations of this study, the cohort is predominantly White. Therefore, the experiences of minority patients may not be accurately reflected in this study. Another limitation of this study is that the questionnaires obtained to collect the data were all self-reported by the patients. Furthermore, there is some evidence to suggest that sleep duration and fatigue may be prodromal symptoms of cancer, and this study did not examine the direction of the relationship between symptoms . Future


Cancer pain remains a significant problem worldwide. It is often undertreated and presents in about half of cancer patients. Although several guidelines and pharmacological interventions for cancer pain management (CPM) exist, inadequate assessment and undertreatment of cancer pain are well-documented globally, especially in developing countries, including Libya. Perceptions, cultural and religious beliefs of healthcare professionals (HCP), patients, and caregivers about cancer pain and opioids are reported as barriers to CPM globally. This qualitative descriptive study aimed to explore Libyan HCPs’, patients’, and caregivers’ views and religious beliefs about CPM and involved semi-structured interviews with 36 participants: 18 Libyan cancer patients, 6 caregivers, and 12 Libyan HCPs. Thematic analysis was used to analyse the data. Patients, caregivers, and newly qualified HCPs were concerned about poor tolerance and drug addiction. HCPs perceived a lack of policies and guidelines, pain rating scales, and professional education and training as CPM barriers. Some patients were unable to pay for medicines if they faced financial difficulties. Instead, patients and caregivers emphasised religious and cultural beliefs for managing cancer pain, including the use of the Qur’an and cautery. Our results suggest that religious and cultural beliefs, lack of knowledge and training in CPM among HCPs, and economic and Libyan healthcare system-related factors negatively affect CPM in Libya.The online version contains supplementary material available at 10.1007/s10943-023-01763-1. Cancer pain is a significant problem for many cancer patients worldwide because it is often associated with adverse effects on people’s Quality of Life (QoL), including physical, social, psychological, and financial well-being Ferrell, . The preOpioid analgesics, such as morphine, remain the most effective method/treatment recommended for CPM WHO,  and are Many barriers to effective CPM exist, including HCPs, patients, caregivers, and healthcare system-related factors. For example, negative attitudes and lack of knowledge towards CPM among HCPs, patients, and caregivers, and a lack of policies and CPM guidelines in health systems were reported as barriers to adequate CPM Kwon, . FurtherSome cancer patients and their caregivers may develop misconceptions about CPM depending on their cultural background. One study found that American Indian patients, caregivers, and HCPs believed that expressing pain was seen as a sign of weakness, and complaining about cancer pain will only extend their vulnerability . Nevertheless, I forbid my followers to use (cauterisation) branding with fire.” . However, there was probably a misunderstanding about this narration, as the authentic narration is that the Prophet (PBUH) Evidence suggests that HCPs should recognise and understand that patients often refer to their religious, spiritual, and cultural beliefs when considering medical treatment . The authors faced a challenge while selecting a qualitative design for this study, as at the beginning, they thought phenomenology would be an appropriate design. However, after extensive reading of the literature and consulting with qualitative researchers, the authors found that none of the well-known qualitative research designs, including ethnography, phenomenology, grounded theory, narrative, and case study Chase, , were suPurposive sampling was used in this study to recruit individuals who have experience with cancer pain and CPM. Libyan cancer patients, who were seeking oncology treatment at an oncology centre in Egypt, their family caregivers, and Libyan HCPs (oncologists and oncology nurses) who were having training courses in oncology, were recruited through either a receptionist or an oncology nurse at an oncology centre in Alexandria, Egypt. Inclusion criteria were adults over 18 from the following groups; Libyan oncology doctors and nurses, advanced cancer patients, and caregivers. Patients eligible to participate had been diagnosed with advanced cancer at stages (II & III and IV), associated with pain based on their hospital records, and patients who were waiting for chemotherapy or radiotherapy or waiting to see their doctors. Staff at this site (oncologist practice manager and oncology nurse) screened patients’ records to identify if patients were meeting the eligibility criteria for this study. Caregivers were adults who had been caregivers for a minimum of 3 months and travelled with their patients to Egypt for treatment; HCPs had worked in a Libyan oncology setting for more than six months. Only participants who could give written consent to participate and without communication difficulties were included.The first author  collected data via face-to-face semi-structured interviews. All interviews were taken individually in a private and quiet room for participants’ privacy and confidentiality at the SUN oncology centre, Egypt. The interviews were conducted in Arabic and lasted approximately 30 to 45 min. A semi-structured interview was chosen as it combines the strengths and eliminates the weaknesses of structured and unstructured interviews, and it is the most commonly used approach in health research for qualitative data gathering  analysed the data using thematic analysis  from the Qur'an. That makes me feel better and relaxed because this reciting helps me endure my pain. For instance, as Allah says in the Qur'an (And We send down of the Qur'an that which is a cure and a mercy for the believers)” Verse (17:82 Surat AL-Isra). P10“As Muslims, people usually are positively affected by the Qur'an and the prayer, so they commonly use them as supportive strategies alongside the treatment to cope with cancer and pain. For example, we usually use Al-Ruqyah Al-Shariah . We also read or listen to the Qur'an and do prayer to support our patients; after that, the patient usually feels peaceful and relaxed. Accordingly, I do not prefer my brother to use pain medications like morphine for CPM...” C5The Qur'an was often used by patients, caregivers, and some HCPs to help patients cope with their disease, anxiety, and pain. Some patients relied on reciting verses from the Qur’an to support themselves in managing their condition and specifically their cancer pain. Similarly, the majority of caregivers said that they often used the Qur'an to relieve the patient’s distress that could be associated with cancer and pain. Some caregivers preferred to use the Qur'an instead of painkillers for CPM. This could be why some Libyan patients and their caregivers refused to use opioids for CPM in the current study:“………, we usually use different treatment methods, including medication and religious support. For example, Allah says in the Qur'an , verse (2:153 Surat L-Baqarah). This verse can be used to comfort and support the patient during his/her treatment. Nevertheless, we usually advise patients to take their pain medications for cancer pain, as some patients and their caregivers usually prefer to use religious beliefs only as a coping strategy to cope with cancer pain. In this case, we as the medical team cannot do anything as this is their wishes and choice.” D1Similarly, some HCPs reported the use of verses from the Qur’an alongside medical treatment as a coping strategy to help and support their patients in coping with their cancer and pain. They believed such a strategy usually helped their patients tolerate or minimise distress associated with stressful procedures during cancer and pain treatments. However, they (HCPs) did not believe that Qur’an could cure cancer and relieve cancer pain. This finding indicates that the use of the Qur’an could help to distract patients from their disease and anxiety:Relying exclusively on religious beliefs to cope with pain can be a barrier to CPM because some patients and their caregivers might reject pain medications because they believe the Qur’an and prayer will relieve such suffering. Although several patients and their caregivers were satisfied with using the Qur’an and prayer to manage cancer pain, this could influence how some patients and caregivers refused to use opioid analgesics for managing pain with cancer.“……...when I was diagnosed with cancer, I did use the Kaiy, as my family took me somewhere  to do it,.……...after that, I felt comfortable, as the pain has gone. Thus, I have not used painkillers anymore, and I prefer to use Kaiy for my cancer pain.” P15“Some caregivers prefer to use the Kaiy to manage their patients’ cancer and pain instead of medicine, as it can be done in one time and faster. After applying the Kaiy, the patients and their caregivers feel relaxed as they believe it can treat cancer and relieve pain. Thus, family caregivers usually convince their patients to do so and leave the hospital as the last option.” C4“…..., our community is affected by their cultural beliefs, especially uneducated people. Therefore, some of them usually use cautery instead of medical treatment before coming to the hospital. This results in a delay in cancer and pain management. For example, some patients often come with advanced cancer and severe pain, as they tried alternative medicine  before they came to the unit.” D2Many patients and their caregivers discussed cautery (Kaiy—ironing the place of cancer or pain with fire) as an alternative therapy for CPM. For example, some patients and their caregivers believed that cautery was the faster way to treat the disease and pain. Therefore, they preferred to use it instead of medical CPM. The majority of HCPs acknowledged that a lack of education contributed to patients and their caregivers’ preference for cautery as an alternative therapy to CPM:Many HCPs believed that a lack or low level of education contributed to cancer patients and their caregivers’ preference for cautery as an alternative therapy to CPM. These results imply that cultural beliefs (i.e. the use of cautery) could be a barrier to effective CPM, especially for poorly educated patients and caregivers. Thus, it can be suggested that the use of cautery is another issue that influences CPM in Libya.“……. I did not use painkillers for my cancer pain, and I endured my pain as we spent all the money on cancer treatment, so I could not afford to pay for painkillers. My husband had to sell his car and borrowed money to pay for cancer treatment, food, travel, and accommodation expenses.” P3“….. the cost of cancer treatment and stay at a private hospital were expensive. Thus, we did struggle to afford full money. For example, we did pay for the operation of about 27.000 Libyan Dinars. Furthermore, the cost of cancer treatment, travel, hotel, and food. All these costs overburdened us.” C5Financial difficulties may also be a barrier to CPM. For example, most patients said they had experienced financial hardships due to cancer procedures and treatments. Some patients reported selling their properties and borrowing money to pay for their cancer treatments. Similarly, some caregivers with difficult financial circumstances emphasised that cancer-related costs had an impact on the whole of their families:This consequence could lead to some patients might experience cancer pain, and they had to endure their pain untreated, as they might not have enough money to pay for such medication, or they may not want to bother their families about extra costs related to pain medication for their CPM.“……. As oncology doctors and nurses, we do not have enough knowledge of CPM, as nobody in our team has training in CPM. Therefore, some professionals usually focus on treating the disease itself. Few doctors sometimes use textbooks and internet resources for CPM and their daily work experience in a cancer care setting. However, many doctors and nurses do not often pay attention to cancer pain.” D3“…… In Libya, many nurses lack knowledge and experience in CPM, as we did not have training or education courses in CPM. Hence, nurses usually do not prefer to talk about CPM. Libyan nurses generally have a limited duty, and CPM is not a part of our duty. Nurses in Libya only do the doctors’ requests.” N5Most HCPs believed they lacked comprehensive knowledge of CPM and attributed this to an absence of CPM training for HCPs. Thus, they believed that managing patients with cancer pain was a challenge. Other doctors said that they used self-education and personal experience in cancer care settings for CPM:Accordingly, managing patients with cancer pain was a challenge that HCPs could face in Libyan hospitals. Some Libyan physicians used their self-education and personal experience in cancer care settings to manage patients with cancer pain. This outcome indicates that CPM might be inadequately managed as many HCPs showed a lack of knowledge about CPM.“As my duty, I always measure each patient's vital signs, including temperature, pulse rate, respiratory rate, and blood pressure. However, I never professionally measured the patient's pain level, as we do not have pain measurement tools in our clinic………….” N5“We do not have guidelines for CPM. Accordingly, I usually assess and manage cancer pain based on my experience from the daily setting and the patient's facial expression…...” D6Many HCPs said their hospital did not have protocols, policies, or guidelines for CPM in place. Instead, they tended to subjectively assess and manage cancer pain without using standard pain rating scales or specific guidelines. Most doctors also relied on their personal experiences in oncology settings to assess and manage cancer pain:This could result in cancer patient’s pain may be under-measured and mismanaged due to a lack of pain rating scales and guidelines for CPM, which could result in inadequate CPM in Libya.This study aimed to explore Libyan HCPs, patients, and caregivers' views and religious beliefs about cancer pain and its management. To the best of our knowledge, this is the first qualitative study to explore Libyan HCP, patient, and caregiver perceptions and beliefs about CPM. Factors that contribute to perceptions and beliefs of HCPs’, patients’, and caregivers’ attitudes to CPM include religion, culture, and economy, alongside the healthcare systems in Libya. The impact of these factors on HCP, patient, and caregiver perceptions and beliefs negatively impacts access to and use of appropriate CPM in Libya.Similar to the findings of an earlier study ” (Verse 17:82 Surat AL-Isra) was commonly used by some cancer patients and their caregivers. However, it has been stated that the meaning of cure as expressed in this verse does not mean that the Qur’an cures the diseases like cancer and relieves physical pain, as some Muslims have thought. Rather than physical pain, the verse means that the Qur’an cures the spiritual diseases in people’s chests and hearts, such as jealousy, animosity, and hate  WHO,  and NatiFurthermore, Libyan HCPs do not refer to any guidelines for CPM, including NICE and WHO. Although Libyan HCPs had work experience in Libyan cancer care settings, experience in oncology units only may not be sufficient to improve CPM in Libya . Accordingly, further research with large sample size is required to fully understand contextual differences in Libya's current state of practice regarding CPM and HCPs’ attitudes and knowledge towards cancer pain and opioids for CPM in Libya.This qualitative study shows that Libyan patients, caregivers, and HCPs hold negative CPM views due to religious and cultural beliefs. Furthermore, lack of knowledge, training in CPM, and experience in palliative care among Libyan HCPs might prevent effective CPM. Moreover, the economic and Libyan healthcare system-related factors are barriers to effective CPM. To address these concerns, developing and evaluating interventions, such as CPM education and training, would be necessary to improve patients’ outcomes with cancer pain in Libya.One recommendation for future study can be that further research with other HCPs, including surgeons, anaesthesiologists, general practitioners (GP), hospital managers, and policymakers, is required. Another recommendation is that a study that includes participants from all parts of Libya is needed because the inclusion of participants in the current study was from Eastern Libya only.Supplementary file1 (DOCX 27 KB)Below is the link to the electronic supplementary material.