The effect of adding alpha lipoic acid (ALA) to pulsed radiofrequency (PRF) for treatment of lumbar-sacral pain was evaluated.to evaluate the effect of using ALA as an adjuvant therapy with PRF for treatment of chronic lumbosacral radicular pain caused by herniated disc.One hundred twenty patients with lumbo-sacral radicular pain allocated into 2 groups. Group I: treated with PRF at 42°C for 120 seconds. Group II: treated as in group I, plus oral ALA 600 mg  three times per day (1800 mg/day) for 3 weeks then 600 mg once daily for 2 weeks. The lumbo-sacral radicular pain evaluated using the numerical rating pain score and Oswestry Disability Index.Success rate was significantly higher in group II at 3 and 6 months after intervention. The median values of the numerical rating pain score and the Oswestry Disability Index were significantly lower in group II with no significant difference in Epworth Sleepiness Scale. No major complications were reported in both groups.The current study supports the use of ALA with PRF on the dorsal root ganglion for treating lumbosacral radicular pain. Therefore, LSRP can be regarded and treated as a common example of neuropathic pain.Chronic lumbosacral radicular pain (LSRP) is primarily a neuropathic pain condition; its annual prevalence in the general population varies from 9.9% to 25%, meaning that it is the most common neuropathic pain.,6 Nerve root compression can increase oxidative stress, which may lead to axonal degeneration and myelin degradation. Reactive oxygen species enhance synthesis of inflammatory cytokines and other inflammatory mediators that play an important role in inflammatory mechanism and the loss of axonal electrical conductivity.,8The main cause of LSRP is nerve root compression by herniated disc, ligaments bulge as a part of the degenerative process, and facet joint hypertrophy or the effect of epidural adhesion after spine surgeries. And since that date, ALA has been used in a variety of medical conditions, as cardiovascular diseases and diabetes mellitus. ALA is a multifunctional antioxidant and is effective in improving symptoms in diseases with an underlying oxidative stress elements. ALA reduces lipopolysaccharide-induced inflammatory responses in human monocytic cells. It also mediates cyclooxygenase-2 and inducible nitric oxide synthase during inflammatory conditions with oxidative stress.In the early 1950s, Reed and coworkers extracted alpha lipoic acid (ALA) from bovine liver,,17 ALA commonly used for treatment of some neuropathic pain and peripheral nerve injuries because it has antioxidant and free radical scavenging properties.,19 It is believed to have a beneficial role in improving nerve conduction, and reducing pain and numbness and paresthesias in diabetic neuropathy.Several studies reporting the beneficial results of single pulsed radiofrequency (PRF) treatment or PRF in combination with conventional radiofrequency for the treatment of chronic LSRP have been published.We hypothesized that ALA could reduce the progression of the nerve pathology via its anti-inflammatory action in the affected nerve. Therefore, in this study, we evaluated the effect of using ALA as an adjuvant therapy with PRF of the affected dorsal root ganglion (DRG) for treatment of chronic LSRP caused by herniated disc. Our primary outcome was assessment of the degree of pain relief and the occurrence of any complications was the secondary outcome.22.1The study was prospective, randomized, and open label started in August 2013 and was completed in March 2017 at Pain Unit, Department of Anesthesia, ICU and Chronic Pain Management, Assiut University Hospital.2.2All patients were informed verbally and in writing about the study, and they signed a detailed written informed consent about the procedure and the nature of the study after local ethical committee approval and registration in ClinialTrials.gov ID: NCT03428139.2.3 and not responding to medical and conservative treatment such as physiotherapy, exercise therapy, analgesic medications or epidural injections. The diagnosis of nerve root pain was made based on reproduction of pain with known reliable and valid nerve root pain provocation procedures and neurologic assessment of sensation to pin prick, deep tendon reflexes and motor strength. Magnetic resonance imaging (MRI) was obtained in all patients using 1.5T MRI scanner , the diagnosis of disc protrusion was confirmed, and electromyography was done for documentation of nerve root dysfunction.Inclusion criteria included patients over 18 years with severe chronic LSRP and paresthesia in the affected dermatome of more than 6 months duration caused by herniated disc. Their pain intensity was ≥7 on the numerical rating scaleExclusion criteria included patients with history of previous spine surgery or indications for surgical intervention as significant severe and progressive motor deficits, cauda equina syndrome. Patients were excluded if they have some Other medical conditions as advanced malignancy, known concurrent neurological or neurodegenerative disease, including those with impaired neurotransmission e.g. myasthenia gravis, multiple sclerosis, spinal cord injury, pregnancy and nursing, active psychiatric or mental conditions, or those who takes other drugs with antioxidant effects such as vitamin A, vitamin C, vitamin E.Patients with contraindication to the technique itself were also excluded as coagulopathy, allergy/sensitivity to lidocaine anesthetic or/ and non-ionic contrast media.2.4Sequentially allocation was the type of randomization that we used to allocate patients in 2 different groups. Patients were enrolled based on sequentially numbered, according to the order in which they commence treatment at the clinic by a software program. A secretary of the pain unit was responsible to enroll and register patients in an appropriate group.2.5 Group II: Each patient in this group treated with PRF as in group I plus oral ALA 600 mg  three times per day (1800 mg/day) for 3 weeks then the dose was reduced to 600 mg once daily for 2 weeks. Studies showed that a dose of up to 1800 mg of ALA for 3 weeks are safe, after that the dose should be reduced to avoid oxidative damage of chronic high dose.,25One hundred twenty patients were sequentially allocated to be in one of 2 groups (60 in each). Group I: Each patient in this group treated with PRF on the affected DRG at 42°C for 120 seconds.2.6The patient placed in the prone position with a pillow under the lower abdomen to provide an easy approach to the intervertebral foramen. Under complete aseptic condition, 2 ml of 1% lidocaine  used for local anesthesia of the skin prior to the placement of the RF electrode  under C-arm fluoroscopic control. In the lumbar segments, the electrode was positioned near to the DRG, which typically corresponded to the dorsal-cranial quadrant of the intervertebral foramen on lateral view, and on anteroposterior view, the tip was located midway in the pedicle column. The electrode advancement was depending on the stimulation criteria below. Once the electrode was in a correct position, the stylet then replaced by the radiofrequency probe. PRF current applied for 20 ms, at 2 Hz, for 120 seconds. The maximum target temperature was 42°C (Neurotherm 1100).The final positional confirmed by the following methods:1.Sensory stimulation (50 Hz) threshold under 0.6 volts, which made paresthesia in the usual distribution of radicular pain.2.Motor stimulation caused no muscle contraction at corresponding myotome below 2 volts to ensure that the probe was far away from ventral root cell and so close to DRG.Weak muscle contraction above 2 volts was accepted to be targeted treatment. PRF current applied for 20 ms, at 2 Hz, for 120 second. The maximum target temperature was 42°C (Neurotherm 1100).2.7All patients were admitted after the procedure into a ward for at least 2 hours with, recording of any adverse effects or complications. Blood pressure and pulse oximetry continuously monitored using Patient Monitor Umec12, Mindray, China. Any complaints such as pain, vomiting, or leg weakness was reported. Vomiting was treated by ondansetron 4 mg through intravenous route, whereas pain in the back or leg managed by reassurance and non-steroidal analgesic drugs after excluding serious events. Before discharge, each patient received the necessary instructions and contact numbers.2.8Patients’ responses to the treatment were followed up on subsequent visits to the pain clinic at 3 and 6 months for the degree of radicular pain relief and the occurrence of any complications. If a patient was unable to attend for follow-up, a detailed telephone interview was conducted by a pain physician blinded to the patient group.Numerical rating score: The radicular pain was evaluated using standard 11-point scaled with 0 being no pain, and 10 representing the worst pain imaginable. Pain relief was considered a success if the treatment resulted in a numerical rating scale <4 points for at least 12 weeks.Oswestry Disability Index: Lumbo-sacral pain was assessed by the Oswestry Disability Index (range 0–100), for the 10 items of the score, each mean score  was recorded separately and compared.Satisfaction score: The patients’ satisfaction grades, which were presented as very good (grade I), good (grade II), fair (grade III), bad (grade IV), or very bad (grade V), were also evaluated by questionnaire. “Satisfied” was defined as a response of very good or good in the questionnaire.The Epworth Sleepiness Scale 0 = would never doze, 1 = slight chance of dozing, 2 = moderate chance of dozing and 3 = high chance of dozing. Score Results: 1 to 6 less chance to sleep, 7 to 8 average sleep and 9 and up Very sleepy.2.9 which was conducted in the same setting, to calculate the sample size. This was based on an 80% power of the study and a 95% confidence interval. We included 60 patients in each group to achieve these parameters.We relied on the previous study,2.10P values were considered statistically significant if <.05 .All data analyzed by using SPSS software (version 20). Per-protocol population was analyzed and all descriptive statistics (quantitative parameters) of the study were done in the form of mean , and median (minimum-maximum), absolute and relative frequencies were used to report qualitative variables. In categorical data, Chi-Squared test was used and Mann–Whitney test was used for non-parametric data. 3Three hundred twenty patients assessed for eligibility; 200 were excluded because they did not meet the inclusion criteria or refused to participate in the study. The remaining 120 patients were allocated and randomly divided into 2 equal groups. Three patients were excluded from statistical analysis due to lost to follow-up. The Group I included 59 patients and group II included 58 patients as shown in the consort flow diagram . There were statistically significant differences in patients who received ALA, compared to patients who did not receive after 3 and 6 months . The median value (minimum-maximum) of pain score for patients who did not receive an ALA was 4 (1–6) after 3 months and it was 4 (2–6) after 6 months, whereas in the group who received the drug it was 3 (0–6) and 3 (2–6) respectively.Pain score Table : Before P = .349). After 3 and 6 months, for patients who did not receive an ALA, the median value went down from 35 (15–60) before the procedure to 17 (5–40) and 15 (10–35) respectively, whereas in patients who received the drugs disability index declined from 30 (20–60) before the study to 10 (5–35) and 12 (10–30) respectively. The P value between the 2 groups was 0.097 after 3 months  and 0.048 after 6 months .Disability score Table : The medP value was .07 . After 6 months, sleep scores of these groups become 9 (7–9) and 9 (7–10) respectively; P value was .132 .The Epworth Sleepiness Scores Table : The medThe success rate Table : The perP < .001) in group II than group I at 3 and 6 months after the procedure. Ten patients (10.7%) at 3 months and 20 patients (34.5%) at 6 months in group II had grade I satisfaction score versus 0% in group I.The patients’ satisfaction grades Table : The oveSide effects: There were no neurological deficits such as motor loss or hypersensitivity in either of the groups. Some cases in both groups complained of burning dermatomal pain and leg weakness which relieved after a short period. Most Patients who received ALA reported gastric pain and 3 cases of them did not complete the full dose of treatment, but they were not excluded from the study because they missed the last days’ doses  because they did not fully understand the instructions .4The results in our study showed that ALA could lead to better pain relief and function ability with patient satisfaction and increase the success rate of treatment up to 6 months, when used as an adjuvant treatment with DRG pulsed radiofrequency in the people who were suffering from lumbo-sacral radicular pain resulted from herniated disc. It could be proposed that radicular pain in sciatic nerve roots arises from a complex interaction of inflammatory, immune, and pressure-related elements. The study of Das et al, 2018 supported the concept that chronic radicular pain is a centrally mediated neuroimmune phenomenon and the mechanism of action of DRG PRF treatment is immunomodulatory.Lumbo-sacral radicular pain commonly affects sciatic nerve and lower lumbar nerve roots and the lifetime incidence of this condition is estimated to be between 13% and 40% potential to become chronic and intractable, with major socioeconomic implications. and it has been used to treat many other painful conditions such as shoulder pain and occipital neuralgia.Van Zundert et al, 2007 concluded that the PRF treatment adjacent to the cervical DRG was advocated and reported to show significant pain relief compared with placebo at 3 months follow-up for the treatment of cervical radicular pain,ALA has been described as a potent biological antioxidant, a detoxification agent, and a diabetes medicine; used mainly for treating diabetic neuropathy conditions. It has been also used to improve age-associated cardiovascular, cognitive, and neuromuscular deficits, and has been implicated as a modulator of various inflammatory signaling pathways. Various long term studies using both oral and IV administration have not resulted in any significant adverse effects when compared to placebo. There have been some cases of spontaneous hypoglycemia due to the development of insulin autoimmune syndrome associated with the administration of ALA.ALA has been well tolerated with minimal and mild side effects usually occur only at doses greater than 600 mg. Possible side effects include nausea, gastric pain, vomiting, and vertigo. In addition, in IV administration, local pain during infusion and redness are common.The meta-analysis of the study of Ziegler et al, 2004; provided evidence that treatment with ALA (600 mg per day iv.) over 3 weeks is safe and significantly improves both positive neuropathic symptoms and neuropathic deficits to a clinically meaningful degree in diabetic patients with symptomatic polyneuropathy.Battisti et al, 2013; reported a statistically significant reduction of pain and functional disabilities in patients who received ALA. Pain improved after a few weeks of treatment and this improvement was statistically and clinically significant. Four patients could not continue the treatment due to severe gastric pain. They concluded that treatment with ALA and Superoxide dismutase (SOD) has a great benefit to improve functional disabilities and decrease the need for analgesics in chronic LSRP patients.Ranieri et al, 2009; cited that 6 weeks of oral treatment with ALA and gamma-linolenic acid (GLA) in combination with rehabilitation therapy alleviated neuropathic symptoms and neurological deficits in patients who are suffering from radicular neuropathy. We used ALA at a dose of 1800 mg per day for 3 weeks then 600 mg per day for another 2 weeks, however, the effect of ALA continued up to 6 months. ALA is known to have both free radical scavenging and nutritional effects.,41 We assume that these effects allowed the compressed nerves to improve its function better than the use of PRF alone. The clinical success of ALA in improving pain, disability and satisfaction when added to PRF could at least be attributed partially to its ability to improve the nerve function and inflammation via the above-mentioned mechanisms.In our study, ALA was added to PRF in treatment of chronic LSRP. Nerve root compression is known to increase oxidative stress. Reactive oxygen species enhance synthesis of inflammatory cytokines and other inflammatory mediators. PRF treatment modulates lymphocytes and neuroinflammatory markers in chronic radicular pain, Human DRG PRF treatment modulates cerebrospinal fluid lymphocytes and neuroinflammatory markers in chronic radicular pain. cited). ALA also exert multi-level immunomodulatory functions,,44 since both ALA and PRF to DRG share immunomodulatory effects we may suggest ALA may enhance the immunomodulatory effects of PRF on the DRG.PRF of the DRG showed an immunomodulating effect, causing a shift in the immune system balance with a decreased production of pro-inflammatory cytokines such as TNF-α and IL-1 and a raised anti-inflammatory status.However, many patients experienced improved disability and pain scores after treatment but were not satisfied. This could be attributed, in part, to not fulfilling their expectations. In addition, the chronicity of the problem may have its psychological impacts. On the other hand, no patient in either groups reported (very bad) in the satisfaction score at 3 and 6 months, and no patient in group II reported (bad) at 6 months, this could be attributed to the partial improvement of pain and disability. Anyhow, satisfaction scores are multifactorial, and sometimes are difficult to explain as patients expectations, psychological status, doctors behavior, nursing and staff care, life style and many other variables can possibly affect patients satisfaction.The present study has some limitations. First, because the aim of the study was to provide evidence of the benefit of ALA as adjuvant therapy with no placebo medication used, participants and medical stuff were not blinded. Short-term period of the study is another limitation and we recommend further studies with follow up period up to 12 month.5The current study supports the use of ALA with PRF on the DRG for treating LSRP resulting from a herniated disc. The pain score significantly decreased at 3 and 6 months, and improvement in disability score at 6 month without any significant side effects. We postulate that oral supplementation of ALA helps in reducing progression of the nerve pathology via its anti-inflammatory action in the affected nerve.We thank all our participants and staff of Pain Unit, Assiut University hospital, without whose efforts none of this work would have been possible.Conceptualization: Ayman Mamdouh Osman.Data curation: Khaled A. Abdelrahman, Mohammed Galal Aly.Formal analysis: Khaled A. Abdelrahman, Abdelhady S. Ali, Waleed S. Farrag.Investigation: Ayman Mamdouh Osman.Methodology: Khaled A. Abdelrahman, Waleed S. Farrag.Project administration: Abdelrady Shehata Ibrahim.Supervision: Mohammed Galal Aly, Waleed S. Farrag.Validation: Abdelhady S. Ali.Writing – original draft: Abdelrady Shehata Ibrahim, Abdelhady S. Ali.Writing – review & editing: Waleed S. Farrag.


The-Optimal-Lymph-Flow (TOLF) is a patient-centered, web- and mobile-based mHealth system that delivers safe, easy, and feasible digital therapy of lymphatic exercises and limb mobility exercises.The purpose of this randomized clinical trial (RCT) was to evaluate the effectiveness of the web- and mobile-based TOLF system for managing chronic pain and symptoms related to lymphedema. The primary outcome includes pain reduction, and the secondary outcomes focus on symptom relief, limb volume difference measured by infrared perometer, BMI, and quality of life (QOL) related to pain. We hypothesized that participants in the intervention group would have improved pain and symptom experiences, limb volume difference, BMI, and QOL.A parallel RCT with a control–experimental, pre- and posttest, and repeated-measures design were used. A total of 120 patients were recruited face-to-face at the point of care during clinical visits. Patients were randomized according to pain in a 1:1 ratio into either the arm precaution (AP) control group to improve limb mobility and arm protection or The-Optimal-Lymph flow (TOLF) intervention group to promote lymph flow and limb mobility. Trial outcomes were evaluated at baseline and at week 12 after the intervention. Descriptive statistics, Fisher exact tests, Wilcoxon rank-sum tests, t test, and generalized linear mixed effects models were performed for data analysis.P=.02). Patients who received the TOLF intervention were significantly more likely to achieve a complete reduction in pain  and soreness . Significantly lower median severity scores were found in the TOLF group for chronic pain  and general bodily pain . Compared with the AP control group, significantly fewer patients in the TOLF group reported arm/hand swelling (P=.04), heaviness (P=.03), redness (P=.03), and limited movement in shoulder (P=.02) and arm (P=.03). No significant differences between the TOLF and AP groups were found in complete reduction of aching (P=.12) and tenderness (P=.65), mean numbers of lymphedema symptom reported (P=.11), ≥5% limb volume differences (P=.48), and BMI (P=.12).At the study endpoint of 12 weeks, significantly fewer patients in the TOLF intervention group compared with the AP control group reported chronic pain  in proportions of patients who took pain medications compared with the AP control group, which had a 5% increase (from 40% [24/60] to 45% [27/60]). A 12% reduction (from 27% [16/60] to 15% [9/60]) in proportions of patients with ≥5% limb volume differences was found in the TOLF intervention, while a 5% increase in the AP control group (from 40% [24/60] to 45% [27/60]) was found. In conclusion, the TOLF intervention can be a better choice for breast cancer survivors to reduce chronic pain and limb volume.Clinicaltrials.gov NCT02462226; https://clinicaltrials.gov/ct2/show/NCT02462226RR2-10.2196/resprot.5104 Annually, more than 260,000 women are diagnosed with breast cancer, and currently there are more than 3.8 million breast cancer survivors in the United States . Even yeWhile significantly more breast cancer survivors with a diagnosis of lymphedema experience pain (45.2%), tenderness (52.4%), aching 61.9%), or soreness (31%), a substantial amount of breast cancer survivors without a diagnosis of lymphedema also experience pain (40%), tenderness (47.3%), aching (30%), or soreness (32.7%) %, or sor. DespitePain and lymphedema symptoms are debilitating late complications that impact the breast cancer survivors’ quality of life (QOL) ,3,5,11. While more research is needed to explore the exact etiology of persistent pain and lymphedema symptoms , physiologically, the accumulation of lymph fluid in the affected area or limb may create undue pressure on nerves, producing feelings of pain, aching, tenderness, soreness, burning, tingling, stabbing, and numbness as well as inducing sensations of swelling, heaviness, tightness, and firmness ,15. Accu2 increase in their BMI ) ,17,19. APerometry  was performed on each arm as it was held horizontally. The perometer maps a 3D graph of the affected and nonaffected extremities using numerous rectilinear light beams, and interfaces with a computer for data analysis and storage. A 3D limb image was generated and limb volume was calculated. This optoelectronic method has an SD of 8.9 mL (arm), <0.5% of limb volume with repeated measuring ,19. We ut-scores indicate greater pain impact/worse health  attrition rate). There were no statistical differences in demographic and treatment characteristics between patients that completed the study and the 6 patients who did not. No statistical differences were also found between participants in the TOLF intervention and AP control groups in terms of demographic and treatment characteristics except that participants in the TOLF intervention group had higher weight compared with those in the AP control group at baseline prior to the intervention. As a result, the randomization scheme based on the presence of pain, aching, soreness, or tenderness created 2 relatively similar patient profiles .As shown in P>.99), aching (P=.42), soreness (P=.12), tenderness (P=.28), and general bodily pain (P>.37). At the study endpoint of week 12, significantly fewer patients in the TOLF intervention group compared with the AP control group reported chronic pain . No significant differences were found between the TOLF and AP groups in terms of proportion of patients who reported aching (P=.05), soreness (P=.12), or tenderness (P=.25) as well as general bodily pain (P=.28).As shown in P=.005) and soreness  compared with patients who received the AP control at week 12 after the intervention. There were no significant differences in complete reduction of aching (P=.12), tenderness (P=.65), and general bodily pain (P=.16) between the TOLF and AP groups.As presented in P=.08), aching (P=.05), soreness (P=.07), tenderness (P=.13), or general bodily pain (P=.56) between the TOLF intervention and AP control groups  and general bodily pain .At baseline, there were no significant differences in terms of median severity of chronic pain (l groups . At weekP=.14), aching (P=.23), soreness (P=.22), and tenderness (P=.18).Cumulative link mixed effects models were used to predict the ordinal pain outcomes  across the 4 measurement time points and to determine group differences in the changes during the study time. As shown in Binomial mixed effects models were used to assess group differences in the prevalence of chronic pain, aching, soreness, and tenderness across the study time points. Model results  indicateP=.22). Results of the binomial mixed effects model to assess group differences in the prevalence of general bodily pain across the study period are shown in A cumulative link mixed effects model was also used to predict severity of general bodily pain across the 4 time points and to determine whether the 2 groups differed in how pain scores vary across the 4 study time points. As t112.9=1.30, P=.20) in mean QOL by PIQ-6 scores between the TOLF intervention (54.1 [SD 7.5]) and AP control (56.1 [SD 9.3]). At the study endpoint of week 12, there was no significant difference in mean QOL by PIQ-6 scores  between the TOLF intervention (48.4 [SD 7.9]) and the AP control (50.7 [SD 8.1]). As more improvement in the PIQ-6 scores was found in the TOLF intervention group at week 12 after the intervention, we conducted a subsequent linear mixed effects model predicting PIQ-6 scores across the 4 study time points and confirmed that PIQ-6 scores were significantly improved during the study  in the TOLF and AP groups, and that changes in PIQ-6 were not statistically different between the TOLF intervention and AP control groups , heaviness (P=.03), redness (P=.03), and limited movement in shoulder (P=.02) and arm (P=.03). As shown in Participants reported no adverse events of performing the TOLF lymphatic exercises and limb mobility exercises. In terms of self-reported adherence to the assigned interventions, 87% (52/60) of participants reported performing the TOLF lymphatic exercises twice a day as prescribed, while 83% (50/60) of participants reported performing limb mobility exercises twice a day as prescribed.The therapeutic lymphatic and limb mobility exercise intervention is an essential component of the TOLF self-care pain management program ,23. The P=.005) and a medium effect for complete reduction in soreness .A recent a single-arm feasibility clinical trial with a pre- and posttest design to assess the effects of the TOLF therapeutic lymphatic exercise intervention demonstrated that a single session of a Kinect-enhanced TOLF intervention immediately reduces pain, swelling, and lymphedema symptoms in breast cancer survivors . This cuCurrent pain management relies heavily on pharmacological agents, such as opioids and nonsteroidal anti-inflammatory drugs ,31, whicManaging pain and lymphedema symptoms is critical to reduce the risk of lymphedema. Breast cancer survivors who report pain on the affected ipsilateral upper limb or body are nearly twice as likely to develop lymphedema . For breThe TOLF lymphatic exercises were designed to decrease lymph fluid levels. In a previous study , 97% of The strengths of the RCT are a safe novel digital intervention targeting the lymphatic system for chronic pain, 5% (6/120) attrition, rigorous study design with a larger sample size over 100 patients, and the consecutively identified participants with chronic pain. The use of technologically driven digital therapy not only enhanced the fidelity and transparency of the intervention delivery but also the reproducibility of the intervention, which may enhance the generalizability and dissemination of the intervention. The technologically driven delivery model enhanced the patients’ ability to learn to perform the assigned exercise therapy given that they were able to review the assigned exercise therapy on their own schedule and pace virtually anytime and anywhere. Another strength was the daily 5-minute routine of TOLF lymphatic exercises, which was easy for patients to establish in their own routine.IL13 and lymphatic gene VEGFC  patients reported performing the TOLF lymphatic exercises twice a day as prescribed and 83% [50/60] reported performing AP limb mobility exercises. Lack of real-time monitoring limited the study’s ability to explore dose sensitivity for pain. Future study may use wearable devices to monitor patients’ adherence. Accumulation of lymph fluid in the affected area or limb leads to chronic inflammation resulting in pain for breast cancer survivors ,29. Painne VEGFC ,25. FutuThe results of this RCT showed significant benefits of the TOLF intervention for chronic pain, soreness, general bodily pain, and specific lymphedema symptoms  among breast cancer survivors in comparison with the AP control. The TOLF intervention resulted in a 13% reduction (from 40% [24/60] to 27% [16/60]) in proportions of patients who took pain medications compared with the AP control, which had a 5% increase (from 40% [24/60] to 45% [27/60]). In addition, a 12% reduction (from 27% [16/60] to 15% [9/60]) in proportions of patients with ≥5% limb volume differences was observed in the TOLF group and a 5% increase in proportions of patients in the AP group (from 40% [24/60] to 45% [27/60]). These findings suggest that the TOLF intervention should be a better choice for pain management and limb volume reduction in comparison to the AP control. The TOLF intervention is safe, efficacious, and affordable as a replacement or complement therapy for chronic pain management for millions of breast cancer survivors. The low-cost, detailed description of interventions, and technologically driven delivery model of the TOLF make it relatively easy to implement TOLF in clinical practice or at home.


Surgeons often see patients with pain to exclude organic pathology and consider surgical treatment. We examined factors associated with long-term opioid therapy among patients with foot/ankle, anorectal, and temporomandibular joint pain to aid clinical decision making.Using the IBM MarketScan® Research Database, we conducted a retrospective cohort analysis of patients aged 18–64 with a clinical encounter for foot/ankle, anorectal, or temporomandibular joint pain (January 2007–September 2015). Multivariable logistic regression was used to estimate adjusted odds ratios for factors associated with long-term opioid therapy, including age, sex, geographic region, pain condition, psychiatric diagnoses, and surgical procedures in the previous year.The majority of the cohort of 1,500,392 patients were women (61%). Within the year prior to the first clinical encounter for a pain diagnosis, 14% had an encounter for a psychiatric diagnosis, and 11% had undergone a surgical procedure. Long-term opioid therapy was received by 2.7%. After multivariable adjustment, older age , region , recent surgical procedure , male sex  and recent psychiatric diagnosis  were independently associated with long-term opioid therapy.Among patients with foot/ankle, anorectal, or temporomandibular joint pain, the risk of long-term opioid therapy significantly increased with older age, recent psychiatric diagnoses and surgical history. Surgeons should be aware of these risk factors in order to make high quality clinical decisions in consultations with these patients. •Pain diagnoses commonly seen by surgeons often have psychiatric comorbidities.•Psychiatric disorders increase risk for long-term opioid therapy.•Older patients are at higher risk for long-term opioid therapy. The medTo effectively manage such pain diagnoses, surgeons must be aware of the risk factors for opioid dependence. One such risk factor is sex, as sex-related biologic differences in pain perception  and pharEven when surgical consultation for acute or chronic pain reveals no discernible organic etiology of pain, patients often continue to seek care from surgeons for their symptoms, simply because there are no other physicians who feel qualified to manage the problem. The surgeon, who is the specialist of a particular anatomic site, thus bears the responsibility of offering non-operative treatment or referral to other appropriate specialists if available. Finding an effective treatment strategy may be hindered by the highly specialized nature of modern medicine, where a holistic approach to addressing pain in a discrete area may be necessary but overlooked.To this end, we aimed to fill a critical gap in the understanding of patients with pain syndromes that overlap with surgical indications. We chose three discrete anatomic sites associated with pain syndromes for which patients often seek surgical consultation—foot/ankle, anorectal, and temporomandibular joint. Assessing the three different pain syndromes in one analysis allowed us to elucidate commonalities and differences associated with the risk of long-term opioid treatment. For each pain condition, we sought to determine how opioid treatment differs by sex, age, geographic region, psychiatric diagnoses, and recent surgery. Our hypotheses were that patients across the three different anatomic sites of pain would have similar risk factors for long-term opioid therapy, and that women would have higher risk for long-term opioid therapy due to a higher risk for certain psychiatric illnesses such as depression, anxiety, and somatization disorders.22.1ClinicalTrials.gov .This retrospective cohort study was determined to be exempt from review by the institutional review board due to the deidentified nature of the data. The IBM® MarketScan® Research Database was queried for adult patients aged 18–64 with an inpatient or outpatient encounter for at least one of three chronic pain conditions from January 2007 to September 2015: 1) temporomandibular joint (TMJ) pain , 2) anorectal pain , or 3) foot/ankle pain (ICD-9: 719.47). We ended the study period before implementation of International Classification of Diseases, Tenth Revision to maintain diagnosis consistency using ICD-9 codes. The index pain encounter was defined as the first encounter for the pain condition. This study has been registered in 2.2The primary outcome, long-term opioid therapy (LTOT), was defined as receipt of >90 days’ opioid supply within 6 months after the index pain encounter, with no supply gaps over a month (>31 days) [2.3Unadjusted analyses were performed to assess associations between patient characteristics and opioid use with chi-square tests for categorical variables, two independent sample t-tests for normally distributed continuous variables and Wilcoxon-Mann-Whitney test for nonparametric continuous variables. Frequency counts and percentages are reported for categorical variables, means (SD) and median (IQR) are presented for continuous variables. In multivariable analysis, we calculated logistic regression models to examine the independent effects of selected patient factors on LTOT and new LTOT. Multivariable models were calculated for the overall cohort  as well as stratified models by pain condition. We report adjusted odds ratios (aOR), 95% confidence intervals (CI) and p-values. Statistical significance was assessed at the level of p < 0.05. All analyses were performed using SAS 9.4 . This work has been reported in line with the STROCSS criteria .3The cohort included 1,500,392 patients who had at least one inpatient or outpatient visit for the indication of foot/ankle, anorectal, and TMJ pain. The majority of the cohort were women (61%). Almost all index pain encounters were outpatient visits (99.5%). A healthcare visit for the primary indication of a psychiatric diagnosis within the previous year was observed for 14% of this cohort; women were more likely to have had such a visit compared to men . Women were also more likely to have undergone a surgical procedure within the previous year .Characteristics of each pain cohort were detailed in 3.1A small proportion of the overall cohort received LTOT (2.7%). When stratified by pain condition, women with TMJ and anorectal pain were more likely to receive LTOT than men, with small but statistically significant sex differences . Men with foot/ankle pain were more likely to receive LTOT than women . Stratified multivariable models revealed a significantly higher odds of LTOT for men with foot/ankle pain , but no significant sex differences in LTOT for patients with anorectal pain  or TMJ pain  .Fig. 1Ad3.2Stratified analyses by pain condition subgroups indicated similar associations between LTOT and age, geographic region, encounters for psychiatric disorder in the preceding year, and surgery in the preceding year . Older pStratified multivariable models indicated similar results as the overall model: older age, region of residence, and recent history of a surgical procedure and recent psychiatric diagnosis were associated with higher odds of receiving LTOT .3.3After excluding 24,926 patients who had received LTOT during the year prior to the index pain encounter, the analysis of new LTOT was performed on a cohort of 1,475,466 opioid-naïve patients. Only 6406 patients (0.43%) received new LTOT, which was similar between women (0.41%) and men (0.47%).The multivariable regression analysis demonstrated similar patterns of association as the univariate analysis, where men were slightly more likely to be prescribed new LTOT than women after controlling for other covariates. Patients who had encounters with a psychiatric diagnosis or a surgical procedure in the preceding year had significantly higher odds of receiving new LTOT regimen after adjustment for covariates (psychiatric diagnosis: aOR, 2.23, 95% CI 2.10–2.36, p < 0.001; surgical procedure: aOR, 1.75, 95% CI 1.64–1.87, p < 0.001, 4This study examined the risk factors for long-term opioid use in patients presenting with new diagnoses of foot/ankle, anorectal, and TMJ pain. These diagnoses may have potential surgical treatments, but may also be caused by conditions that cannot be corrected surgically. We found that recent psychiatric diagnoses, recent surgery, residence outside the Northeast region and older age were independently associated with long-term opioid use in all three pain conditions. Contrary to our hypothesis that women would be at greater risk for long-term opioid therapy, our analyses found no sex differences in LTOT for patients with TMJ or anorectal pain, and 16% lower odds of LTOT for women with foot/ankle pain. These risk factors and patterns were reflected in the analysis of new LTOT as well.Notably, patients seen for psychiatric diagnoses in the preceding year had nearly 2.5 times the odds of requiring LTOT as those without those diagnoses. Mood disorders accountd for over 40% of these psychiatric diagnoses, with anxiety, OCD, and psychogenic disorders accounting for the majority of the remainder. Our findings are supported by studies that have found associations between psychiatric disorders and initiation and use of prescribed opioids . TMJ paiConsistent with prior epidemiological reports of chronic pain conditions, there was a high proportion of women in our study population . While tThis study has several limitations – mostly due to the inherent characteristics of retrospective analysis and claims data, which preclude the ability to make causal interpretations. Additionally, we were unable to include patients 65 and older since this database was a private insurance claims and thus would not have included full claims information on the older beneficiaries of Medicare.5In a health care system that is increasingly specialized and siloed, our findings demonstrate the importance of patient-centered and multidisciplinary approaches to treat highly-specialized pain syndromes. It is important for surgeons to recognize the risks associated with initiation of chronic opioid use in this patient population, as comorbid psychiatric disorders are likely to complicate the management of pain. Further investigation to elucidate connections between psychiatric diagnoses and pain is critical to understand the pathophysiology of these disorders and to develop effective treatment strategies. Understanding the risk factors for LTOT in patients presenting for evaluation of pain symptoms that may or may not be surgically treated will inform treatment decision-making for surgeons and other providers who see these patients.No conflicts of interest to declare.


In this retrospective study, resting-state functional connectivity (FC) in patients with migraine was analyzed to identify potential pathological pain processing patterns and compared them to those in healthy controls (HCs). The FC patterns in patients between pre- and post-acupuncture sessions were also analyzed to determine how acupuncture affects neurological activity and pain perception during the migraine interictal period.In total, 52 patients with migraine without aura (MwoA) and 60 HCs were recruited. Patients with migraine were given acupuncture treatment sessions for 4 weeks. As a primary observation, functional magnetic resonance images were obtained at the beginning and end of the sessions. HCs received no treatment and underwent one functional magnetic resonance imaging (fMRI) scan after enrollment. After the fMRI data were preprocessed, a region of interest (ROI)-to-ROI analysis was performed with predefined ROIs related to pain processing regions.p-value (p-FDR) < 0.05]. The FCs were found to be mainly between the cingulate gyrus (CG) and the insular gyrus, the CG and the inferior parietal lobule (IPL), the CG and the superior frontal gyrus, and the middle frontal gyrus and the IPL. The second analysis indicated that acupuncture treatment partly restored the different FCs found in the first analysis (p-FDR < 0.05). Furthermore, subgroup analysis found different brain activity patterns in headache-intensity restored condition and headache-frequency restored condition. Lastly, the correlation analysis suggested a potential correlation between FCs and clinical symptoms (p < 0.05).The first analysis showed significantly different FCs between patients with MwoA and HCs [false discovery rate corrected This study suggests that pain processing is abnormal in migraine, with significantly abnormal FCs in the frontal, parietal, and limbic regions. This finding could be a typical pathological feature of migraine. Acupuncture has been identified to relieve headache symptoms in two ways: it restores the pain processing function and regulates pain perception. Migraine is defined as a neurological disorder characterized by a recurrent headache that lasts 4–72 h with nausea, photophobia, and phonophobia . WorldwiChronic pain is defined as lasting at least 3 months and not fully responding to treatment . The impHowever, there is no separate migraine generator for headaches, and the brain networks interact and affect headache symptoms in a complex way . PatientAs an efficacy treatment for migraine , researcThis retrospective study aimed to investigate the resting-state brain activities in patients with migraine to find potential pathological pain processing patterns and compare them to those in HCs. Patterns in patients between pre- and post-acupuncture sessions were analyzed to discover how acupuncture regulates the neurological activity and affects pain perception during the migraine interictal period. To this end, this study first compared the differences in FC between patients with migraine without aura (MwoA) and HCs. Pre- and post-acupuncture treatment comparisons followed this comparison in patients with MwoA with region of interest (ROI)-to-ROI FC analysis. Furthermore, this study has also conducted a subgroup analysis by assigning patients with migraine into clinically significant improvement groups (responders) and no significant improvement groups (non-responders) to determine how acupuncture affects pain perception and migraine attacks. Finally, correlations between FCs and clinical symptoms were obtained using linear bivariate correlation.In total, 52 participants with MwoA and 60 HCs were recruited from the third teaching hospital and campus of Chengdu University of Traditional Chinese Medicine.The inclusion criteria for MwoA patients were as follows: (1) right-handedness, 17–45 years old; (2) meets the MwoA diagnosis criteria of the International Classification of Headache Disorders; (3) has migraine lasting at least 6 months, with at least one attack per month in the last 3 months; (4) has taken no migraine preventive medications for at least 3 months. Participants were excluded when one of the following criteria existed: (1) alcohol or drug abusers; (2) participant was pregnant or breastfeeding; (3) suffering from other severe psychiatric, neurological, cardiovascular, respiratory, or renal disorders; (4) suffering from other chronic pain disorders or having a history of head trauma; (5) suffering a contraindication to MRI scanning, such as claustrophobia; and (6) suffering contraindications to acupuncture, such as coagulation disorders or long-term anticoagulant medication use.Meanwhile, HCs needed to meet the following inclusion criteria: (1) 17–45 years old; (2) right-handedness; and (3) absence of headache or other chronic pain disorders. The exclusion criteria for HCs were the same as those in patients with migraine.www.clinicaltrials.gov . The participants provided written informed consent to participate.All participants have undergone clinical assessment, physical examination, and laboratory tests to detect underlying diseases before recruitment. The ethics committee of the First Teaching Hospital of Chengdu University of Traditional Chinese Medicine reviewed and approved the study protocol. The study was registered on the standards for reporting interventions in clinical trials of acupuncture (Yanglingquan (GB34), Qiuxu (GB40), Waiguan (SJ5); (2) Xiyangguan (GB33), Diwuhui (GB42), Sanyangluo (SJ8); and (3) Zusanli (ST36), Chongyang (ST42), and Pianli (LI6)  filiform acupuncture needle.The intervention reported in this study followed puncture . Only acpuncture . The preli (LI6) . All acudeqi sensation; (2) the needle was retained for 30 min after obtaining deqi sensation. The treatment sessions lasted for 4 weeks, with a total of 20 acupuncture sessions. HCs received no acupuncture treatment.Two licensed acupuncturists administered all the acupuncture treatments. The acupuncture manipulation procedure was as follows: (1) the acupuncture needles were inserted perpendicularly 5–15 mm and manipulated to achieve Patients agreed not to use any regular migraine medications during the study, but ibuprofen (300 mg extended-release capsules) was allowed as a rescue medication when severe pain is experienced.Guidelines for controlled trials of drugs in migraine, headache intensity and headache frequency were recorded using a headache diary  with an eight-channel phased-array head coil at the West China Hospital MRI Center of Sichuan University. The scanning schedule was as follows: HCs underwent one MRI scan after enrollment. Participants with migraine underwent MRI scans before and after the acupuncture treatment sessions . Each scan included T1-weighted imaging and resting-state imaging.Participants were then asked to stay awake and keep their heads still during the scan, with their eyes closed and ears plugged. The T1 images were obtained using a fast spoiled gradient recalled sequence . The BOLD images were obtained using echo-planar imaging .t-test or Chi-square test. All statistical evaluations in this study used two-tailed tests; the significance level was α = 0.05, with a statistical threshold at p < 0.05 to be considered statistically significant.All clinical observation data from this study were statistically analyzed using SPSS 25 software . Between-group comparisons were then performed using independent According to the American Pain Society consensus statement on the clinical importance of treatment outcomes in chronic pain clinical trials, a more significant clinical symptom improvement is considered when there is a 30% improvement in pain . Thus, tMRI data were preprocessed with the CONN functional connectivity toolbox (20.b) . The defWith the CONN toolbox default denoising pipeline, noise components from the cerebral white matter, subject-motion, outlier scans or scrubbing, and constant and first-order linear session effects were regressed. Then, the band beyond 0.008–0.09 Hz was removed after regression using a band-pass filter.The ROIs selected in this study were based on the pain matrix theory . Based oWeighted ROI-to-ROI FC analysis has characterized the condition-specific FC values among the set of ROIs mentioned above. The analysis proceeded as follows. First, connectivity matrices were computed using a weighted least-squares linear model with predefined temporal weights identifying each condition. Then, all functionally connected data were analyzed at CONN using a general linear model. Conditions and contrasts were then defined as follows:(1)For the difference between patients with MwoA and HCs: the between-subjects specification was set to HCs + patients with MwoA (1–1), with the first scan set as the between-conditions specification.(2)For the difference between pre- and post-acupuncture treatments: the between-subjects specification was set to patients with MwoA, with pretreatment + posttreatment (1–1) set as the between-conditions specification.(3)For the differences between responders and non-responders in headache intensity or frequency compared with post-acupuncture, a multiple regression analysis (joint effects) was conducted; the between-subjects specification was set to patients with MwoA + acupuncture responders + non-responders , with the between-conditions specification set to pretreatment + posttreatment (1–1).p-value (p-FDR) < 0.05  < 0.05 . SubsequIn total, 52 patients with MwoA and 60 HCs finished the MRI scan. The case-control matching analysis was implemented in SPSS 25.0 to match demographic characteristics between the participants with MwoA and the HCs. After case-control matching analysis, four participants with MwoA were excluded because they could not be matched by age or gender. Thus, 48 participants with MwoA and 48 age- and sex-matched HCs were analyzed. No statistical difference was noted between the HCs and participants with MwoA in terms of gender, age, height, and weight.p < 0.001). Nevertheless, the mean headache frequency improvement was not significant at 6.42 per month (p > 0.05). Furthermore, the SAS score and SDS score were noted to significantly improve (p < 0.01)  .p > 0.05). Simultaneously, significant differences were observed between the headache-intensity responders and non-responders after treatment (p > 0.05)  .p > 0.05). Nevertheless, a significant difference was found in the duration of headache between responders and non-responders (p < 0.01)  .The quality assurance plot was checked before conducting the FC analyses. No patients with MwoA or HCs were excluded depending on the number of volumes in which the head position was 0.5 mm different from the adjacent volumes, which was more than 20% .p-FDR < 0.05). Meanwhile, patients with MwoA were found to have increased FCs between CG and SFG than HCs (p-FDR < 0.05)    . Two FCs < 0.05) . An FC b < 0.05) . Another < 0.05) .p-FDR < 0.05). Also, patients with MwoA had increased FCs between Amyg and MFG, Hipp and MFG, Hipp and INS, IPL and INS, IPL and MFG, IPL and SFG, and Tha subregions than pre-acupuncture (p-FDR < 0.05)    . Among t < 0.05) . The sig < 0.05)  and (2)  < 0.05) .F-test showed significantly increased FCs between Amyg and MFG, Amyg and INS, IPL and SFG, IPL and MFG, Hipp and SFG, Hipp and MFG, Hipp and INS, and CG and SFG affected acupuncture therapeutic effects compared with posttreatment (p-FDR < 0.05) (p > 0.05) and the rate of improvement in headache intensity (p > 0.05).Joint effects were found between the headache-intensity response groups and non-responders. The  < 0.05) . Among tp-FDR < 0.05) (p > 0.05) and the rate of improvement in headache frequency (p > 0.05).Unlike the joint effects between the headache-intensity responders and non-responders, the headache-frequency responders had different unique patterns with increased FCs mainly between the Tha subregions compared with posttreatment ( < 0.05) . Also, nIn this study, we investigated the different FC patterns between patients with migraine and HCs. We have also examined the differences before and after acupuncture treatment and the differences between responders and non-responders. As per our findings, it was demonstrated that FCs were altered in participants with migraine compared to HCs, and these altered FCs were mainly in the CG and INS, CG and IPL, CG and SFG, and MFG and IPL. The analysis found that the FC with significant differences mentioned above was restored after acupuncture treatment. Furthermore, significant differences were noted between responders and non-responders. The different FCs between the headache-intensity responder and the non-responder were mainly determined in the Amyg, INS, IPL, SFG, and MFG. In contrast, the different FCs within Tha subregions were found between the headache-frequency responder and the non-responder. Lastly, the correlation analysis suggested a potential correlation between FCs and clinical symptoms.To date, a large number of neuroimaging studies have demonstrated the structural and functional alterations in patients with migraine. Most of those regions are associated with multiple aspects of pain processing. Several recent resting-state fMRI studies suggested abnormal FC in SN, which was found to be crucial in stimulus detection and allocation of attentional resources . SchmitzMoreover, brain activation features can vary between studies, such as increased FC in the periaqueductal gray (PAG), anterior insula, and anterior cingulate cortex with other regions . BecauseIn this study, FC analysis showed that patients with migraine had decreased FCs in the left MFG and IPL, IPL and SFG, IPL and MFG, IPL and CG, INS, and CG than those in HCs. Conversely, compared to HCs, patients with migraine were observed to have increased FCs in the CG and SFG, IPL, and INS. The most frequent regions between these increased or decreased FCs were associated with CG, followed by the PPC regions, participating in spatial and attention processing. Again, the PFC and insula relate to higher levels of neural activity, and these related regions construct the basic framework for pain stimulation discrimination.via dorsal streams involving PPC and dorsolateral prefrontal cortex (dlPFC). The discrimination of pain intensity is described as a non-spatial sensory feature that activates a network of areas, including the anterior insular cortex and PFC. The model by Classical pain models emphasize the role of primary and secondary somatosensory cortices in the processing of sensory features of noxious stimuli but rarely distinguish between different sensory dimensions. In the correlation analysis, the results illustrated that there were potential correlations between clinical symptoms and neurological features. From the perspective of neural activity, the frequency of headache attacks will reduce if the synchronization between CG and SFG is elevated, suggesting there are pathological information processing flows in migraine patients, which directly lead to the persistence of incomplete pain information processing. And this incomplete processing flow may have led to potential pain amplification, known as central sensitization, and manifesting as allodynia in patients with migraine . It is wAfter acupuncture treatment, the abnormal FC of the second-order perceptual matrix in patients with migraine had been restored. Besides, FC analysis indicated that the Hipp, Amyg, and Tha subregions contain increased and decreased FCs, which could be related to the non-specific analgesic effect of acupuncture, indicating that acupuncture treatment affects the limbic system. Studies have suggested that acupuncture has a modulatory effect on the limbic system, which is often associated with the Amyg and Hipp . The AmyAcupuncture manipulation begins with stimulation of multiple peripheral sensory receptors activating the somatosensory cortex, which is the same as tactile stimulation of somatosensory overlying areas mediated by activation of the limbic system . FurtherOf the 48 participants with migraine, 24 were assigned as headache-intensity responders, whereas 19 were headache-frequency responders based on the acupuncture response definition. In contrast to the differences between pre- and post-treatment FC in all patients, the brain activities differed significantly from the headache-intensity responder. It is mainly characterized by SFG, which is consistent with the pre- and post-treatment differences in all patients but does not contain FC changes within the Tha. PFC activation was associated with pain relief after receiving electroacupuncture. deqi.” Acupuncture has been determined to exhibit significant analgesic effects only when patients experience the sensation of deqi   . There itension)  and is atension) . The aboIn contrast, brain areas associated with the limbic system were found to be more associated with headache attacks in patients with migraine. In the pain processing networks, pain discrimination processes are controlled by the limbic system processing, which is more related to the neuropathological mechanisms at the beginning of the migraine – indicating that pain discrimination and integration processes are the basis of migraine attacks. As the disease progresses, this function’s allostasis is overloaded before the limbic system, followed by central sensitization . SubsequCentral nervous system alterations in pain processing-related functions were also found in patients with chronic pain, thus representing the non-specific effects of the disease. The pathological basis of these changes includes adaptive remodeling of neural pathways and secondary reactive gliosis in brain regions . FC pattUnlike previous studies ,b, this In conclusion, this study has demonstrated that abnormal central neural activity patterns of the pain processing-related regions exist in patients with migraine, and this abnormal activity is primarily in the frontal, parietal, and limbic regions, suggesting that impaired integration of pain spatial and intensity information could be a typical central pathological feature of patients with MwoA. Thus, acupuncture can relieve headache symptoms by regulating the brain regions above as a specific therapeutic effect and modulating neural activity in brain regions related to the nociceptive areas as non-specific analgesics.Determining the specificity of acupuncture treatment in pain mechanism is inadequate for a single study; thus, future studies should focus on comparing other headache types and other pain types to clarify the specificity of acupuncture. In addition, a possible association between duration and frequency improvement of headache was found during this study, suggesting a relationship between migraine duration and central mechanisms, which could be a topic of future research.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the First Teaching Hospital of Chengdu University of Traditional Chinese Medicine. The patients/participants provided their written informed consent to participate in this study.LL and FZ conceived and designed the study. QX, GH, JC, and SW recruited the participants. ZT and TY analyzed the data. ZT drafted the manuscript. YG, LL, and FZ revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Proper pain evaluation and management are therefore considered an important treatment goal. This study assessed the prevalence of pain, the prescribing patterns, and the efficacy of pain control measures in cancer patients at the Radiation Oncology Unit of the Lagos University Teaching Hospital, Lagos.this was a longitudinal study design recruiting adults attending outpatient clinics. Participants were assessed at initial contact and again following six weeks using the Universal Pain Assessment Tool developed by the UCLA Department of Anaesthesiology.among the patients reviewed, 34.0% (118 of 347) were at the clinic, referred for initial assessment following primary diagnosis. All respondents had solid tumours; the most common was breast cancer. The prevalence of pain at initial assessment was 85.9% (298 of 347), with over half of respondents, 74.5% (222 of 347) characterising their pain as moderate to severe. Over a quarter, 28.9% (100 of 347) of patients were not asked about their pain by attending physicians, and none of the patients had a pain assessment tool used during evaluation. In 14.4% (43 of 298) of patients, no intervention was received despite the presence of pain. At six weeks review, 31.5% (94 of 298) of patients had obtained no pain relief despite instituted measures.under-treatment of cancer pain remains a significant weak link in cancer care in (Low-to-middle-income country) LMICs like Nigeria, with a significant contributor being physician under-evaluation and under-treatment of pain. To ensure pain eradication, the treatment process must begin with a thorough evaluation of the patient's pain, an explicit pain control goal and regular reevaluation. Poine”, meaning penalty. It was believed that the Greek goddess of revenge, Poine, was sent to punish the mortals who had angered the gods [The history of pain in human affliction is a long and dreadful one. The word “pain” itself originated from the Latin word “the gods . From ththe gods . Even woIn 1811, French writer and courtier Frances Burney underwent a mastectomy for suspected breast cancer without any anaesthesia or analgesia. She documented her ordeal in a very graphic and vivid letter to her sister, thus producing one of the earliest and most detailed, albeit gruesome, accounts of a mastectomy ,4. With Pain is one of the most common symptoms experienced by people living with cancer . An estiThe obstacles to proper management of pain in resource-constrained settings like Nigeria are numerous and inflected by factors peculiar to economically challenged countries . A consiStudy design: this project employed a longitudinal study design to recruit adult patients with cancer seen at the Radiotherapy and Oncology clinic of the Lagos University Teaching Hospital (LUTH).Study setting: Nigeria is the most populous country in Africa, with an estimated population of 200 million and accounts for over 100,000 new cancer cases every year. Lagos is the most economically advanced and populated city in Nigeria, and LUTH is one of the largest teaching hospitals in Nigeria, located in the former capital, Lagos state, providing care for patients with cancer referred from all over the country and neighbouring states. The hospital has over 700 beds; and is equipped with medical care infrastructure, training programs, and research infrastructure [tructure . This sttructure . The Radtructure .Study participants: study participants included all adult patients with histologically confirmed cancer who presented to the outpatient clinics for first treatment following diagnosis or follow up treatments and were willing to participate in the study. Patients in remission or cancer survivors who attended the clinics for follow up were excluded from the study. Patients with recurring cancers and second cancers were also excluded. Ethical approval for this research was obtained from the Health Research and Ethics Committee of the LUTH before the commencement of the study, and each patient was educated on the study protocol, possible benefits, risks and voluntary nature of the survey before recruitment. Written informed consent was given and signed by all patients before data collection.Study variables and data sources: in all participants, information was collected with the aid of a pre-designed data collection tool that recorded parameters such as sociodemographic and clinical characteristics of the patients. At this initial review, pain assessment and severity were determined using the Universal Pain Assessment Tool developed by the UCLA Department of Anaesthesiology [esiology . Each paBias: potential sources of bias for this study were from selection bias of patients in later stages of their diseases, as such with a higher likelihood of pain. This was controlled for, in the study design by the use of the same criteria for recruitment for all adult patients with cancer seen at the clinic regardless of the disease stage or clinical condition. Another anticipated source of bias was from recall by patients regarding their pain assessment. This was mitigated in the design phase by a cross-reference of patients´ reports with physician documentation of pain.Study size: the study was carried out over five months between July and December 2016. All patients seen in the clinics who meet the study criteria and consented to the study were included until the study duration elapsed. A total of 358 patients were enrolled.Quantitative variables and statistical methods: the data were analysed using the IBM SPSS Statistics for Windows . Descriptive analysis was used in reporting variables such as participants' sociodemographic and clinical characteristics, the prevalence of pain and the pattern of analgesics prescribed and reported using frequency tables and charts. A comparison was made between the prevalence and severity of pain at the initial and follow up review. Factors including gender, stage at diagnosis and stage at care were associated with the presence and severity of pain to check for significance. Missing data were excluded from analyses. A P-value of <0.05 was taken as significant.Participants: a total of 358 clinic attendees were asked to fill an interviewer-administered questionnaire. Of these, 347 were adequately completed and subsequently analysed, giving a response rate of 95.7%.Descriptive data: female respondents outnumbered males at a ratio of almost 1.5: 1, with the majority of respondents falling within the World Health Organization definition of middle- (35-54 years) and older- (55-74 years) aged adults. Of the respondents, 34.0% (118 of 347) were new patients attending the clinic for the first time for treatment following their diagnosis, while 66.0% (229 of 347) were previously registered patients who had been seen on least one previous occasion for treatment. All respondents had solid tumour types, with the most prevalent primary cancer sites been Breast in 43.5% (151 of 347), Cervix in 16.1% (56 of 347), Head and Neck in 14.7% (51 of 347); and Prostate cancers in 8.1% (28 of 347) patients  based on a score of 1 or more on the Universal Pain Assessment Tool, 14.1% (49 of 347) of patients had pain scores of 0 on the Universal Pain Assessment Tool, representing no pain at all. In patient with pain, 25.5% (76 of 298) had mild pain (1-3), 56.7% (169 of 298) of patients had pain scores in the moderate range of the Universal Pain Assessment Tool (4-7) and 17.8% (53 of 298) described pain as severe (8-10). The self-reported primary cause of pain was the cancer as seen in 90.9% (271 of 298) of patients. Additional sources of pain identified were medical tests and investigations such as blood tests or biopsies and treatment modalities, including chemo- or radiation- therapy. Non-cancer related causes of pain were reported in 8.7% (26 of 298) of patients. These included pre-and co-existing conditions such as Arthritis, Diabetic Neuropathy and Migraine disorders (isorders .In 14.4% (43 of 298) of patients with pain, no pain-directed treatment was prescribed. The only strong oral opioid available at the oncology pharmacy at the time of the study was Morphine. In 79.5% of patients with pain (237 of 298) of the patients were offered oral analgesic medications. In general, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) were the most common analgesic prescribed to patients with pain as seen in 67.8% (202 of 298) of patients, Oral NSAIDs were prescribed three times more than oral Opioids. Parenteral analgesia was prescribed to 12.1% (36 of 298) of patients, of which parenteral NSAIDs was given in 6.4% (19 of 298) and Opioids in 5.7% (17 of 298) of patients with pain in almost equal proportions . In 6.4%Over a quarter, 28.9% (100 of 347) of the patients seen reported that their attending physician did not ask if they were in pain. Even in patients who were asked about their pain, they uniformly stated that their attending physician used no pain assessment tool of any kind or any measure of pain severity quantification to assess their pain during clinic consultations, treatments or follow-ups. At follow up review at 6 weeks, 77.5% (231 of 298) of the patients with pain at initial review were re-interviewed, 22.4% (67 of 298) were lost to follow-up. Of the patients with pain at the initial review. 46.0% (137 of 298) had obtained relief from the instituted pain relief measures, indicated by a lower pain score on the Universal Pain Assessment Tool,  of the respondents had not obtained pain relief; indicated by unchanged or higher pain scores when compared to the initial interview. There was a statistically significant association between the presence and severity of pain and the stage diagnosis of cancer and stage at treatment. There was a statistically significant association between the gender of the patient and the perception of pain severity but not the presence or absence of pain .The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage . It furtIn this study, the prevalence of pain was at 85.9% (298 of 347); this finding isn't far removed from a similar study carried out in cancer patients in at the University College Hospital, Ibadan Nigeria where the prevalence of pain was 73.8% . It was Over a quarter, 28.9% (100 of 347) of the patients seen in this study were not asked about their pain by the physician that attended to them. This means that for every ten patients attended to, up to 3 walked away without being asked by their doctor if they were having any pain. All respondents uniformly reported that the attending physician had not used any tool to assess their pain's intensity. This finding is in stark contrast to a study in the US which found that almost all 300 of the centres surveyed used some form of the pain assessment tool, most commonly the Numeric rating scale, with at least half of them including adequate pain control as an indication of quality assurance . PerhapsOnly 6.4% (19 of 298) of the patients with pain received a strong opioid analgesic, despite the finding of moderate pain in 56.7% (169 of 298) and severe pain in 17.8% (53 of 298) of patients with pain reviewed. This disparity may be used as a marker of inadequate pain control as opioid analgesia is the gold standard for controlling moderate to severe cancer pain . Other sCurrent cancer pain management guidelines encompass both pharmacologic and non-pharmacologic approaches such as psychotherapy and interventional modalities like surgical and ablative techniques . RespondAlternative pain control therapies should be explored and employed more often. Cognitive-behavioural therapies and coping mechanisms may be as effective in managing a cancer patient's pain as medication. More research into these areas would serve to improve knowledge and possibly, patient quality of life. Pain control should be included as a stand-alone treatment goal at the start of cancer treatment, regardless of treatment intent . This would serve to encourage physicians to view the alleviation of pain as a priority instead of an addition. The authors recognise that a possible limitation of the study is the possible recall bias from the patients who were asked about the physician evaluation of their pain. However, case records were reviewed to mitigate this bias for documentation of pain evaluation and management to corroborate patient accounts.Pain is arguably the most common symptom experienced by cancer patients and encountered by Oncologists. How unfortunate then that despite several published guidelines for assessing and managing pain, undertreatment of pain continues to plague oncology practice in Nigeria. This study reflects a high pain prevalence among adult patients with cancer attending a Nigerian clinic, with accompanying under-evaluation and under-treatment. This physicians´ under-evaluation and undertreatment of pain coupled with the unavailability of gold standard medications for pain treatment all contribute to the persistence of poorly controlled pain in patients living with cancer in this clinic and arguably other oncology clinics in Nigeria. The physician must remember always to treat the patient, not just the disease. Pain control must be regarded as a fundamental part of the individual's well-being and management goal, without which there can be no conclusion of declaring that patient as “treated”. We need continued pieces of literature, clinical discussions and tools, and advocacy for implementation of findings to bring this crucial area into care and justify its importance so that patients are treated comprehensively as they face cancer and its disabling impact.Pain is a common but often avoidable or manageable aspect of the cancer journey;Proper pain control significantly impacts the quality of life of the patient with cancer.Pain management of patients with cancer in Lagos is suboptimal;A major contributor to suboptimal pain management in patients with cancer is the physician under-evaluation of pain during clinic visits.


Literature provides unclear evidence of the effectiveness of many physiotherapy interventions on pain intensity, quality of life, and functional ability in hemophilic patients, and suggests that rehabilitation programs should be focused on functional goals and the disability of patients.The aim of the present study is to present the outcome of a case series of patients with hemophilia in which a rehabilitation program has been carried out on the basis of a specific individual patient's functional impairment.Fifty-one patients were enrolled: 32 patients (Rehab Group) received a rehabilitative treatment, 19 patients for different reasons  did not receive rehabilitation (Control Group). The rehabilitation program was planned with respect to the emergent problems: musculoskeletal pain, joint range of motion limitation, muscle flexibility, walking difficulties, the appearance of hematomas/hemartro, and postural problems. All the patients were assessed at baseline (T0), after 1 month (T1), and after 3 months (T2) through visual analogic scale for musculoskeletal pain, the Hemophilia Joint Health Score for joint range of motion, the Functional Independence Score in Hemophilia for disability, and postural assessment by visual inspection.A significant reduction of pain and improvement of Hemophilia Joint Health Score and Functional Independence Score in Hemophilia score was found in the Rehab Group along with the follow-up. Pain in the Control Group was lower with respect to the other group at baseline and significantly decreased after 1 month.A rehabilitation program focused on individual impairment of patients with hemophylia determined satisfying results in terms of pain control, functional, and disability improvement in 3 months follow-up. Between 35% and 50% of patients with hemophilia report living with chronic musculoskeletal pain,4 with consequent limitations in mobility and independence, increased anxiety, restriction in activities of daily life, and reduced quality of life. Results of a recent survey highlight pain are mostly managed by the hemophilia specialists themselves, followed by a physiatrist and a physiotherapist. Currently, the main strategies indicated to manage musculoskeletal pain are pharmacological treatment, rehabilitation including physical therapy, and intra-articular injections. However, while evidence supports the role of physical exercise in promoting a reduction of perception of pain, and a better musculoskeletal function,,7 there is unclear evidence of the effectiveness of many physiotherapy interventions on pain intensity, quality of life, and functional ability in these patients. In addition, it has been suggested that the rehabilitation program should be tailored to patients and be focused on the functional goal and on the slow achievement of autonomy which, once reached, must be maintained over time.Hemophilia is a rare congenital coagulation disorder caused by the deficit or absence of clotting factors VIII (hemophilia a) and IX (hemophilia B).The aim of the present study is to present the outcome of a case series of patients with hemophilia in which a tailored rehabilitation program has been carried out on the basis of the specific musculoskeletal impairment.22.1This is a retrospective study, approved by the local Ethical committee . All the patients included in the study signed an informed consensus.2.2The entire cohort of hemophylic patients referred to the rehabilitation outpatient dedicated clinic in the years 2018 to 2019 were included in the study. The only exclusion criterion was age less than 6 years. Therefore, out of 52 patients, 1 child aged 2 years was excluded, and the other 51 patients were enrolled. Of these, 32 patients received, at different times, a rehabilitative treatment for the following reasons: musculoskeletal pain, joint range of motion limitation, muscle flexibility restriction, walking difficulties, the appearance of hematomas/hemartro, and postural problems. These patients were allocated to the Rehab Group. The remaining 19 patients were subjects who, despite needing to undergo rehabilitation, could not do it due to the distance from the hospital, or for family reasons. These patients received the same periodical assessment of the Rehab group, and were allocated to the Control Group. Symptomatic patients in this group were treated only with painkillers.2.3The rehabilitation program was planned individually on patients with respect to the emergent problems assessed by clinical examination, with the following objectives: resolve/prevent hemarthro/hematoma, recover/maintain range of motion, recover/maintain muscle strength, prevent articular deformity, improve posture, and walking. The following activities were delivered: functional reeducation , global postural reeducation, walking training, physical therapy (low-level laser therapy and kinesio-taping in the site of hematoma/hemarthro).The rehabilitation program took place in 20 sessions (from Monday to Friday) lasting 60 minutes. Specifically, it included joint mobilization exercises, also in traction, and muscle stretching. Both methods are low-load maneuvers that allow to maintain or restore the tissue (muscles and tendons), promoting the proper joint movement. Muscle strength recovery was carried out through the initial execution of isotonic exercises, followed by low-load and high-repetition exercises. Achieved good muscle control and initial recovery, we proceeded on with the execution of isometric exercises, first with open and then with closed kinetic chain, followed by concentric and finally eccentric exercises. prevents relapses. Hemarthrosis and hematomas can be considered the basis of the altered neuromuscular control provided by joint and muscle-tendon receptors. Furthermore, global postural re-education techniques were associated to improve the static and dynamic postural structure, and consequently the load distribution.This was associated with the proprioceptive-education through the use of oscillating tablets, irregular surfaces, and visual biofeedback for the recovery of the execution of the specific gesture which, according to Wagner et al,Finally, the various phases of the gait were analyzed and, based on the errors found, exercises aimed at improving gait patterns and patient education to recognize compensations and errors were performed, so they could correct themselves autonomously during the day.All hemophilic patients continued with prophylaxis as per the protocol prescribed by the hematologist. The intake of COX-2 inhibitors and/or analgesics was forbidden for the entire duration of physiotherapy to eliminate confounding factors in the outcome of the study.2.4All the patients in both Groups were assessed at baseline (T0), after 1 month (T1), and after 3 months (T2). For the Rehab Group, T0 coincided with the pre-rehabilitation assessment and T1 the assessment at the end of the rehabilitation program. and the Functional Independence Score in Hemophilia (FISH). The postural assessment was carried out in static posture, observing the alignment of the patient in different planes, noting the position of the cervical and thoracic spine, the relationship of the thorax and the pelvis, and the position of the shoulder girdle.The following measures were used for outcome assessment: visual analogic scale (VAS) for joint pain , the Hemophilia Joint Health Score (HJHS),The HJHS measures joint health, in the domain of body structure and function , of the joints most commonly affected by bleeding in hemophilia: the knees, ankles, and elbows. It provides a maximum score of 124 points (a higher score is worse).FISH is a performance-based assessment tool to objectively measure an individual's functional ability. It includes the assessment of 8 activities: eating, grooming, dressing, chair transfer, squatting, walking, step climbing, and running. Each activity is graded from 1 to 4 according to the amount of assistance required to perform the activity. The maximum score is 32 (the greatest autonomy).2.5All continuous data were summarized in terms of mean ± standard deviation. Analysis of variance for repeated measures with post hoc pairwise comparisons by Sidak test was used to analyze VAS, HJHS along with the follow-up in the Rehab Group. Friedman non-parametric test followed by Wilcoxon post hoc pairwise test corrected for multiple comparisons with Bonferroni was used in the Control Group, due to the small number of patients.The statistical analysis was performed using the statistical package for social sciences (SPSS), software version 15.0  by a statistical consultant from our institute.3For the Rehab Group, the mean age at the time of admission to the clinic was 34.4 years old , all males. The diagnosis was as follows: 19 patients had severe hemophilia A, 5 had mild-moderate hemophilia A, 4 had severe hemophilia B, 1 had mild hemophilia B, and 3 other diagnosis . All patients were on specific drug therapy. Nine patients were students, 5 were office workers, 5 were unemployed, 3 were workmen, 8 were professionals in various fields, and 2 were retired. All the patients have suffered from an arthropathy or an emarthro at different sites: elbows, knees, and ankles. Fourteen patients played regularly some sport activity, 18 patients none.For the Control Group, mean age at the time of admission to the clinic was 24.4 years old , all males. The diagnosis was as follows: 8 patients had severe hemophilia A and 11 had mild-moderate hemophilia A. All patients were on specific drug therapy. Eleven patients were students, 2 were office workers, 4 were workmen, 1 was unemployed, and 1 was military. Eleven patients have suffered from an arthropathy or an hemarthro at different sites: elbows, knees, and ankles. Eleven patients played regularly some sport activity and 8 patients none. General data of patients are reported in Table The 2 groups differed for age since the Rehab Group was older as a mean age (34.4 ± 14.7) with respect to the Control Group (24.2 ± 16.5), and also with a greater number of patients with severe hemophilia A and arthropathy (19 in the Rehab Group vs 8 in the No Reha Group).Results of outcome assessment in the 2 groups in terms of pain control, functional ability, and disability along the follow-up are reported in Table P < .0001) and a further significant decrease vs evident at 3 months follow up . Functional ability as measured by means of the FISH also significantly increased after rehabilitation  and was stable at 3 months follow up (28.3 ± 4.1). HJHS score also significantly improved after rehabilitation  and remained stable at 3 months follow up (23.8 ± 23.5). Pain in the Control Group was lower with respect to the other Group at baseline (3 ± 2.6) and significantly decreased after 1 month (2.6 ± 2.4) (P = .023). No other changes were evident along with the follow-up both for FISH and HJHS in this group.Pain in the Rehab Group significantly decreased after rehabilitation ,17,18 and joint mobilizations.,16,19The availability of medical treatment with coagulation factors for patients with hemophilia has completely changed the rehabilitation approach to these patients.,20However, if we consider the increasing interest in optimizing profilaxyx treatment on an individualized patient pharmacokinetic profile, similarly, in our opinion, it is very important that also the rehabilitation program could be planned on the basis of individual clinical-functional features of the patients, and not proposed with standardized protocols. Each patient in fact has its own manifestation of disease, with different sites involved, and joints and muscles affected by arthropathies and contractures of different levels of severity. That is why, the individual assessment in terms of impairment, disability, and participation is of paramount relevance to customize the rehabilitation program to the specific needs of patients.In the present study patients with chronic pain and musculoskeletal complications due to hemophilia were assessed through clinical evaluation for pain (VAS), joint impairment (HJHS), postural alignment, walking abnormalities, and functional ability (FISH). According to the individual features of the patient a rehabilitation program was planned. Our findings demonstrated an improvement of all the scores we used as an outcome measure, up to 3 months after treatment, thus supporting the effectiveness of the program undertaken compared to the Control Group in which only pain improved, without any significant change in functional limitation and disability.4.1As a limitation of the study, patients in the intervention group were older than controls and with much more severe forms of hemophilia, joint involvement, the intensity of pain, and disability, but just for these reasons, they had been deemed worthy of a specific rehabilitation.In the group of patients who did not carry out a rehabilitation program and that we used as a Control Group, no change was found, except a slight reduction of pain, probably related to the medicaments for pain control. Of course, the approach used in the present study has the limit that it is not reproducible in other studies because the rehabilitative intervention was based on a problem-solving approach through a rehabilitation program addressed to the specific problems of the single patient. Furthermore, the allocation of patients in the 2 groups was based on the delivery or not of rehabilitation, without randomization. Methodologically more robust studies, in particular randomized controlled studies, are desirable to demonstrate the rehabilitation effectiveness in these patients.5In conclusion, a rehabilitation program based on individual impairment for patients with hemophylia was demonstrated to provide satisfying results in terms of pain control, functional, and disability improvement at 3 months follow-up. An open problem remains the consolidation of the results obtained and the prevention of deterioration of the musculoskeletal condition. Cycles of rehabilitation planned on specific emerging clinical problems can be periodically delivered, but it is very important that patients maintain a correct lifestyle, participate in fitness, or adapted physical activity programs to guarantee long-term physical wellness.Conceptualization: Giulia Letizia Mauro, Maria Grazia Benedetti.Data curation: Dalila Scaturro, Sofia Tomasello.Data Collection: Giuseppina Passantino.Investigation: Giulia Lomonaco, Maria Grazia Giuseppina Farella.Methodology: Dalila Scaturro, Antonio Frizziero, Maria Grazia BenedettiSupervision: Giulia Letizia Mauro, Maria Grazia Benedetti.Writing – original draft: Dalila Scaturro, Giulia Letizia Mauro, Antonio Frizziero, Maria Grazia BenedettiWriting – review & editing: Antonio Frizziero, Maria Grazia Benedetti