There is no sufficient evidence on the effectiveness of acupuncture for neuropathic pain. This protocol describes a study that aims to evaluate the effectiveness and safety of electroacupuncture combined with conventional medicine for patients with intractable neuropathic pain, when compared with conventional medicine alone.This study is a prospective, open-labeled, randomized, cross-over clinical trial. A total of 40 patients with neuropathic pain who had a numeric rating scale (NRS) score of over 4 despite receiving conventional treatment for more than 3 months will be enrolled. Participants will receive conventional treatment for neuropathic pain (treatment C) or treatment C combined with 12 additional sessions of electroacupuncture treatment (treatment A) for 6 weeks. Participants will be randomly assigned to 1 of the 2 sequence groups (AC and CA group) with a 1:1 allocation. The differences of responder in the composite efficacy outcomes, which consist of the NRS, Brief Pain Inventory-Short Form (BPI-SF) pain subscale, and global assessment at 6 weeks after randomization will be examined as the primary outcome. Secondary outcomes include differences in the NRS, the Short-Form McGill Pain Questionnaire, BPI-SF, Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Medical Outcomes Study Sleep Scale, global assessment, EQ-5D, and incremental cost-effective ratio at 6 and 15 weeks after randomization. Adverse events, vital signs, and physical examinations will be recorded to evaluate safety.The study protocol for this trial will provide up-to-date evidence on the effectiveness and safety of electroacupuncture for patients with intractable neuropathic pain. The results will be disseminated through a peer-reviewed journal and conference presentations.https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=13410& ltype=&rtype=Clinical Research Information Service, ID: KCT0003615. Registered on March 12, 2019.  This could easily progress to chronic and refractory pain, which presents a great challenge in terms of management. Conventional pharmacological treatments for neuropathic pain include antidepressants and antiepileptics; however, the number of patients who achieve satisfactory pain relief is low, and is only 10% to 25% more than patients receiving placebo. Moreover, high comorbidity rates accompanied by chronic neuropathic pain, such as insomnia, anxiety, or depression, further makes the treatment challenging, and patients seek alternative treatment strategies including acupuncture treatment.Neuropathic pain develops after injury to the nervous system, and is often accompanied by maladaptive changes in the somatosensory nervous system. or inactivation of the myofascial trigger point. Acupuncture analgesia can also be induced segmentally by the gate-control theory of pain. Needling of some acupuncture points located at the extremities can generally reduce pain through descending inhibitory pain control by serotonin and noradrenaline.,9 Recently, clinical evidence on acupuncture for chronic pain, which is similar to nociceptive pain, has been well-established through many systematic reviews–12 and clinical guidelines.,14 A meta-analysis assessing 20,827 individual patient data from 39 trials suggested that acupuncture is an effective treatment option for chronic pain, including nonspecific musculoskeletal pain, osteoarthritis, headache, or shoulder pain, and that its effects persist over time, with only a small decrease at 1 year. The guidelines published by the American College of Physicians recommend that acupuncture should initially be selected for patients with chronic low back pain. However, when focusing on neuropathic pain such as diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia, or failed back surgery syndrome, there is no sufficient evidence on the effectiveness of acupuncture.Some studies have proposed the mechanisms of acupuncture for pain reduction. The local analgesic effects of acupuncture are mediated by adenosine A1 receptors explored effectiveness of electroacupuncture (EA) for patients with moderate to severe neuropathic pain despite already receiving conventional oral medications, and assessed the feasibility of a large-scale trial. The results showed that EA significantly decreased the intensity of pain in neuropathic patients, especially burning sensations, electric shock-like pain, and mechanical hyperalgesia. Furthermore, the number of acupuncture sessions was a significant factor for favorable results of reducing pain intensity. Based on our previous trial, we designed a large-scale, prospective, open-labeled, randomized, cross-over clinical trial to evaluate the effectiveness and safety of 12 sessions of EA for the treatment of neuropathic pain.Our pilot study22.1The aim of this study is to determine the effectiveness and safety of EA treatment for neuropathic pain when added to conventional neuropathic pain pharmacotherapies compared with no EA treatment. The pain intensity, function, quality of life, global assessment, and adverse events will also be assessed.2.2This study is a prospective, open-labeled, randomized, cross-over clinical trial conducted at Seoul National University Hospital (SNUH) Pain Center and Kyung Hee University Korean Medicine Hospital (KHUKMH) in South Korea.2.2.1A total of 40 patients with chronic neuropathic pain who did not achieve satisfactory pain relief despite receiving conventional treatment for more than 3 months will be recruited in SNUH Pain Center. The expected recruitment period is from December 2019 to May 2021. Participants will be recruited through advertising on the bulletin boards of the hospital, internet homepages of the hospital, public institutions, and through the media.2.2.2This study is a cross-over trial that aims to compare conventional medical treatment (treatment C) with conventional medical treatment and an add-on EA treatment (treatment A) for patients with intractable neuropathic pain. A cross-over design was planned in which participants will be randomly assigned to 2 groups (AC and CA groups) according to the 2 treatment sequences.Screening will be conducted after receiving written informed consent from the participant at SNUH Pain Center Visit 1). They will then be randomly assigned to 1 of the 2 sequence groups: the AC group and CA group (Visit 2). The first treatment period will be conducted for 6 weeks. In the case of “treatment A”, during the treatment period, a total of 12 EA sessions will be performed for 6 weeks at KHUKMH. After the first treatment period, evaluations will continue at SNUH Pain Center (Visit 3). After a washout period of 2 weeks, participants will undergo a pain evaluation period for 7 days (Visit 4). If the average numeric rating scale (NRS) pain score, which is self-recorded in a diary, is 4 points or more during this period, patients will proceed to the second treatment period. If it is less than 4 points, the same “treatment C” will be maintained. The second treatment period will also be conducted for 6 weeks, as in the first treatment period, followed by a final evaluation (Visit 5). Figure . They wi2.32.3.1Participants who meet the following conditions will be included:1.Patients aged 19 years and over at screening.2.Patients who have peripheral neuropathic pain and satisfy criteria A) and B), and have criterion C) or D) identified on examination, depending on the conditions.A)Have a confirmed medical history of diagnosis for neuropathic pain according to clinical findings.B)Symptoms, history, and physical examination of patients suggest peripheral neuropathic pain.C)Electromyography/nerve conduction study or evoked potential test suggest peripheral neuropathy.D)Ultrasonographic examination at screening reveals lesions that indicate peripheral entrapment syndrome or peripheral neuropathy.3.Have unsatisfactory pain relief despite appropriate conservative treatment for more than 3 months before screening.4.Have a score ≥13 on the Korean version of the PainDETECT Questionnaire (PD-Q) at screening.5.Have an average score ≥4 on the NRS measured by a pain diary during the 7-day screening period before randomization.6.No evidence of disease recurrence in cancer survivors.7.Patients who can voluntarily consent to the study, understand the process of the study, and adequately write a reportable questionnaire.2.3.2Participants will be excluded if any of the following conditions are satisfied:1.Have other severe pain not related to the target disease that could cause confusion during pain assessment at screening or randomization.2.Use prohibited concomitant therapies within 7 days prior to screening, or change to concomitant medications with restricted usage within 14 days prior to screening.3.Have a clinically significant unstable nervous system, ophthalmological disease, hepatobiliary disease, respiratory disease, blood disease, cardiovascular disease, or mental disease within 12 months before screening.4.Used EA treatment at the affected area within 1 month before screening.5.Are pregnant, breastfeeding, or expecting a pregnancy during the study period.6.Have implanted medical devices such as spinal cord stimulators, implantable drug delivery systems, pacemakers, automatic defibrillators, aneurysm clips, vena cava clips, and skull plates.7.Have brain damage, symptomatic brain metastases, or epilepsy.8.Have abnormal skin conditions that would prevent proper application of the EA treatment.9.Are participating in other interventional clinical trials within 30 days before screening or present.10.Have severe bleeding tendency: low doses of oral aspirin and a general dose of antiplatelet/anticoagulant medication generally do not limit study participation, but only when apparent risk is predicted by the investigators judgment.11.Use immunosuppressive drugs.2.4The randomization table was generated using SAS Version 9.2  to assign patients to the AC group or CA group in a 1:1 ratio by the block randomization method. After obtaining informed consent, participants who satisfy the inclusion/exclusion criteria will be allocated on a web-based basis according to this randomization table. A random allocation table will be created at the Medical Research Collaborating Center (MRCC) of SNUH, and will be operated through web random allocation. The outcome assessors, data managers, and statisticians will be blinded to the allocation.2.5 which was developed through a consensus of acupuncture specialists based on western medical acupuncture techniques as well as traditional meridian theory. EA treatment will be performed by Korean medicine doctors who graduated after 6 years of Korean medical college education and have at least 8 years of clinical experience. A total of 12 acupuncture sessions for 6 weeks will be performed using 0.25 × 40 mm disposable sterile acupuncture needles , which will be retained for 15 minutes. Up to 20 acupuncture points will be chosen by the practitioner based on traditional Asian medicine and western medical perspectives,17 for local, segmental, and general stimulation. Local stimulation is defined insertion of the needle at a classical acupuncture point, tender point, or trigger point near the painful area. Segmental stimulation is insertion of the needle around area innervated by the same meridian or spinal nerve as that of the painful region. If direct needling to the local and segmental points exacerbates the pain, perisegmental points that are close to the affected segment, such as those above and below the area, or those on the opposite side of the equivalent contralateral segment will be used. Distal points which are located in the extremities for general stimulation will be chosen to treat the comorbidities of chronic pain according to traditional theory, such as insomnia , depression/anxiety , or fatigue .The EA treatment was modified from our pilot study,Electrical stimulation will be delivered using an EA device  with 2 Hz , 2 to 6 Hz , 120 Hz , or 2 to 120 Hz   approximately 80% of the maximum intensity.2.6Existing oral and transdermal drugs  should be taken at the existing dose from screening to the end of the study. Depending on the pain intensity, additional prescription of oral acetaminophen is allowed as a rescue medicine for analgesic purposes. If acetaminophen is used, the participant should record the dose of acetaminophen and date in the patient diary. Anticonvulsants and antidepressants, which were being used to control symptoms of existing neuropathic pain, are also taken at the maintenance dose during the study period. Only when there are safety problems with the use of these drugs, dose reduction or discontinuation of these drugs will be permitted if necessary.Subjects who received interventional therapies such as nerve block, iontophoresis, laser therapy, spinal cord irritation, and transcutaneous electrical nerve stimulation have a minimum washout period of 7 days prior to their first visit. These therapies are prohibited in the study period. Other forms of pain relief therapy for neuralgia such as psychotherapy and physiotherapy can be continued from 14 days prior to the first visit if the frequency of therapy does not change; however, these are not allowed to start during the study period.2.72.7.1The proportion of participants who achieved improvement, as measured by the predefined composite efficacy outcome (CEO)  at 6 weeks after randomization, will be used as the primary outcome measurement.2.7.2Secondary outcomes include the differences in NRS score, the short-form McGill Pain Questionnaire, the BPI-SF, the Fatigue Severity Scale, the Hospital Anxiety and Depression Scale, the Medical Outcomes Study Sleep Scale, PGIC, EQ-5D-3L, PD-Q, Patient Satisfaction Scale, and incremental cost-effective ratio at 6 and 15 weeks after randomization will be measured.2.7.3Safety will be examined on every visit by measuring vital signs, performing physical examinations, and recording adverse events (AEs). For vital signs, the degree of change after the treatment period compared to before the treatment period will be summarized as mean, standard deviation (SD), median, minimum, and maximum value. The results of the physical examination will be summarized by the frequency and ratio. AEs will be summarized by the number and ratio of patients who experience AEs and serious AEs. The human chorionic gonadotropin urine test will only be performed in fertile women at the first and fifth visits.2.8This study was developed according to the following hypotheses:0: p1 = p2H1: p1 ≠ p2Hp1 = proportion of participants in the acupuncture group who achieved improvement, as measured by the predefined CEO after 6 weeks from baseline.p2 = proportion of participants in the control group who achieved improvement, as measured by the predefined CEO after 6 weeks from baseline. the patients who achieved significant improvement was 44%, defined as a decrease in NRS, a reduction in PIS of BPI-SF scores of more than 20% from baseline, and change to “minimally improved”, “much improved”, or “very much improved” status, as measured by PGIC. Though there was no control group in the pilot study, we assumed that the conservative estimated proportion in the placebo group will be 10%. Assuming that the period and carryover effect does not exist, the difference in proportions of the 2 groups is 0.34 and within-subject SD is 0.34. Sixteen participants are required for each sequence group with a two-sided significance level of 5% (α = 0.05) and 90% power (1-β = 0.9). Consequently, a total of 40 patients (20 in each group) will be included, accounting for a potential 20% drop-out rate.Based on our pilot study,2.9The analysis set will consist of a modified intention-to-treatment (ITT) analysis set, a per protocol (PP) set, and a safety set. The modified ITT set will include the participants who were randomized, received acupuncture or conventional treatments, and have at least 1 effect assessment after treatment. The PP set will include only participants who received at least 1 assessment and completed the study protocol without major deviation. The safety set will include any participants who received at least 1 acupuncture or conventional treatment after randomization. The modified ITT analysis will be the main analysis of this study.t test or a Wilcoxon rank sum test will be performed for continuous data, and a Chi-Squared test or Fisher exact test will be performed for categorical data.For the descriptive analysis, Student For a confirmatory analysis, the primary endpoint is the proportion of participants who show improvement, as measured by the predefined CEO at 6 weeks after randomization. The carry-over effect will be checked with a linear mixed model, and if the carry-over effect is not significant, the improvement frequency and ratio at 6 weeks for each treatment period in each sequence group will be summarized. The difference of the overall improvement rate (δ) between the groups will be estimated, and the null hypothesis will be rejected as follows:σd: variance of the difference of the improvement rate between the groups within the subjectn: number of participants in each groupIf the carry-over effect is significant, only data from treatment period A will be used and tested using the Chi-Squared test or Fisher exact test. Additionally, the carry-over effect, period effect, and sequence effect will be corrected using a generalized linear mixed model, and then the additional effects of acupuncture will be examined. At this time, the random effect, sequence, treatment period, and acupuncture treatment will be considered as fixed effects, and carry-over effect and period effect will be tested in terms of sequence order and treatment period, respectively. The term with a level of significance greater than 0.3 will be excluded from the model and the add-on effect of acupuncture treatment will be identified.For secondary outcome measurements, continuous data will be summarized as mean, SD, median, and minimum/maximum value for each treatment period in each group, and compared between the 2 groups using a linear mixed model. Categorical data will be summarized as frequency and ratio for each treatment period in each group, and compared between the 2 groups using a generalized linear mixed model.Statistical analyses will be performed by a statistician in the MRCC blinded to the group allocation using SAS Version 9.2 .2.10The independent researcher will conduct regular monitoring to ensure quality control of the data. The researcher will monitor the written informed consent forms, compliance of protocol, and data documents during the study period. Monitoring also check for AEs.2.11,19Participants will be asked to report any AEs including those induced by EA throughout the study period at each visit. The expected AEs related with EA treatment include treatment-related pain, bruising, bleeding, or infection at the local site, nausea, dizziness, or anxiety.If AEs occur during the clinical trial, researchers will investigate the severity of symptoms, relevance to the intervention, action related to the intervention, treatments for AEs, and the result and seriousness of AEs. In the event of serious complications, researchers will provide adequate treatment to patients and terminate the EA treatment early if the patients find it difficult to continue the study. After that, a report will be prepared and submitted to the institutional review board (IRB).2.12The study was designed in accordance with the Helsinki Declaration to protect the participants and was approved by the IRB of the SNUH (H-1810-075-979) and the KHUKMH (KOMCIRB 2018-12-002). Only participants who voluntarily provide written consent after receiving a full description of the study prior to screening will be included. Participants are informed of the potential benefits, risks, alternatives, and responsibilities during the study by the researcher throughout the consent process. The results will be disseminated through a peer-reviewed journal and conference presentations.3This is the study protocol for a prospective, open-labeled, randomized, cross-over clinical trial for patients with intractable neuropathic pain. This study aims to evaluate the effectiveness and safety of EA combined with conventional treatment compared to conventional treatment alone after 6 weeks of treatment. which showed that the protocol was feasible and acceptable for a large scale trial considering the low dropout and high compliance rate. The study identified the appropriate dose of EA treatment, which was 12 sessions, once or twice a week, for 8 weeks. EA twice a week during the first 4 weeks led to an almost 50% reduction in pain intensity from baseline; however, EA once a week for the following 4 weeks did not have a clinically meaningful analgesic effect. Therefore, we will administer a total of 12 sessions of EA treatment twice a week for 6 weeks.This confirmatory trial was designed after adapting the results of our previous pilot trial affective dimensions, overall quality of life, and pain intensity were also improved after EA treatment. Since accompanying symptoms such as insomnia, anxiety, and depression, which are major comorbidities of chronic pain can affect pain intensity,,20 it is necessary to identify the degree to which the analgesic effect of EA treatment correlates with the effect of these symptoms. Therefore, we measured the effect of EA treatment on these comorbidities with validated scales.In our pilot study, Therefore, integrating the assessment of pain intensity and functional disability is recommended for a trial assessing chronic pain, although there are some methodological disadvantages. Based on the results of our previous study, we defined the CEO to include pain intensity, various aspects of pain, and global assessment of the patient, and adapted it for this confirmatory trial.Some studies have suggested that pain intensity alone could not assess the value of interventions and overall experience of patients with chronic pain, and the functional aspect and quality of life should also be comprehensively considered.To summarize, using data from our pilot study, this confirmatory trial was adapted with several improvements, and will assess the effectiveness and safety of EA in patients with refractory neuropathic pain.We would like to thank all members of the research team  at KHUKMH and SNUH pain center.Conceptualization: Seunghoon Lee, Jee Youn Moon.Funding acquisition: Seunghoon Lee, Jee Youn Moon.Methodology and project administration: Seunghoon Lee, Jee Youn Moon, Sang Hoon Lee.Writing – original draft: Seunghoon Lee, Suji Lee.Writing – review & editing: Jee Youn Moon, Chang-Soon Lee, Yongjae Yoo, Sang Hoon Lee.


To evaluate the validity and reliability of the Dutch STarT MSK tool in patients with musculoskeletal pain in primary care physiotherapy.Physiotherapists included patients with musculoskeletal pain, aged 18 years or older. Patients completed a questionnaire at baseline and follow-up at 5 days and 3 months, respectively. Construct validity was assessed by comparing scores of STarT MSK items with reference questionnaires. Pearson’s correlation coefficients were calculated to test predefined hypotheses. Test-retest reliability was evaluated by calculating quadratic-weighted kappa coefficients for overall STarT MSK tool scores (range 0–12) and prognostic subgroups . Predictive validity was assessed by calculating relative risk ratios for moderate risk and high risk, both compared with low risk, in their ability to predict persisting disability at 3 months.In total, 142 patients were included in the analysis. At baseline, 74 patients (52.1%) were categorised as low risk, 64 (45.1%) as medium risk and 4 (2.8%) as high risk. For construct validity, nine of the eleven predefined hypotheses were confirmed. For test-retest reliability, kappa coefficients for the overall tool scores and prognostic subgroups were 0.71 and 0.65, respectively. For predictive validity, relative risk ratios for persisting disability were 2.19 (95% CI: 1.10–4.38) for the medium-risk group and 7.30 (95% CI: 4.11–12.98) for the high-risk group.The Dutch STarT MSK tool showed a sufficient to good validity and reliability in patients with musculoskeletal pain in primary care physiotherapy. The sample size for high-risk patients was small (n = 4), which may limit the generalisability of findings for this group. An external validation study with a larger sample of high-risk patients (≥50) is recommended. Musculoskeletal conditions, such as low-back pain, neck pain, osteoarthritis and rheumatoid arthritis, are the most common cause of long-term pain and impaired physical function , and havMusculoskeletal pain is predominantly managed in primary care, for example by the physiotherapist. Although current evidence shows positive effects of exercise therapy and psychosocial interventions on pain and function in patients with musculoskeletal pain , 10, it The Keele STarT Back-Screening Tool (SBT) is an example of a valid and reliable risk stratification tool developed to allocate primary care patients with low-back pain into three prognostic subgroups , and to apply the appropriate matched treatment . The oriRecently, a modified, generic version of the SBT was developed for patients with the five most common musculoskeletal pain presentations  within the UK , 22. ThiPrior to the start of this study, we formally translated the original English version of the STarT MSK tool into Dutch using a forward-backward translation method according to the guidelines of Beaton et al.  24]. Th. Th24]. In this clinimetric study a prospective observational design was used to evaluate the measurement properties of the Dutch STarT MSK tool. Patients were asked to complete baseline and follow-up questionnaires (5 days and 3 months), and received usual care from their physiotherapist. This study was not subject to the Medical Research Involving Human Subjects Act (WMO) and received a ‘non-WMO’ declaration from the Medical Research Ethics Committee of the University Medical Centre Utrecht, The Netherlands (registration number 18–082).A total of 65 physiotherapists within the authors’ network were invited to participate in this study. Only physiotherapists who were working in primary care and were seeing at least 1 to 2 patients with musculoskeletal pain for a first consultation per week were eligible to participate in this study.The inclusion period for patients was February 2018 to May 2018. Patients were eligible for inclusion when (1) they consulted a participating physiotherapist for musculoskeletal pain  during the inclusion period, (2) it was the first consultation for the current episode of musculoskeletal pain, (3) they were aged 18 years or older, (4) they were able to read and write in Dutch and (5) they had an email address. Patients were excluded when (1) during the first consultation red flags were found indicating a possible specific underlying pathology  responsible for the musculoskeletal pain, (2) they consulted a physiotherapist for pre- or post-operative rehabilitation related to the musculoskeletal pain presentation, (3) they were diagnosed with inflammatory arthritis, spondyloarthropathy or polymyalgia rheumatica, (4) they experienced pregnancy-related pain problems or (5) they had a cognitive impairment.The participating physiotherapists received information about the study procedure during a one-hour in-company instruction. Physiotherapists informed eligible patients about the study and screened them on in- and exclusion criteria. Patients who were willing to participate received an information letter from the physiotherapist. After patients had given permission to be contacted, the researcher (AB) received their contact information from the physiotherapist using a secured messenger service. Patients were then e-mailed by the researcher (AB) and received a link to the informed consent form as part of the baseline questionnaire. The link to the baseline questionnaire was sent within 24 hours after the first consultation with the physiotherapist. Patients could only start filling-in the questionnaire if informed consent was provided. When necessary, a reminder was sent to the patient within 3 days. Respectively 5 days and 3 months after filling in the baseline questionnaire patients received the link to the follow-up questionnaire.At baseline (T0), general patient characteristics including age, gender, educational level, pain site, pain duration and presence of comorbidity were obtained. The prediction of persisting musculoskeletal-related disability was assessed with the Dutch STarT MSK tool, consisting of 10 independent items that cover biomedical and psychosocial prognostic factors . SubgrouFive days after filling-in the baseline questionnaire patients received a follow-up questionnaire (T1) consisting of the Dutch STarT MSK tool, the NPRS to assess the average pain in the past week and the Global Perceived Effect (GPE) scale  to measuThree months after filling-in the baseline questionnaire patients received a follow-up questionnaire (T2) consisting of the SF-36 PF to assess disability, the NPRS to assess the average pain in the past week and the GPE scale to measure recovery.The measurement properties construct validity, test-retest reliability and predictive validity were evaluated according to the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist , 34.A priori we expected a moderate  to high (r ≥ 0.5) positive correlation between STarT MSK item 1 with the NPRS, item 6 with the timeline question of the Brief IPQ, item 7 with the single-item question on ‘comorbidity’, item 8 with the HADS-D, item 9 with the TSK-11, item 10 with the single-item question on ‘pain duration’; and a moderate  to high (r ≤ -0.5) negative correlation between item 2 with the PSEQ and item 4 with the SF-36 PF [r ≥ 0.3, < 0.5) to high (r ≥ 0.5) positive correlation between the STarT MSK bothersomeness item 3 with the NPRS and a moderate  to high (r ≤ -0.5) negative correlation between item 3 with the SF-36 PF, as bothersomeness has been associated with pain and disability [r < 0.3) between item 5 and the NPRS, as this item focuses on the location of pain and not on pain intensity.To evaluate construct validity, we compared scores of the separate STarT MSK items with reference questionnaires. This method was used because the STarT MSK tool is a formative model , which mSF-36 PF . We expesability . FinallyTo evaluate test-retest reliability, we assessed the agreement between scores of the Dutch STarT MSK tool on baseline and after 5 days. The time interval was considered long enough to prevent for recall bias, given the large number of questionnaires patients had to complete at baseline. Next, 5 days were considered short enough to prevent substantial improvement . A sensiTo evaluate predictive validity, we assessed the ability of the Dutch STarT MSK tool to predict persisting disability at 3 months. Persisting disability was defined as a SF-36 PF score equal to or below the baseline median , as stanTo evaluate construct validity, test-retest reliability and predictive validity, a minimal sample size of 50 patients is advised and a sample size of 100 patients is adequate according to the COSMIN checklist , 43. In Statistical analysis was performed using IBM SPSS Statistics version 25.0 . Descriptive statistics were calculated for baseline characteristics of the study population, with continuous variables presented using mean and standard deviations. Categorical and nominal/dichotomous data were presented as proportions for each category.Pearson’s correlations were calculated between specific items of the Dutch STarT MSK tool and their reference questionnaires. The construct validity was defined as good if at least 75% of the a priori hypotheses could be confirmed .= 0.21–0.40 fair agreement, κ = 0.41–0.60 moderate agreement, κ = 0.61–0.80 substantial agreement and κ = 0.81–1.00 almost perfect agreement [The quadratic-weighted kappa was calculated for overall scores of the Dutch STarT MSK tool and prognostic subgroups, with κ ≤ 0 indicating poor agreement, κ = 0.01–0.20 slight agreement, κ greement .To examine calibration of the STarT MSK tool, we calculated the proportion of patients with persisting disability at 3 months in each risk group. Relative risk ratios (RRs) were calculated for medium risk and high risk, each compared with low risk, in their ability to predict persisting disability at 3 months.In total, 44 physiotherapists were willing to participate and instructed. A number of 22 physiotherapists from 11 primary care physiotherapy clinics actually recruited patients. Of the participating physiotherapists, the majority was specialised as manual therapist or sports physiotherapist. A total of 167 patients were recruited, of whom 146 patients were included . Four paOn average, the time between the first consultation of physiotherapy and completing the baseline questionnaire was 2 days. Baseline characteristics of the study population are presented in The highest correlations were found between item 1 with the NPRS and item 10 with the single-item question on ‘pain duration’ . The corIn total, 142 patients (100%) completed the Dutch STarT MSK tool at T0 and T1, of whom 77 patients were regarded as stable. On average, the time between T0 and T1 was 7 days. The quadratic-weighted kappa coefficients for the overall STarT MSK tool scores (range 0–12) and prognostic subgroups  were 0.71 and 0.65, respectively, indicating substantial agreement . DistribIn total, 136 patients (96%) completed the follow-up questionnaire at T2, of whom 73 patients were classified as low risk at baseline, 60 as medium risk, and 3 as high risk for persisting disability because of musculoskeletal pain. The mean (SD) SF-36 PF score at follow-up was 88.2 (14.4). The proportion of patients with persisting disability (SF-36 PF ≤ 80.0) was 13.7% in the low-risk group, 30.0% in the medium-risk group, and 100.0% in the high-risk group . The RRsThe aim of this study was to evaluate the validity and reliability of the Dutch STarT MSK tool in patients with musculoskeletal pain in primary care physiotherapy. The results showed a good construct validity, as 81.8% of the predefined hypotheses were confirmed. Test-retest reliability was substantial for the overall tool scores and prognostic subgroups in the test-retest sample, with quadratic-weighted kappa coefficients of 0.71 and 0.65, respectively. Test-retest reliability remained substantial for the overall scores and decreased slightly to a kappa of 0.60 for prognostic subgroups in the subset of patients reporting stable symptoms between T0 and T1. The predictive validity was sufficient, with RRs for persisting disability of 2.19 (95% CI: 1.10–4.38) for the medium-risk group and 7.30 (95% CI: 4.11–12.98) for the high-risk group, both compared to the low-risk group. The sample size for high-risk patients was small, therefore results for this group should be interpreted with caution.The risk group distribution in our study was different from the distribution in the UK validation study  and STarAlthough the test-retest reliability found in our study suggests that the Dutch STarT MSK tool is able to classify patients into the same prognostic subgroup over time, further research may need to focus on the timing of stratification. We found a quadratic weighted kappa coefficient of 0.65 for prognostic subgroups, indicating substantial agreement. The kappa coefficient decreased to 0.60, indicating moderate agreement, when reliability was calculated using clinically stable patients. It seems more appropriate to consider the test-reliability of prognostic subgroups as substantial since distribution of prognostic subgroups was skewed due to the very low prevalence of patients at high risk, which increases chance agreement and reduces the value of kappa accordingly . AdditioIn our study patients received usual care from their physiotherapist. This methodology was chosen, because it most closely resembles how the tool will be used in physiotherapy practice and it seems not ethical to refrain patients from physiotherapy treatment during a 3-month period. Physiotherapy treatment might have influenced the predictive validity of the Dutch STarT MSK tool. In a study regarding changes in SBT categorisation during routine physiotherapy care, 81.8% of the high-risk, 76.0% of the medium-risk and 11.3% of the low-risk patients were categorised differently within a few weeks . In a DaTo our knowledge, the STarT MSK tool is the only screening tool originally developed to allocate primary care patients with musculoskeletal pain into prognostic subgroups and subsequently stratify for the appropriate matched treatment. The prediction of persisting musculoskeletal-related disability is based on the presence of biomedical and psychosocial prognostic factors at initial assessment. Beneciuk et al. concluded that reliance only on initial (SBT) risk categorisation may have limitations due to changes that might occur following routine physical therapy, and suggested that repeated assessment of risk categorisation can potentially improve prognosis for long-term low-back pain related disability . Given tThe strength of this study is that we evaluated the measurement properties of the Dutch STarT MSK tool in primary care physiotherapy. In the Netherlands, physiotherapists in particular are involved in the treatment of patients with musculoskeletal pain and therefore are likely the primary users of the tool. Another strength is that we achieved an appropriate sample size (>100 patients) and respectively 100% and 96% follow-up rate. The present study has some limitations. First, the setting in which patients were included might have resulted in the low proportion of high-risk patients and limited generalisability of findings. Second, for feasibility and ethical reasons, patients received usual care from their physiotherapists. Effective physiotherapy treatment could have influenced the predictive validity of the Dutch STarT MSK tool. Third, the sample size for high-risk patients was too small to calculate performance characteristics  in order to examine discrimination of the Dutch STarT MSK tool . FinallyThis validation study is a first step toward identifying whether the Dutch STarT MSK tool could be useful for physiotherapy practice. According to the psychometric analysis, the tool showed a sufficient to good validity and reliability in patients with musculoskeletal pain in primary care physiotherapy. Based on these results, the tool can be implemented in Dutch physiotherapy practice, in which it can be used to predict persisting disability at an early stage. Because of the small sample size for high-risk patients (n = 4), generalisability of findings may be limited. An external validation study with a larger sample of high-risk patients (≥50) is recommended. Furthermore, the Dutch STarT MSK tool is not just a prognostic screening tool, but can be used to stratify patients for the appropriate matched treatment as well. Matched treatment packages are available for patients with low-back pain . In addiS1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.


Although mirror therapy (MT) and phantom exercises (PE) have been shown to reduce pain, the efficacy of these methods in terms of pain, quality of life (QoL), and psychological status (PS) has not been investigated and compared to date. The aim of this study was to determine whether there is any difference between MT and PE in the treatment of phantom limb pain (PLP). Forty unilateral transtibial amputees (aged 18–45 years) participated in this study. The subjects were randomly divided into ‘MT group’ and ‘PE group’. QoL was assessed using Short-Form 36 (SF-36), psychological status using the Beck depression inventory (BDI), and pain intensity using a visual analog scale (VAS), before and at the end of the program, and on the 3rd and 6th months thereafter.  All assessments for all parameters improved significantly in both groups (P < 0.05). Comparison of the two groups revealed a significant difference in changes for VAS and BDI in all measurements, and in pre- and posttreatment scores for all SF-36 parameters  in favor of the MT group (P < 0.05).  While pain intensity decreased and QoL and PS improved in both the MT and PE groups, these improvements were greater in the MT group. Phantom limb pain (PLP) is a very frequent painful sensation perceived within the absent part of the amputated extremity. It is mostly reported in the distal part of the phantom limb . PLP can be a distressing phenomenon that becomes chronic and affects the patient’s quality of life (QoL) . The pathophysiology and the etiology of PLP have not yet been fully established (5). Complex peripheral and central mechanisms have been implicated (6). Flor (2) reported reorganization in patients with PLP, expansion of receptive fields affected by pain, and changes in the neuronal activity from the adjacent zone into the deafferented zone, representing the preamputation part of the extremity. The incidence of PLP is 50%–80% after amputation (7). Estimated prevalences of PLP of 78% (8), 59% , 50% (11), 29% (12), and 51% (13) have been reported. The high incidence of PLP makes it important for beneficial and cost-effective treatments to be found (14). Many treatment options for PLP have been suggested. The most commonly used methods in the treatment of PLP include medication, surgical, and anesthetic methods, cognitive-behavioral pain management, and physiological approaches. Electromyography, thermal bio-feedback, transcutaneous electrical nerve stimulation (TENS), acupuncture, ultrasound, and immediate prosthetic implementation have also been used in the treatment of PLP as physiotherapeutic approaches (2). However, there is a lack of high-quality clinical trials to support the effectiveness of these treatments. The evidence level of the effectiveness for these methods was found to be low by several authors (15–18). Mirror therapy (MT) was first used for PLP by Ramachandran (19). MT has been described as the most promising method and as capable of reducing PLP (20). During MT, the patient is asked to place the amputated limb behind a mirror. The patient then moves and watches the reflection of the intact limb in the mirror. This creates a visual illusion of the movement of the amputated side (21). In terms of the mechanisms underlying MT, it has been suggested that the visual illusion generates positive feedback to the motor cortex, thus blocking the pain cycle (22). In addition, MT reverses the neural reorganization of the sensory–motor cortex associated with PLP and thereby has been shown to be effective in reduction of PLP . Ülger et al. (24) developed phantom exercises (PE) based on MacIver’s (25) mental imagery exercises. The PE technique consists of active movements of the sound limb and imagined movements of the phantom extremity (24). PE aims to modify and reverse cortical reorganization and to restore the integrity of cortical information processing using the patient’s own imagination perception. The effectiveness of MT and PE has been investigated in various studies. Promising results have been reported. The present study was designed to evaluate and compare the effects of MT and PE on the severity of chronic PLP, and on QoL and psychological status in lower-limb amputees (LLAs).The study was designed as a prospective randomized clinical trial and was approved by the Hacettepe University ethical committee, Ankara, Turkey (25.11.2010 / HEK 10 / 80 - 16). All participants gave informed consent to participate. Forty , posttraumatic, unilateral transtibial amputees participated in this study. All subjects were regularly attending the Prosthetics and Biomechanics Unit of Hacettepe University. All patients had PLP at the time of inclusion and experienced PLP regularly (at least one episode per week), with an average intensity of at least 40 on a visual analogue scale (VAS). Amputees with systemic disease, mental or cognitive impairment, any other neuropathic pain except for PLP, stump pain, or using any walking aid or drug treatment for PLP and with a history of surgery due to pain were excluded. The patients did not take any medication for pain relief during the study.Before beginning the study, the amputees were assigned to one group using the closed envelop randomization technique. There were 2 groups; each group consisted of 20 subjects. MT was administered to the ‘MT group’ and PE to the ‘PE group’ all for 4 weeks. The exercises were shown and patients practiced in the treatment unit for one session with B.A.K. The subjects were then asked to continue their exercises daily at home. They were checked by phone call every other day and asked to attend the treatment unit once a week during the first 4 weeks. Our aim was to increase the motivation of patients and exercise compliance. During the following weeks, the phone calls and unit visits decreased to once a week and biweekly, respectively. The patient placed the amputated limb inside a mirror box so that it could not be seen. The reflective surface of a 120 × 40 cm rectangular mirror on the box was arranged to face the intact limb. The mirrors were provided to patients for MT applications, except for patients who wanted to buy their own.The subject was asked to perform synchronous and periodic toe and ankle movements 10 times using both the intact and phantom limbs for 15 minutes while looking at the reflection of the intact limb in the mirror. These movements were repeated for 1 session daily for 4 weeks. The exercises were described as ﬂexion/extension, inversion/eversion of the foot, foot rotation around the ankle, adduction with ﬂexion of the toes like clenching, and abduction (spreading) with extension of the toes like unclenching. The last exercise in 1 session was described as relaxation of all muscles after strong contraction of all foot and ankle muscles of both the phantom and intact limbs  (4). Exercises were performed with 15 repetitions. If the PLP disappeared after fewer than 15 repetitions, exercise was ended. The patients were asked to perform the PE daily or in the case of recurrence of PLP in a day. They were asked in which position they felt the phantom limb, and instructed to keep that position, to place the intact limb in the same position as their phantom limb, to move both limbs in opposite directions, and to return them to the starting position again. The patients were asked to repeat these movements a couple of times. These movements were: ankle ﬂexion/extension, inversion/eversion of the foot, adduction with ﬂexion of the toes like clenching, and abduction (spreading) with extension of the toes like unclenching. After the patient felt relaxation in this position, the movements were repeated as knee flexion/extension and hip flexion/extension, respectively  until PLP disappeared (24). All measurements were performed before (t0) and after the procedures (t1), and were repeated at the 3rd (t2) and 6th (t3) months in the follow-up period in the treatment department.At the initial evaluation, we recorded the patients’ clinical and demographic characteristics.The intensity of PLP was measured using VAS score, on which patients could grade their pain along a 100-mm line from “0”  to “100” (the most severe pain). The participants marked the most severe degree of pain on the VAS each day during the 4-week treatment period. The patients were given a printed pain diary. In addition to the pain diary, the intensity of PLP was measured at the t2 and t3 controls (26). QoL was evaluated using the Short-Form 36 (SF-36) questionnaire. This consists of physical functioning (PF), social functioning (SF), role limitation due to physical problems (RP), role limitation due to emotional problems (RE), mental health (MH), vitality (V), pain (P), and general health perception (GH) domains. Possible scores range between 0 and 100. Higher scores indicate better health-related QoL (27). The validity and reliability of the Turkish version was established by Kocyigit et al. (28).The Beck depression inventory (BDI) was used to assess psychological status. This contains 21 items, each scored between 0 and 3. The total possible score is between 0 and 63, with higher scores indicating higher levels of depressive mood (29). The reliability of this scale for Turkey was determined by Hisli (30).SPSS for Windows 21.0 and the “nparLD” and “nlme” packages in R were used for statistical analysis. The distribution of continuous variables was examined with the Shapiro–Wilk test and normality plots. The normally distributed continuous variables were expressed as mean ± standard deviation (mean ± SD), while the nonnormally distributed variables and categorical variables were given by median (range) and n (%), respectively. The continuous demographic features of groups were compared with independent samples t-test and Mann–Whitney U test with respect to the distribution of the variable. The chi-square test was used in the comparison of categorical features. The related test statistics and P-values were presented. The change of pain, quality of life, and depression measurements across assessment time in groups were compared by F1-LD-F1 design. ANOVA type statistics and its P-value were given as a result. Friedman’s test was used for comparison within the groups, and the Mann–Whitney U test was used for analysis between the groups for the aforementioned measurements. Bonferroni-corrected P-values were given.The pain intensity levels of the groups, recorded over 28 days, were analyzed with linear mixed models to detect the any difference. The covariance structure of random effects was set unstructured, as the autocorrelational residuals covariance pattern was determined with respect to the minimum information criteria such as AIC and BIC. AIC, regression coefficient, and their standard errors (SE) were given. P < 0.05 was regarded as indicative of statistical significance. The participants’ demographic and clinical characteristics are presented in Table 1. There were no significant differences in terms of demographic or clinical parameters between the two groups at baseline (P > 0.05). Most of the patients had experienced telescoping as they reported that they felt PLP at the distal part of the phantom limb, especially around the fingers, the heel, and the ankle. PLP appeared immediately after amputation in all of the subjects in our study. Most of the patients reported that they felt PLP when they became tired and after standing for a long time. A few subjects reported that the pain was increased due to prolonged immobility of the stump. Pain was decreased when they moved or lightly rubbed their stumps. Our patients generally described PLP as burning, throbbing, cramping, cutting, stabbing, sharp, and shooting sensations.The change in VAS, QoL scores except role limitation due to physical/emotional problems, and BDI were different between the groups  <0.001, Table 2). No signiﬁcant differences between the groups were observed at baseline in terms of VAS, SF-36, or BDI scores (P > 0.05). The groups were homogeneous in terms of these assessment variables. There was a significant reduction in VAS and BDI scores and a significant improvement in SF-36 PF, SF, MH, and V subscale scores in favor of the MT group at t1, t2, and t3 assessment controls (P < 0.05). Differences between the two groups were observed for the SF-36 RE subscale score at t2, t3 assessments (P = 0.035) and for the SF-36 P and GH subscale sore at t1 assessment  (Table 2). The changes in pain intensity as measured by VAS over a period of 28 days according to the patients themselves are shown in Figure 2. There was no difference between the groups with respect to the baseline pain intensity . Although the pain intensity decreased in both groups over 28 days, the amount of decrease was 0.501 (SE: 0.175) units more in the MT group for each time point than the PT group .Although MT and PE have both been shown to reduce pain, the efficacy of these treatment methods in terms of QoL and PS have not been investigated and compared to date. MT, which has become increasingly popular in the last 20 years, was first tested in an amputee with PLP by Ramachandran (31). Although MT has been shown to reduce pain and improve motor functions in PLP patients, most studies consist of uncontrolled trials or case series. There are only 5 randomized controlled studies with small sample sizes, using heterogeneous methods without comparisons of the protocols (32). We aimed to determine whether there is any difference between MT and PE in the treatment of PLP by the present study. This study has showed that both treatments reduced PLP and improved QoL and psychological status in LLAs. The difference in terms of the efficacy of the two treatment methods was in favor of the MT group.In the two case studies, the subjects’ PLP resolved completely in a couple of weeks . Ramachandran et al. (34) applied MT to an upper-extremity amputee with the use of magnifying and minifying lenses for 2 sessions. PLP intensity decreased from 8 to 0 on VAS with the use of minifying lenses. In randomized controlled trials, PLP intensity of the patients in the MT group decreased significantly more than in the control group . In accordance with previous studies, the pain intensity decreased dramatically from 70.7/100 to 7.5/100 in MT group and from 67.5/100 to 22/100 in PE group on VAS at the end of the treatment period during our study. The patients in the MT group reported significant reduction in pain intensity compared with the PE group. In Ülger’s (24) study, 20 amputees were randomly allocated into one of the two groups. The reduction in PLP in the PE group was significant after 4 weeks. There have been only two studies in the literature using PE. Brunelli et al. (38) used modified phantom exercises combined with progressive muscle relaxation and mental imagery exercises twice a week for 4 weeks. A significant decrease in intensity of PLP was found in the treatment group compared with the control group.In our study, pain intensity decreased in both groups, but the decrease level was higher in the MT group. We attributed this to the effect of visual stimuli on patients while performing exercises during MT. The results of our study are in line with those of various previous studies. However, while studies in the literature have reported positive results, most were uncontrolled trials or case studies of low methodological quality. Those results regarding the effectiveness of MT and PE in PLP are therefore far from conclusive. From that perspective, our results may provide guidance for future studies. The participants in our study reported that PE, and especially MT had a positive and rapid impact on reducing pain compared with treatment methods previously used for PLP. They reported that pain decreased from the first sessions of MT and expressed satisfaction with this novel sensory experience. In one study, SF-36 scores were significantly lower in amputees compared to healthy individuals (39). Another study determined significant differences between individuals with or without PLP in terms of SF-36 subscores (27). In contrast, McCartney et al. (40) reported that PLP had a moderate to significant effect on QoL, but only in a small percentage of patients. Houston and Dickerson (41) evaluated QoL in a study using MT to treat PLP in 14 vascular LLAs for 4 weeks and observed a significant improvement in QoL. Very few studies have investigated the relationship between the treatment of PLP and QoL. According to our study results, QoL improved in both groups, although the level of improvement was significantly higher in the MT group. Our results are similar to those of the limited number of studies in the literature. However, this is the first randomized controlled trial investigating QoL of patients with PLP receiving MT and PE. One of the most important reported predictors of QoL in amputee patients is depression (42). A correlation has been shown between high depression scores, increased pain intensity and low QoL. In our study, patients were initially determined to have a moderate level of depression. This is in agreement with the present data. Darnall and Li (14) tested the effectiveness of self-delivered home-based MT in treating PLP. Although they observed a tendency towards depression in their subjects, they determined no correlation between the level of depressive symptoms and treatment response.General psychological conditions in both groups in our study were positively affected compared to baseline. However, a significant difference between the two groups in favor of the MT group was observed at all t1, t2, and t3 assessments. Few studies have examined changes in psychological status as a result of PLP treatment. Only one study assessed the psychological status of individuals undergoing MT (14). No previous studies have examined the effect of PE on psychological status or compared the effects of the two therapeutic approaches with other treatment methods. Ours is the first randomized controlled study to examine and compare the effects of MT and PE on the psychological status of amputees with PLP and to have achieved positive results. Therefore, while our patients’ pretreatment psychological status was consistent with those in the literature, there are no previous studies against which we can compare our treatment results.The time since amputation was less than 2 years for some of our participants. The intensity of PLP can reduce spontaneously by the time the subject is in subacute phase. This situation should be considered as a limitation that could have affected our study results. The small sample size and the absence of the information about wash-out time for the medications were other limitations of our study. The subjects did not use any medication for pain during the study. However, we did not assess the wash-out time for the medications prior to the study. The number and duration of sessions of MT was higher than the frequency of application of PE. Although the methods of application of MT and PE are different, their mechanisms of action are similar. Therefore, we assume that the difference of effectiveness between the two therapies could be due to a difference in frequency.In conclusion, the treatment procedures in this study reduced PLP and improved QoL and psychological status in the short term. The results were also better in the MT group than in the PE group. Our results demonstrate the applicability of both MT and PE in the treatment of PLP and bring a different perspective to that treatment. We think that both MT and PE may be useful guides for future studies since they are easy to implement, cost-effective, and efficient.The use of MT or PE should now be compared with various treatment methods in studies involving larger numbers of amputees and different amputation levels. Further studies are now also needed to reveal the long-term effects of MT and PE.