DPYD genotype] identifies patients at higher risk for toxicity who may be treated more safely with a lower drug dose. The Netherland's National guideline for colon carcinoma was updated in 2017 to recommend DPYD genotyping before treatment with FP. Pretreatment DPYD genotyping identifies approximately 50% of the patients that will develop severe FP toxicity. The aim of the study was to assess the uptake of DPD testing in the Amsterdam University Medical Centers over time and to evaluate stakeholder experiences to indicate barriers and facilitators of implementation in routine clinical care.The fluoropyrimidines (FP)  are commonly used anti-cancer drugs, but lead to moderate to severe toxicity in about 10–40% of patients. DPD testing [either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the We used a mixed-method approach involving electronic patient records of 753 unique patients and pharmacy information systems analyses and fifteen semi-structured interviews with oncologists, pharmacists, and patients. The constellation perspective was used to identify barriers and facilitators at the level of practice, culture and structure. The proportion of FP users who were DPD tested pretreatment showed an increase from 1% (1/86) in Q2-2017 up to 87% (73/84) in Q4-2018. Unlike a landmark paper published in 2015, the National guideline for colorectal carcinoma followed by meetings to achieve local consensus led to this steep increase in the proportion of patients tested.Facilitating factors for stakeholders to implement testing included the existence of clear protocols,  evidence of the utility, being aware that peers are adhering to standard practice and clear and simple procedures for ordering and reporting. Main barriers included the lack of clear divisions of responsibilities, the lack of consensus on a test approach, long turn-around times and non-user-friendly IT-infrastructures. More professional education on the utility and limitations of pharmacogenetic testing was desired by most stakeholders.While the evidence for DPD testing was sufficient, only after the update of a National guideline and local consensus meetings the proportion of FP users that were DPD tested pretreatment rose to 87%. The implementation of personalized medicine requires stakeholders involved to attune practice, culture and structure. A subset of patients (10–40%) treated with FP experience moderate to severe toxicities, including vomiting, diarrhea, and hand-foot syndrome .DPYD)  eliminated by the liver enzyme dihydropyrimidine dehydrogenase (DPD) . DeficieDPYD) . The gen236G > A . Carrier in 0.3% , leadingDPYD variants is a well-known strategy to detect DPD deficiencies and improve patient safety  in 2016 by the editorial board of Medische Oncologie , 65% of the oncologists test their patients for DPD deficiencies prior to treatment with FP. Results of this poll also showed that the main reasons DPD testing is not yet standard of care are the low prevalence of DPD deficiency (mentioned by 23% of respondents), the minimal cost-effectiveness (15%), the poor availability (4%) and other reasons (58%), such as that no quick test results are possible, the test is not validated, toxicity is not only seen among DPD deficient patients, and the incidence of DPD induced toxicity is rather low  and Amsterdam Medical Center (AMC)] over time, and to evaluate stakeholder experiences to ultimately indicate barriers and facilitators of DPD testing implementation as routine clinical care. The results of this study will hopefully inform colleagues elsewhere who also strive for 100% patient safety in the end, and now are implementing DPD testing step by step. Barriers and facilitators identified in Amsterdam may apply elsewhere too.In discussions about optimal strategies for DPD testing, our AMC colleague Van Kuilenburg  has beenFurthermore, we apply the “constellation perspective”, by structuring the influences on implementation, as mentioned by the stakeholders, in terms of changes in culture, structure, and practice . By doinA mixed methods approach was used involving patient records and pharmacy information systems analyses  and stakeholder interviews . All research was done within Amsterdam UMC, which comprises of location VUMC and AMC. This study was approved according to the national legislation. The Medical Ethical Committee of the VU University Medical Center Amsterdam evaluated the study design and decided that the Medical Research Involving Medical Subjects Act (WMO) does not apply to this study and that further official approval is not required (2019.069).via this platform from EPIC (electronic patient information system) and GLIMS (laboratory information system). For location AMC, also EPIC was used via the Research Data Platform, but laboratory information was extracted from Genesis .The Research Data Platforms of Amsterdam UMC contain retrospective data of different software systems. For location VUMC, data was extracted We selected all patients that started FP treatment  codes: L01BC53, L01BC02, and L01BC06) between the 4th quarter of 2016 up to and including the 4th quarter of 2018. For all patients we collected the following data: anonymously encrypted unique patient ID, ATC codes, medication name, start/stop date of administration, dose, medication status, administration route, and DPD analysis date.DPYD genotyping at Amsterdam UMC location VUMC was evaluated for subsequent quarters by determining the proportion of patients who started FP treatment and were registered as DPD tested. For AMC similar calculations for DPD phenotyping were made. Patients receiving topical 5-fluorouracil (part of ATC code L01BC02) were excluded from the analysis because the guideline applies to systemic use only. Side effects are less likely for topical application. The date of the first administration was used to determine the quarter. The DPD analysis date was used to determine if DPD testing was executed. Additionally, we compared the date of the first administration with the DPD analysis date. All analyses were performed using Microsoft Excel 2016.The implementation of the pretreatment rd quarter of 2017 the Netherland's National guideline for colon carcinoma was updated , two clinical hospital pharmacists , two outpatient pharmacists , one lab specialist (AMC), and four patients . All interviews were conducted face-to-face; 9 interviews by two interviewers (FM and DH) and the other 6 interviews by one interviewer (FM). Informed consent was signed by all participants before the start of the interviews.DPYD genotyping and/or DPD phenotyping, the procedures around DPD testing, the reasons for and experiences with the current approach, and barriers and facilitating factors of implementing this test. Patients were asked about their experience and expectations about the information provision around DPD testing. The interview guides for patients and professionals are available as A semi-structured interview guide was developed based on the constellation perspective  and main themes from literature on barriers and facilitating factors for implementation of pharmacogenomics . The guiInterviews were audiotaped and transcribed verbatim and content analysis was performed using Atlas.ti (Version: WIN 7.5). Transcripts were read and discussed by two researchers . First, recurring topics were labeled. Second, all labels were clustered based on “current practice” and the elements culture, structure, and practice of the constellation perspective in order to identify main themes. Differences in coding were discussed until consensus was reached. Representative quotes were selected and member-checked and translated into English to illustrate findings.nd quarter of 2017. In Q2-2017 1/86 patients were tested. The start of the increase coincides with the updating of the National guideline for colon carcinoma and the local consensus meetings. In the 4th quarter of 2018, 87% of the initiated patients (73/84) was registered as DPD tested.For a total number of 753 unique patients FP was prescribed and 252 patients received DPD testing. In Additionally, we compared the date of administration to DPD analysis date. Ninety-one percent of patients  received FP only after the result of the DPD test was known.The interviews with key stakeholders revealed several themes, including the needs and barriers regarding the implementation of the DPD test in clinical practice. Relevant themes are discussed below, starting with the current situation in the Amsterdam UMCs, followed by the changes that were needed to achieve the current situation and that are needed to improve implementation of pretreatment DPD testing, clustered into the three levels of the constellation perspective .DPYD genotyping for all patients prior to receiving FP treatment.In the interviews, oncologists and a pharmacist of the VUMC expressed that they follow the recommendation to conduct “Yes. For everyone who will get treated with 5-FU or capecitabine we determine the DPYD gene activity.” DPYD genotyping test on four variants In our hospital, performing a DPD test before the start of the therapy is a standard procedure.”“Outpatient pharmacists and one hospital pharmacist of the AMC were unaware of the existence of a DPD test.“Well, I rarely see it [DPD orders/test results]. I don't think it is standard procedure.” “I don't know whether this is standard procedure in this hospital. We at least don't have a role in it.” Patients recalled that they were tested for DPD deficiency. Most of them needed some time and explanation before remembering undergoing the test.“I can't remember exactly and I don't think it has been said emphatically. When they took a liver biopsy, they also analyzed that [DNA test]. That is when I received the gene passport, which was used to determine whether I could possibly receive different therapy. So, maybe I knew it [being tested] this way.” In general, oncologists and pharmacists did not know why either the genotyping or phenotyping DPD test was chosen.“No, I have no idea. I have never looked into that [choice for genotyping].” Opinions vary about the turnaround time of the test in the VUMC, but it perceived as too long by many. Some oncologist stated that it could take up to two weeks, another mentioned half a week, another 7–8 days and a pharmacist thought it would be a maximum of three days.The duration of the phenotyping is 4–10 days according to a lab specialist and the successive genotyping may take up to two weeks, but is often done quicker. Oncologists of the AMC experienced that it may take up to two weeks, but approximately a week to 10 days when no further genotyping needs to be done.“Then [when no aberrant values have been found]it takes approximately a week.” The turnaround time is seen as an important barrier by AMC oncologists.“Yes, I think that's [waiting a week] too long.” All interviewees expressed that oncologists, as head practitioners, have the main responsibility for initiating the DPD test.“I have the impression that this [oncologist is responsible for having DPD test result before start] view is shared by all. I simply cannot order treatment when I haven't seen it [DPD test result] [… ].” According to a hospital pharmacist of the VUMC, they check whether DPD has been assayed. AMC pharmacists indicated that they are not involved in the process. Oncologists of the AMC, however, expressed that the nurses often check whether DPD results are known.“The oncology nurses will always double check if it is safe to start with the DPD test included.” Although outpatient pharmacists and the AMC pharmacist indicated that they are not involved, they expressed interest in the monitoring of medication and the need for clarity of the procedures and responsibilities.“I think it is an important part of our responsibility to check this, yes.” “Legally this is correct. In practice, both doctors as well as pharmacists and other healthcare providers are responsible for doing something with aberrant lab values or results, but this must always happen in full agreement between professionals. In the outpatient pharmacy we work with 2 systems (AIS CGM Pharmacy and ZIS EPIC), which makes it more complicated to properly check and record data as well as any follow up actions.” “[… ], so I think it is important that we are getting involved with the implementation of such a project [DPD testing for patient receiving fluoropyrimidines] and if that hasn't been the case, then it's a bit disappointing.” Oncologists and a lab specialist are not aware whether and in what way the pharmacists are involved and have generally no contact with each other. Only some oncologist indicated to have contact about logistics or to answer questions concerning adjusting the treatment dose. Hospital pharmacists are unaware of any involvement of the outpatient pharmacists and vice versa.“There might be some uncertainty. [… ] Most of the time it [capecitabine] is provided by the outpatient pharmacy. I don't know whether they perform a check” All oncologists expressed that they informed their patients about the DPD test, most of them prior to the start of the therapy. The communication included information on why the test was done and if applicable how the dose of medication was reduced. One oncologist indicated that patients are only informed more extensively when the test results are aberrant.“We communicate more extensively when it [DPD test result] is aberrant and we will give a lower dose of chemotherapy. [… ] When it [test results] is okay, I inform the patient that the DPD results are good and no adjustment of the therapy needs to be made.” According to the patients the information provision was sufficient. Patients for whom the start of the therapy was longer ago did not remember exactly when the information was provided.“Yes, she told me [enough information].” One patient who recently started therapy added that, although the information was sufficient, a simpler (in layman's terms) explanation of what the DPD test exactly is would have been favorable.The main themes identified as important for changing culture regarding pretreatment DPD testing were evidence , willingness to follow guidelines, shared views with coworkers and the perceived need to start treatment as quickly as possible after diagnosis.DPYD genotyping is advised. Most participants were convinced of the importance of this test in order to prevent toxicity and FP related death. However, in general interviewees had no clear idea why the current approach (genotyping or phenotyping) was chosen.In the guideline In general, VUMC oncologists indicated that the test is clinically useful, however, some oncologists questioned the need and clinical utility of the test as they mentioned that the occurrence of toxicity due to DPD deficiency is low and the test not able to perform 100% accurately.“Look, I think you have to test many people to really significantly reduce morbidity or mortality. It is worth a lot to prevent every death, that's the truth of course, but we actually encountered severe toxicity once a year at most. Very few. [… ] but recently there have been publications on routine screening to prevent toxicity, so there is [some] more evidence.” “Well, I have always heard that it wasn't a good test and that you will still not find 50% of the people [with a DPD deficiency], or something like that.” Another oncologist expressed the importance of having a realistic understanding of the limitations of the test.“Yes, I think people are pretty aware right now, but I can imagine that in the future the story will be; you can have toxicity, but when you do that test then you won't have it. So I think it is very important to keep saying that this is only a small part of the possible gene abnormalities and apart from genetic [causes], you can also have toxicity due to other reasons.” Also oncologists of the AMC expressed that they were convinced of the clinical usefulness of the DPD test.“The DPD deficiency is proven by science and is very important, so we can treat our patients safe.” However, one of them questions whether the current approach in AMC is evidence-based.“Well a barrier for me, or not particularly a barrier, but more a doubt why or to what extent it is evidence-based what we do with the phenotyping. Everyone knows about the evidence of cost effectiveness of the genotyping [4 variants], but we phenotype. So, that I find a bit hard.” Pharmacists are enthusiastic about DPD testing, even when they indicated that it is not yet standard procedure. One hospital pharmacist expressed that besides guidelines, the scientific evidence for DPD testing is important.“But when there is scientific evidence and guidelines state that the pharmacy needs to monitor it, then I will definitely do so.” A lab specialist expresses that in order to provide the best possible patient care, not costs but rather the effectiveness of the test [in preventing toxicity] should be leading in future decisions about which DPD test (genotyping/phenotyping) to use.“Having a DPD deficiency is a contraindication for being treated with 5-FU or capecitabine. So, providing a patient a suboptimal test, when knowing there is a better test, I think one doesn't act ethically.[… ] So, I understand the [need for evidence on] cost effectiveness, but I also think it gets a bit exaggerated sometimes.” “That was a patient who was diagnosed by a hospital as a carrier of one of the four pathogenic variants [c.1905+1G > A] in the DPD gene. Fortunately, they also sent us a blood sample and we actually found a complete DPD deficiency when we analyzed the DPD enzyme activity. When we performed an extensive analysis of the DPD gene (DPYD) we discovered that the patient was heterozygous for an amplification of part of the DPYD gene. Such an amplification is very rare and this patient was eventually treated with only 0.8% of the normal dose and would have died if treated with 50% of the normal dose, which is the recommended dose for carriers of this particular variant”.An experience with an aberrant genotype that potentially would have been missed with the current DNA test was described by a lab specialist:In general, oncologists expressed that they simply follow the guideline. However, they also indicated that prior to the implementation of the DPD test they were already able to monitor patients adequately. They expressed that the DPD test is a helpful tool, but remaining critical on what is best for the patient is important.“I think it can contribute, but may also give false security [… ] I don't see it as a holy grail.” “[… ] before [implementation of the DPD test] we haven't done it for very long. Back then we dosed on the basis of how the patient was doing in the first weeks, and since it is not that prevalent, there is something to say for that as well [… ]. On the other hand, the impact of DPD deficiency can be huge, with serious morbidity and mortality that can be avoided by a relatively simple DPD test.” DPYD genotyping, when patients have been treated successfully during a previous treatment cycle of 5 FU.However, they do not always follow the protocol. According to an oncologist (VUMC) they do not order “Then we have proof that it is well tolerated.” Many oncologists indicated that waiting for test results could take (too) long, which causes an unnecessary delay. As a solution they mentioned that they start treatment on a lower dose, before test results are available.“The DPD test will take 2–3 weeks to be known. If it is necessary we will start our therapy 50% lower dose until the results are to be known.” “Certainly, when it causes a hassle and when you have to postpone, then you think I'll just start and will raise the dose later, or I call [the patient] after three days and then I'll still be able to reduce the pills you know, they take it every day, you have some room to play a bit.” A facilitating factor to implement DPD genotyping is that views were shared with their co-workers, according to the interviewees.“Well, in the same way. Everyone is convinced I think, that one way or the other you have to test on such a lowered function of the DPD enzyme and whether that is genetic or phenotypic, that doesn't really matter. [… ], but everyone is convinced that a test has to be performed I think.” “Yes, they[my colleagues] support that.” One oncologist indicated that a possible reason for why DPD testing was not part of standard procedures before the update of the guideline in 2017, was the fact, that the lead oncologist lacked personal belief in the added value of DPD testing.“I think it is the policy of the head of the department, whom is then not convinced.” The three main themes identified as important for changing structure were: logistics (process automation)/infrastructure, protocols and education.Most oncologist of the VUMC indicated that the process of ordering a DPD test is cumbersome and hence expressed that the non-automated process is a disadvantage.“A very inconvenient method; with a lab form from the Erasmus  that we fill out by hand and sent with the patient to the blood test [facility], which will then be sent [to the Erasmus]. “[… ], I think actually the fact that I have to print out and then fill out, that I actually find that the most annoying.” AMC oncologists indicated that the DPD test is ordered digitally in EPIC  and expressed that they do not see any logistic barriers. Pharmacists perceived the lack of a link between several software-systems as a barrier for implementing the test and further implementation of pharmacogenetic testing and expressed that a prerequisite for proper functioning of the process is that all systems communicate.“Definitely, but a barrier is that not all support and systems work optimal. [… ] Logistics are kind of a challenge and that may be why it [DNA medication pass] isn't used that much. [… ] So, I think it [optimal systems and support] is a prerequisite for how this will work.” Pharmacists also expressed that only ten contraindications can be registered in the outpatient pharmacy system, which requires expansion when more pharmacogenetic tests will be performed.A main prerequisite for implementation of the DPD test are the protocols and agreements. Most oncologist expressed that they perform the test, because it is the protocol.“[… ] Since we have made the decision to not start before [having a DPD test result], we adhere to this.” “Yes, it is an obligation. So it is seen as a fault to not test.” “Yes. Before [the guideline update] we did not do that [DPD genotyping], but since the recommendation has been included in the guideline, we adhere to it.” This opinion is also shared by a lab specialist, who indicated that including the instruction to perform DPD testing in a protocol promotes compliance.“I think that in general healthcare is very protocol driven, so when something is not in a protocol, you will not see changes so quickly.” The reports with the test results were perceived as adequate and stakeholders indicated to have enough knowledge to change the treatment dose appropriately.“That [the dose advice] is included [in the VUMC report], we don't need to look it up.” However, one oncologist of the AMC acknowledged that it would be of great support when the test result report could include instructions on how to interpret the test results.“Well, no. I often have to call, because it is unclear to me. So, yes, I think this could be better. I think when you have results that state it is normal or reduced that it also immediately says, in this range the advice is to start with this much of a percentage of the normal dose. That is not included.” Generally, oncologists and pharmacists indicated that knowledge was sufficient. However, some mentioned more professional education is needed; that education could possibly benefit doctors in training.“Yes [education is a prerequisite], especially when we will be involved.” “Well, it is, I think for people in training it will be good to know why we do it.” Over a two-and-a-quarter years' time period, 753 patients started FP treatment at Amsterdam UMC. The proportion that was DPD tested before the start of the treatment started to increase around the time of the publication of National guideline for colorectal carcinoma, which was also discussed at local meetings to achieve consensus between oncologists and pharmacists at a local level. The publication of a landmark paper two years before had no effect in terms of implementation. The increase of the proportion of patients tested continued to the fourth quarter of 2018, when 87% was achieved. Guidelines clearly are very important for implementation, as well as multidisciplinary local meetings to achieve consensus at a local level.According to our data, around 13% of patients were not tested against the end of the study period. Perhaps some of these had received FP treatment before, without experiencing side effects, or had been tested in other hospitals. The possibility, however, that DPD-testing could have been “forgotten” for some patients led to renewed discussions in 2019. Since the goal is to achieve 100% pretreatment DPD testing in order to maximize patient safety, additional checks have been built recently in the medical protocols, the electronic ordering system, and dispensing protocol by both the clinical as well as the out-patient pharmacists. Protocols for these different sites were attuned. Also on the oncology wards, nurses started to check DPD status as part of their standard protocol.The 2017 National guideline applies to colon cancer, but apparently the uptake of DPD testing increased overall. From a biological point of view evidently similar toxicity is at stake. From an implementation point of view it is remarkable to see that a protocol in one field may stimulate implementation of innovation overall.DPYD genotyping for all patients prior to receiving FP treatment, in the VUMC the patients are tested for 4 genetic variants of the DPYD gene, while at the AMC a conscious decision to use a phenotypic test first was made, followed by genotyping for aberrant results.Since the update of the guideline to conduct DPYD-variants explains only part of the variance, potentially the sensitivity of the test could be improved with phenotyping. In theory the use of assays that determine enzyme activity first, could be more predictive.Since genotyping of a limited number of Although no agreement exists on the best test-approach, in general stakeholders are convinced of the clinical utility of DPD testing prior to FP treatment. Multiple stakeholders seem to realize that cost-effectiveness for genotyping is demonstrated, but some are convinced that phenotyping first is a better (more sensitive) method. A large prospective head-to-head comparison would be needed to identify the optimal algorithm, either one assay or a combination. Studies comparing (cost-)effectiveness of different approaches therefore seem to be warranted.Another pressing issue that arose from the interviews was the need for a more clear division of responsibilities. Although, when asked, most stakeholders expressed that it was the oncologist's responsibility that the test was performed, no clear division of roles seemed to have been agreed upon. Especially the role of the (outpatient) pharmacist could be more formalized, at least as having a responsibility to check whether standard procedures have been followed to ensure drug safety: in this case preventing toxicity in patients with potential aberrant DPD geno- and/or phenotypes.DPYD-variants for reasons of medication safety. They mentioned that information in simple language was needed. For the patients it was not relevant whether or not the assay was a DNA test. They liked the idea of having possession of their own DNA test results, as well as data sharing of these results between health care professionals.Patients appreciated being tested for In general, facilitating factors for stakeholders to implement pretreatment testing included the existence of clear protocols,  evidence of the utility, being aware that peers are adhering to standard practice and clear and simple procedures. Main barriers included the lack of clear divisions of responsibilities, the lack of consensus on a test approach, long turn-around times and non-user-friendly IT-infrastructures. More education about the utility of pharmacogenetic testing, but also the limitations of such tests was desired by most stakeholders.While we describe the situation in Amsterdam UMC only, the process we undertook to study the ongoing implementation of DPD testing before FP treatment can hopefully inspire others. While competencies required by pharmacists and other health care professionals have often mentioned knowledge and academic skills, we here illustrate the importance of the successful integration of pharmacogenomics into health and public policy. Training efforts should also include the development of implementation skills. Should other researchers repeat this study, we hope that more than 87% pretreatment testing is found, since we strive for 100% patient safety. The barriers and facilitators that we identified can hopefully contribute to optimal implementation.The study reports data from two Amsterdam University Medical Centers only. Whether the proportion of patients who have been DPD tested before the start of FP treatment increased to the same extent in other centers needs to be investigated. Local lessons on barriers for implementation, however, can inform other centers on the implementation of DPD and other pharmacogenetic tests. We have also shown that more clarity can be achieved on roles and responsibilities, to achieve optimal patient safety.Personalized medicine is gaining ground. In terms of implementing new tests to give the right dosage of the right medication to the right person at the right time, it is needed to have clear evidence, professional guidelines, local consensus on the practical implications of guidelines and a clear division of roles and responsibilities. Patients want to be informed about pharmacogenetic testing in simple wording. Research has to show the pros and cons of genotyping vs. phenotyping after which the two locations of Amsterdam UMC will choose one approach. The evaluation of the test has to take both test properties  and cost-effectiveness into account. DPD testing is an opportunity to improve patient safety.The datasets generated for this study are available on request to the corresponding author.PB, MC and MB developed the project, FM and DH performed interviews, TR provided methodological input and analysed the interviews, DH took care of the quantitative analyses. All authors discussed and reviewed the draft versions of the manuscript and agreed on the final text.The study was funded by the Personalized Medicine program of the Amsterdam Public Health Research Institute.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.


Shoulder pain is reported to be one of the major challenges faced in the functional recovery of patients in rehabilitation following a stroke. In such cases, transcranial direct current stimulation (tDCS) has been used as an additional therapeutic tool for improvements in central and peripheral pain. The aim of the proposed study is to evaluate the effect of tDCS when combined with upper limb physical therapy on pain intensity and functional improvement in stroke survivors with shoulder pain in the hemiplegic limb.A randomized, placebo-controlled, double-blind, clinical trial is proposed. The volunteers will be randomly allocated to receive passive movement on the upper limb, which will be performed by the therapist for 20 min followed by either active tDCS or sham tDCS (current stimulation for 30 s) during simultaneous physical activity of the upper limb (“mini-bike”) for 20 min, totaling 40 min of intervention performed in 10 consecutive sessions. The anode electrode will be positioned over the primary motor cortex with a current of 2 mA and the cathode electrode will be positioned in the supraorbital region contralateral to the anode. The primary outcome will be shoulder pain intensity, which will be measured using the visual analog scale (VAS) on three occasions: 1) pre-intervention; 2) after 10 interventions ; and 3) 30 days after the end of the interventions. The secondary outcomes will be motor performance, upper limb function, and quality of life.RBR-8F5MNY. Registered on June 2, 2017.Brazilian Registry of Clinical Trials, The online version of this article (10.1186/s13063-019-3266-y) contains supplementary material, which is available to authorized users. Stroke is the second most common cause of death and the third most common cause of disability . This coShoulder pain is a frequent complication of a stroke, with an incidence ranging from 34% to 85% [The pathophysiology of shoulder pain poststroke may have multifactorial causes. Authors suggest that it may be related to spasticity , musculoThe assessment and treatment of poststroke shoulder pain (PSSP) is largely based on the assumption that pain is due to biomechanical alterations within the shoulder joint after stroke. However, current treatment often provides limited pain relief, leading to a considerable number of patients with persistent pain. This suggests that PSSP may not be merely due to simple nociception from the shoulder joint . SensitiThe supraspinal somatosensory system may become sensitized, uninhibited, and/or functionally  or structDCS is defined as a noninvasive brain stimulation technique with neuromodulatory action that alters cortical activity and excitability , 23. It One study with fibromyalgia syndrome reports that increased excitability of this region of the brain enables the enhancement of motor control and, consequently, better pain control . AnotherThere is evidence that pain relief in patients with chronic pain submitted to noninvasive brain stimulation may be related to the restoration of normal corticospinal and intracortical excitation induced by such stimulation , 30, as The modulation of intracortical inhibition is also critical for fine motor control (the selective activation of muscles during motor tasks)  and is aConsidering the relationship between pain and motor performance and the fact that long periods of cortical stimulation can have lasting effects on brain function, such as an increase in the intrinsic plasticity of the motor sensory system and the enhancement of the effectiveness of other therapeutic tools, it is believed that the combination of tDCS and physical therapy may lead to a reduction in pain. This combined therapy is expected to enhance the motor performance of patients with PSSP as well as improve both sleep quality and quality of life. Indeed, stimulation is effective at relieving a number of chronic pain conditions, especially in patients who are resistant to drug therapy , 40.Therefore, the aim of the proposed study is to evaluate the effect of tDCS, when combined with upper limb physical therapy, on pain level and functional improvements in stroke patients with hemiplegic shoulder pain. As a secondary endpoint, we intend to correlate the analgesic effects of tDCS therapy and upper limb physical activity with the effects on motor performance and determine the influence of this therapeutic modality on sleep quality and quality of life.A randomized, placebo-controlled, double-blind, longitudinal, clinical trial is proposed.The primary outcome of this study will be the intensity of shoulder pain, which will be measured using the visual analog scale (VAS). The VAS will be administered on three occasions): 1) pre-intervention; 2), after 10 interventions; and 3) 30 days after the end of the interventions. The secondary outcomes are motor performance and quality of life.Participants will be recruited from the physical therapy clinics of the University Nove de Julho, São Paulo, Brazil.The SPIRIT checklist can be found as Additional file Individuals who meet the following inclusion criteria will be asked to participate in the study: 1) adults (> 18 years of age) with a diagnosis of chronic stroke  (there aThe exclusion criteria are: 1) contraindication for noninvasive brain stimulation ; 2) muscular inelasticity (spasticity) > 3 on the affected upper limb, evaluated by the Modified Ashworth Scale ; 3) progFor the calculation of the sample size, the primary endpoint of the study (shoulder pain intensity at rest measured by VAS) was considered to be directly related to the intervention and has been widely used for this purpose. The calculation was performed considering a level of significance  of 0.05 and an 80% study power, considering a clinically important difference of ≥ 3 points on the VAS . Based oThe allocation of the participants to the different groups will occur using a simple lottery procedure. Treatment codes (active or sham stimulation) will be placed in opaque envelopes , 48. A rThe NeuroConn DC-STIMULATOR PLUS device has settings that enable the selection of the active stimulation mode or sham mode by entering codes. A researcher not involved in the treatment or evaluations will program the equipment with the code to which the patient was allocated. The type of stimulation (active or sham) will not be perceptible by visual cues or the external functioning of the device. Therefore, neither the researcher who will place the equipment on the patient nor the patient will know which treatment he/she is receiving (a double-blind study).All evaluations will be performed prior at baseline (preintervention), after the 10 treatment sessions (postintervention), and 30 days after the end of the treatment sessions (follow-up).Pain intensity will be measured using the VAS, which consists of a horizontal straight line measuring 10 cm, with 0 cm corresponding to the absence of pain and 10 cm corresponding to maximum pain , 49. TheThe motor performance of the upper limb and its functioning will be evaluated on three occasions  using the measures below.The SPADI is a questionnaire used to measure dysfunction and disability associated with shoulder pain . The numThe DASH is a questionnaire composed of 30 items developed to measure symptoms and disabilities caused by upper limb disorders in a heterogeneous population, the objective of which is to determine differences between groups of individuals through the comparison of the impact of upper limb disorder  on physical functions and symptoms. The score ranges from 0 (absence of dysfunction) to 100 (severe dysfunction) . DASH haMotor function of the upper limbs will be analyzed using the Fugl-Meyer Assessment of Motor Recovery after Stroke Scale, which was designed specifically for the evaluation of patients with hemiparesis stemming from a stroke. The scale is divided into five domains: motor function, sensory function, balance, joint range of motion, and joint pain. The motor function domain includes the measurement of movement, coordination, and reflex activity of the shoulder, elbow, fist, hand, hip, and ankle, totaling 100 points  . In the A goniometer, which is a device consisting of two plastic rods (one fixed and one movable) and a compass to allow determination of joint angles , will beFor this evaluation, the volunteer will be seated with the upper limbs supported on the arm rests of the chair and the elbows at 90 degrees. Grip strength will be measured in both hands using the Jamar® dynamometer  with the handle in the second position, which results in greater grip strength . The AmeQuality of life will be measured using the Stroke-Specific Quality-of-Life Scale (SSQOL), which is a standardized, validated scale that specifically addresses the quality of life of stroke survivors . The scaDepressive symptoms will be evaluated and graded with regard to severity using the Beck Depression Inventory (BDI), which is a self-administered questionnaire composed of 21 items. Each item is scored from 0 to 3 points. The total ranges from 0 to 63 points and is interpreted as follows: 0 to 10 indicates the absence of depression; 11 to 18 = mild depression; 19 to 29 = moderate depression; and 30 to 63 = severe depression . The BDISleep-related disorders will be analyzed using the Pittsburgh Sleep Quality Index (PSQI). This questionnaire is composed of 24 items, 19 of which are self-administered and subdivided into seven domains: 1) subjective sleep quality; 2) sleep latency; 3) duration of sleep; 4) habitual effectiveness of sleep; 5) sleep disorders; 6) use of sleeping pills; and 7) daytime dysfunctions. Five additional questions are answered by the person who shares the same bedroom as the individual participating in the evaluation. The sum of the seven domains ranges from 0 to 21 points, with higher scores denoting poorer sleep quality. A score greater than 5 indicates major difficulties in at least 2 components or moderate difficulties in more than 3 components. The PSQI will be determined at the preintervention evaluation and 30-day follow-up. The reliability of this measure is 0.82  , 67.The use and amount of medications, such as analgesics, anti-inflammatory agents, antidepressants, and anticonvulsants, will be measured with the aid of a questionnaire designed by the authors of the study, which will contain the complete data of each patient.All patients will receive passive manipulations, such as massage, stretching, and passive joint movements, which will be administered by a therapist on the painful upper limb for 20 min. Next, tDCS will be administered over the cerebral cortex and the patient will receive stimulation for 20 min while performing physical activity with the upper limbs (“mini-bike”). The total physiotherapeutic treatment will be 40 min. Active or sham tDCS and physical activity will be performed at a frequency of five sessions per week for 2 weeks, totaling 10 sessions .2 (5 × 7 cm) and the anode will measure 25 cm2 (5 × 5 cm). Both electrodes will be enveloped in sponge soaked in saline solution. During active tDCS, the intensity of the current will be 2 mA, administered for 20 min.Stimulation will be performed using the NeuroConn DC-STIMULATOR PLUS and administered over the primary motor cortex (M1) of the damaged hemisphere. Unbalanced bipolar anodal stimulation will be administered with the anode positioned over either C3 (left hemisphere) or C4 (right hemisphere), following the 10/20 electroencephalogram system. The cathode will be positioned in the supraorbital region contralateral to the anode . The catSham stimulation will be performed with the device in the sham setting. The montage will be the same as that in the active stimulation group, but the device will only be activated for 60 s, with a gradual increase in current during the first 30 s (ramp up) to give the volunteer the sensation of stimulation, followed by a gradual decrease over the subsequent 30 s (ramp down). Sham tDCS will be administered by a therapist who will not participate in the evaluations.Possible adverse effects stemming from noninvasive brain stimulation will be determined using the TDCS Side Effects Questionnaire (a version translated into Portuguese) after each session and immediately after the intervention protocol .Physical activity will consist of active movements of the upper limbs using a “mini-bike” . For this, the patient will be positioned in a chair with a 90° backrest and feet resting on the floor. The mini-bike will be positioned on a table, which will allow free arm movements. The patient will perform active movement or active-assisted movements  . This acDescriptive data and characteristics of the patients  will be represented by mean and standard deviation or median and interquartile range. The normality of the data from the VAS, DASH, Fugl-Meyer, SSQOL, range of motion passive shoulder, and hand grip strength will be analyzed by the Shapiro-Wilk test.p < 0.05 will be considered indicative of statistical significance. All analyses will be processed using the SPSS program .If the normality hypothesis is accepted, the analysis of variance (ANOVA) followed by the Bonferroni test will be used, when necessary, to perform the comparison analysis between groups. If the normality hypothesis is rejected, the Kruskal-Wallis test will be used. The Mann-Whitney test will be used to compare the results of the study treatment periods (pre- and post-treatment and 30-day follow-up). Pearson or Spearman correlation coefficients will be calculated to determine the strength of correlations between pain and secondary outcomes . A value of At the time of manuscript submission we were recruiting patients. The study in question is expected to be completed in November 2018.Additional file 1:SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents. (DOC 122 kb)


Pain is one of the most common and unpleasant symptoms that distress the well-being of patients with cancer. Considerable evidence supports the validity and reliability of the McGill Pain Questionnaire (MPQ) and its short forms, the SF MPQ and SF MPQ-2—which are the most widely used tools for pain assessment—in terms of patients with cancer. Pain and its characteristics are best assessed using validated and culturally adapted tools developed in participants' mother tongue. Although many pain assessment tools are available worldwide, only a limited number of them have been translated into Sinhala language and validated in Sri Lanka. We aimed to translate SF MPQ-2 into Sinhala language and validate using Sinhala-speaking patients suffering from cancer pains in Sri Lanka.  Translation has been conducted according to the guidelines laid down by Mapi Research Trust, in five stages, namely, forward translation, backward translation, expert opinion, cognitive debriefing interviews, and proofreading. The questionnaire was administered among 207 patients attending Apeksha Hospital, Sri Lanka, who are suffering from cancer pain. Content validity was tested using expert opinion, and face validity, by interviewing patients with cancer pain. Factor structure was tested through a factor analysis, and reliability, by internal consistency with Cronbach's alpha.  A total of 207 participants , aged between 20 and 80 years, were included in the study. Factor analysis identified four factors compatible with studies done in other countries, which explained 53.5% of the variance. The analysis of data indicated Cronbach's alpha of neuropathic, affective, intermittent, and continuous subscales as 0.768, 0.791, 0.824, and 0.789, respectively, which were over the acceptable threshold of 0.70. Confirmatory factor analysis supported the four-factor model.  SF MPQ-2-Sinhala version is a statistically proven reliable and valid pain descriptor which can be utilized to evaluate pain suffered by patients with cancer in Sri Lanka whose mother tongue is Sinhala. Pain, which is one of the most common symptoms encountered by patients with cancer, is defined by the International Association for the Study of Pain  as an unMcGill Pain Questionnaire (MPQ) long form was developed in 1975 by Melzack, enabling measuring sensory, affective, and evaluative qualities of pain , 5, whicAccording to the Annual Health Statistics 2016, neoplasms are ranked as the second leading cause of deaths in Sri Lanka since 2009 . MeegodaSubjects were selected using the consecutive sampling method, from patients who suffer from cancer pain and who attend the Pain Clinic of Apeksha Hospital , Maharagama, the premier cancer treatment centre in Sri Lanka. Patients over 18 years of age, who were diagnosed with any type of cancer and who are suffering from pain related to primary lesion, secondaries, radiotherapy, or chemotherapy for at least a duration of 3 months, were included in the study. Out of these patients, the patients of different ethnic groups and who are capable of comprehending Sinhala language were chosen. Patients, whose pain is a result of any cause other than cancer triggered within a month from the time of assessment and, those who were frail, mentally unfit, disoriented with evidence of brain metastases and are unable or unwilling to give informed consent were excluded from the study. The sample size was calculated considering the rule of thumb of 5–10 subjects per item . There wThe translation was carried out in 5 steps: forward translation, back translation, review by experts, cognitive debriefing, and proofreading as per guidelines given by original authors of Mapi Research Trust. The forward translation was conducted by two native translators fluent in both languages. Out of them, a language expert and a subject expert were selected in order to produce the best possible translated version of the questionnaire. Two translators were not known to each other, and translations were done individually and separately. The two forward Sinhala translations were compared with each other and with the original English version by the PI and the experts who were fluent in both languages. Backward translation was conducted by two independent translators who were blind to the original English version, and retranslated the Sinhala into English language. One of them was a professional translator and the other was a consultant anaesthetist specialized in pain medicine. Content validity of the Sinhala version was carried out using the Modified Delphi Technique . Face vaThe principal investigator collected data from September 2017 to June 2018, using the translated SF MPQ-2-Sinhala version as an interviewer-administered questionnaire. Data on demographic characteristics, cancer type, treatments, duration of pain, duration of disease, and other comorbidities like diabetes and hypertension were also collected using an interviewer-administered questionnaire.p < 0.05 was considered statistically significant. Factor structure was tested by exploratory factor analysis (EFA) with direct oblimin rotation, and a value of 0.4 was considered mandatory for the loading of each factor, considering the sample size [Statistical analysis was performed using SPSS version 20.0 for windows. Demographic data were analyzed by means of descriptive statistics. For all tests, ple size . The Kaiple size .CFA was performed using Lisrel 10.20 for windows to evaluate the adequacy of the models. Four-factor model was evaluated, and the indices used to evaluate model fit include the absolute fit indices , goodness of fit index (GFI), adjusted goodness of fit index (AGFI), and standardized root mean square residual (SRMR)), relative fit indices (comparative fit index (CFI) and nonnormed fit index (NNFI)), and parsimony fit indices (parsimony goodness of fit index (PGFI) and parsimonious normed fit index (PNFI)). RMSEA values of <0.05 indicate a good fit to the data; values between 0.05 and 0.08 are an acceptable fit; values between 0.08 and 0.10, a marginal fit; and values >0.10, a poor fit . For theApproval was obtained for the translation of SF MPQ-2 from Mapi Research Trust, France, and ethical approval was obtained from the Ethics Review Committee, Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri Lanka. Permission for data collection was obtained from the Director, Apeksha Hospital, Maharagama, and informed written consent was obtained from all the study participants.n = 112) males and 45.9% (n = 95) females in the age range of 18–80 years with an average age of 54.2 years (SD ±13.2). Thirteen participants' data were incomplete for one or more items and, therefore, were excluded from the analysis. Sample 2 consists of 384 participants.As shown in Cronbach's alpha values for subscales of continuous, intermittent, neuropathic, and affective were 0.789, 0.824, 0.768, and 0.791, respectively. All the values for “alpha if item deleted” were lower than corresponding subscale values except for “Tiring-exhausting,” which showed a very small increase in alpha of 0.001. Therefore, the Cronbach's alpha coefficient revealed an acceptable internal consistency for the subscales of the SF MPQ-2-Sinhala version.th factor. The scree plot revealed a clear break after the 4th component. Using Cattell's scree test, it was decided to retain four components for further investigation [The EFA indicated that the KMO value of the SF MPQ-2-Sinhala version to be 0.743, and factors extracted with eigenvalues of >1. Five factors with a variance of 58.4% were extracted, and only one item was loaded  for the 5tigation . This watigation . Then faf = 203) (p < 0.000), and the absolute fit indices were as follows: RMSEA = 0.0517, GFI = 0.916, AGFI = 0.895, and SRMR = 0.0606. Relative and parsimony fit indices were as follows: CFI = 0.829, NNFI = 0.806, PGFI = 0.735, and PNFI = 0.630. The four-factor model came up with better indices closer to the desired values in absolute, relative, and parsimony fit indices.For CFA, the robust maximum likelihood method (RML), which was adjusted for nonnormality of the data, was used to estimate the model parameters. The four-factor model gave a chi-squared value of 410.971  by a value of 0.001 if deleted. However, as the item “tiring/exhausting” is a frequently used term among patients with pain, having considered this fact, it was decided to retain the item “tiring/exhausting” in the questionnaire.Reliability analysis was conducted by testing the internal consistency using Cronbach's alpha. Cronbach's alpha coefficients were computed for each subscale and ranged from 0.76 to 0.82; all of which lie above the commonly accepted thresholds for internal consistency. The results are comparable with those of the original study and other language versions, as illustrated in EFA was carried out to explore the possible underlying factor, and CFA was used to verify the factor structure. Identification of factor structure was conducted with the sample 1 data, and verification of factor, with sample 2 data, considering the recommendations , 29. FacOne of the limitations of the study is that the patients who participated in it were being diagnosed with different types of cancers, with reported pains in different sites of their body. In order to widen generalizability of results, further studies are recommended to be conducted among the patient groups with different types of cancers with reported pain in different sites.In conclusion, SF MPQ-2-Sinhala version is a statistically proven, reliable, and valid pain descriptor, which can be used in clinical research as well as in the routine clinical evaluation of Sinhala-speaking patients presenting with pain related to cancers.


R = −0.698, P = 0.037). Acupuncture could relieve pain in PD patients by modulating brain regions related to both sensory-discriminative and emotional aspects. The present study might increase the confidence of users that acupuncture is an effective and safe analgesic tool that can relieve PD-related pain.Non-motor symptoms of Parkinson's disease (PD) have been receiving increasing attention. Approximately half of patients with PD have experience PD-related pain. We investigated the effect and mechanism of acupuncture in patients with PD who have pain. PD patients with pain were divided into acupuncture group and control group. Nine patients completed acupuncture treatment; seven patients who received only an analgesic agent underwent resting-state functional magnetic resonance imaging (rs-fMRI) twice. fMRI was performed to evaluate the functional connectivity of the brain regions. After treatment, a decrease in total scores on the King's Parkinson's Disease Pain Scale (KPPS) and Unified Parkinson's Disease Rating Scale was observed in the acupuncture group . In the acupuncture group, increased connectivity was observed in four connections, one in the left hemisphere between the middle temporal gyrus (MTG) and precentral gyrus, and three in the right hemisphere between the postcentral gyrus and precentral gyrus, supramarginal gyrus and precentral gyrus, and MTG and insular cortex. A significant correlation was noted between the changes in functional connectivity and KPPS. The involved connection was between the left middle frontal gyrus and the right precentral gyrus ( The non-motor symptoms (NMS)  of ParkiPain in PD might be a consequence of motor fluctuations, dystonic muscle contraction, deep visceral pain, and musculoskeletal pain –4. It caAcupuncture has long been used clinically for pain relief , such asPain is a complex experience including not only sensory but also emotional dimensions. Resting-state functional magnetic resonance imaging (rs-fMRI)  is an efThe present study was approved by the ethics committee of the Chang Gung Medical Foundation Institutional Review Board . Written informed consent was obtained from each participant after full explanation of the details of the study procedures. The study complied with the principles of the Declaration of Helsinki.Patients with PD who had pain were consecutively enrolled at the outpatient clinic of the Neurology Department of Chang Gung Memorial Hospital in Taiwan. The diagnosis of idiopathic PD was made according to the UK Brain Banks Network criteria . The incThe following assessments were used to evaluate patients' clinical status: (1) KPPS , which iAll patients underwent evaluations and their first rs-fMRI examination at baseline; patients in the treatment group and control group underwent the second evaluation after acupuncture treatment and 10–14 weeks after the first examination, respectively.All patients had maintained the same antiparkinsonian medications during the study. Analgesic agents were prescribed according to usual clinical routine. Non-steroidal anti-inflammatory drug (NSAID) is the major analgesic agent in our patients. During this study, they kept their analgesic agent as tolerable, and routine analgesic agent would be added if needed. However, no patient asked for more analgesic medication during the whole study in both groups.Acupuncture treatment consisted of one to three sessions per week that were separated by at least 1 day and lasted for 8 weeks. All of our patients completed a total of 16 treatments. The patients in the acupuncture group underwent the third evaluation 3 months after stopping acupuncture treatment. The flow chart of this study is shown in The acupuncturists were all well-trained, had been licensed for at least 3 years, and did not participate in any clinical assessments. The needles used for acupuncture were non-recycled and 0.30 × 40 mm in size. In accordance with recommendation from traditional theory, three acupoints were consistently used throughout the complete treatment course, including Bai-Hui GV20), Shen Guan (77.18), and Yanglingquan (GB34) , Shen Gu. Shen Gu3, and flip angle = 9°. The single-acquisition time was 248 s.Images were acquired using a 3-Tesla MRI scanner . The structural images were acquired with a T1-weighted magnetization-prepared rapid acquisition gradient-echo sequence using the following imaging parameters: repetition time/echo time/inversion time = 2,000 ms/2.63 ms/900 ms, 160 axial slices of voxel size = 1 × 1 × 1 mm*-weighted gradient-echo echo planar imaging sequence using the following parameters: repetition time/echo time = 3,000 ms/45 ms, flip angle = 90°, field of view = 192 × 192 mm, slice thickness = 3 mm, matrix = 64 × 64, and voxel size = 3 × 3 × 3 mm3. A total of 160 measurements were acquired. The single-acquisition time was 8 min. Moreover, subjects were instructed to rest with their eyes open and not move.Results for rs-fMRI were acquired with a T2www.mni.mcgill.ca).Image processing was conducted using DPARSF (Data Processing Assistant for Resting-State fMRI) software version 2.2 in MATLAB R2017b . Individual images were resliced into 2-mm isotropic voxels and spatially smoothed with an 8-mm Gaussian filter; the following recommended procedures were also performed: realignment, coregistration, segmentation, and spatial normalization to Montreal Neurological Institute space  on the basis of the automated anatomical labeling template. The functional connectivity between ROIs was calculated as the signal similarities in time series by using Pearson's correlation coefficients, which resulted in a functional connectivity matrix with 6,670 connections ([116 × 115]/2) in each subject. Fisher's z-transformation was performed to normalize the correlation coefficients. Visualization of the ROIs with significant changes in connectivity was performed with the BrainNet Viewer .Analysis of the patient demographic data and Spearman's correlation was performed using IBM SPSS Statistics version 24 software . Statistical analysis of the functional connectivity (Wilcoxon signed-rank test and feature selection method of least absolute shrinkage and selection operator) was performed using MATLAB software.The clinical score changes between the baseline evaluation and after treatment were revealed by performing the Wilcoxon signed-rank test between acupuncture and control groups .Different contrasts were analyzed by Wilcoxon signed-rank test, including (a) acupuncture group between two-time points (conA), (b) control group between two-time points (conB), (c) the acupuncture vs. the control group at baseline (conC), (d) the acupuncture vs. the control group after the acupuncture treatment (conD).P < 0.05.The correlation between the changes of functional connectivity and changes in neuropsychological scores was also investigated using Spearman's rank correlation. Prior to the correlation test, the least absolute shrinkage and selection operator was used to select significantly relevant ROI links among all functional connections. The statistical significance threshold was set at Sixteen enrolled subjects were divided into two groups. Nine patients completed acupuncture treatment; seven patients who received only the analgesic agent completed two fMRI courses.P = 0.114; VAS, P = 1.000), disease duration (P = 0.918), motor severity , or levodopa equivalent daily dose (P = 0.918), nor was a significant difference observed in psychological aspects  or cognitive aspects .At baseline, no significant difference was found between patients with and without acupuncture treatment in terms of pain severity , but no significant differences were observed in BDI-II, PDSS-2, PDQ-39, and MMSE scores. The changes of clinical performance are summarized in After treatment, decreases in KPPS and UPDRS total scores were observed .The washout effect was assessed 3 months later in six patients who completed treatment. The KPPS in the washout phase was average 11.8, which showed no significant change with after-treatment KPPS (No connection showed significant difference in the conA and conB. Two significant connections were found in the acupuncture vs. control group at baseline (conC). The involved connections were (1) between left middle temporal gyrus and left rectus; and (2) between left rolandic operculum and right biventral lobule of cerebellum. Four significant connections were found in the acupuncture vs. control group after completed the acupuncture treatment (conD). The involved connections were (1) between right flocculus of cerebellum and left superior temporal gyrus; and (2) between right flocculus of cerebellum and left postcentral gyrus; (3) between right flocculus of cerebellum and right postcentral gyrus; (4) between left lobule centralis of cerebellum and left opercular part of inferior frontal gyrus.The contrast between the acupuncture and the control group in the baseline (conC) was used as a control condition in the analysis of therapeutic effect of acupuncture.R = −0.698, P = 0.037)  .In three subdomains of KPPS, significant correlations were found between the reduction in score and changes in functional connectivity. The involved connections in the subdomain of musculoskeletal pain were located between the right posterior cingulate gyrus and right cerebellar lobule IX, between the right caudate nucleus and right transverse temporal gyrus, and between the left cerebellar crus II and right cerebellar lobule IX. In the nocturnal pain subdomain, the involved connection was between the precentral gyrus and the medial orbitofrontal cortex (OFC) in the right hemisphere. In the radicular pain subdomain, the connections were between the right parahippocampal gyrus and left cerebellar lobule VI. Details of significant correlations are listed in In the current study, we hypothesized that the mechanism of pain relief through acupuncture in patients with PD, could be provided by altering pain matrix in the brain. In the acupuncture group, no significant difference between two time points might be attributed to the small sample size in our study. However, in the baseline, the difference of functional connectivity between inferior-middle temporal gyrus and rectus could be related to anxiety status in patients with Parkinson's disease . TherefoWe also observed a modulation of brain connectivity within a pain-related neural network, which might be related to pain relief in the S1, MTG, insular gyrus, and medial orbitofrontal cortex (OFC). We further demonstrated that pain relief by acupuncture is effective and might improve cognitive function. Pain relief could be observed from reduction of KPPS score in the acupuncture group (−46.2%), compared with the control group, although both groups received a conventional analgesic agent (NSAID) during the whole study period.In addition, a significantly decreased total UPDRS score was noted, which might suggest that the clinical improvement achieved by acupuncture might not be limited to pain relief alone. The prolonged effect of pain relief was observed for at least 3 months after 16 acupuncture courses. In this regard, acupuncture could provide neurologists and patients with an alternative analgesic approach.Patients with PD who received acupuncture treatment showed improvement in KPPS and total UPDRS scores but not in neuropsychological measures , which might suggest that the fixed acupoint treatment was effective for pain relief mainly in the sensory-discriminative aspect. The pain source can be categorized into affective-motivational and discriminatory aspects that individually form medial and lateral pathways. The medial pathway projects from the medial thalamus to the anterior cingulate cortex and insular cortex and is related to affective-motivational aspects. The lateral pathway projects from the lateral thalamus to the primary and secondary somatosensory cortices and the insular cortex and is related to the sensory-discriminative aspect . The senOn the other hand, changes of brain connectivity indicated that the pain relief of acupuncture may be attributable to the increase in connectivity of regions, including S1, MTG, supramarginal gyrus, and insular cortex, which are functionally associated with modulating the general pain pathway and may change the perception of pain from nociceptive receptors to the pain matrix .The S1 is considered to be a major node in the localization and discrimination of pain . ChronicOn the basis of the correlation analysis between the changes of functional connectivity and KPPS scores, we found that the increased connectivity between the left middle frontal gyrus and right precentral gyrus was negatively correlated with total KPPS score. This finding might suggest that stronger connectivity between these regions could be linked to more effective pain relief. The precentral gyrus was reported to be responsible for providing relief from chronic pain . MoreoveMoreover, we discerned other correlations between changes in functional connectivity and individual domains of the KPPS. In domain 4 of the KPPS, which measures nocturnal pain, we found that the increased functional connectivity of the OFC and precentral gyrus is associated with the reduction of nocturnal pain. Specifically, the medial OFC is connected to the striatum and dopaminergic nuclei . NocturnWe also found a persistent pain relief effect of acupuncture in our study. That is, the effect of acupuncture persisted even after stopping acupuncture for 3 months. The persistent effect might further attract new interest in the investigation of acupuncture for the modulation of brain plasticity in the pain matrix .In conclusion, acupuncture could relieve such specific pain in patients with PD by modulating several regions of the brain related to both sensory-discriminative and emotional aspects, especially those correlated with the S1, MTG, insular cortex, prefrontal cortex, and middle frontal gyrus. Moreover, the OFC is a specific region involved in nocturnal pain. The use of rs-fMRI in our study might provide imaging-based evidence for clinical improvement of acupuncture treatment strategy. The current study might increase the confidence of users that acupuncture might be an effective and safe analgesic tool for pain relief in patients with PD.The present study is limited by a relatively small sample size, but the analgesic effect was prominent in our patients receiving acupuncture treatment. We did not perform sham acupuncture in another group of control subjects, however, acupuncture was shown to be more effective than sham treatment in a meta-analysis of chronic pain . This isAll datasets generated for this study are included in the manuscript/supplementary files.The studies involving human participants were reviewed and approved by The ethics committee of the Chang Gung Medical Foundation Institutional Review Board . The patients/participants provided their written informed consent to participate in this study.S-WY, Y-RW, and J-JW contributed the conception and design of the study. S-WY, S-HL, C-CT, Y-CH, Y-SC, and B-YY organized the database. S-WY and S-HL performed the statistical analysis. S-WY wrote the first draft of the manuscript. S-HL wrote sections of the manuscript. KC provided the appropriate pain evaluation in PD patients. All authors contributed to manuscript revision and read 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.


The 12 patients on whom a single-blind response test was performed experienced a statistically significant reduction in pain in the area where the phenytoin 10% cream was applied in comparison to the area where the placebo cream was applied (p < 0.01). Thirty minutes after the test application, the mean pain reduction on the NRS in the areas where the phenytoin 10% cream and the placebo cream were applied was 3.3  and 1.1 , respectively. In all 16 patients, the phenytoin plasma levels were below the limit of detection. So far, no systemic side effects were reported. Two patients only reported local side effects: a transient burning aggravation and skin rash. CONCLUSION: In this case series, the phenytoin cream had reduced neuropathic pain considerably, with a fast onset of analgesic effect.BACKGROUND: Neuropathic pain can be disabling, and is often difficult to treat. Within a year, over half of all patients stop taking their prescribed neuropathic pain medication, which is most probably due to side effects or disappointing analgesic results. Therefore, new therapies are needed to alleviate neuropathic pain. As such, topical analgesics could be a new inroad in the treatment of neuropathic pain. In 2014, we developed a new topical formulation containing either phenytoin or sodium phenytoin. After optimization of the formulation, we were able to reach a 10% concentration and combine phenytoin with other co-analgesics in the same base cream. OBJECTIVE: To describe a series of 70 neuropathic pain patients who were treated with phenytoin cream. MATERIAL AND METHODS: Cases treated with phenytoin 5% or 10% creams were gathered. The mean onset of pain relief, the duration of effect, and reduction in pain intensity measured on the 11-point numerical rating scale (NRS) were all studied. A single-blind response test with phenytoin 10% and placebo creams was conducted on 12 patients in order to select responders prior to prescribing the active cream. Plasma phenytoin concentrations were measured in 16 patients. RESULTS: Nine patients applied phenytoin 5% cream, and 61 patients used phenytoin 10% cream. After grouping the effects of all of the patients, the mean onset of pain relief was 16.3 min (SD: 14.8), the mean duration of analgesia was 8.1 h (SD: 9.1), and the mean pain reduction on the NRS was 61.2% (SD: 25.0). The mean pain reduction on the NRS while using phenytoin cream was statistically significant compared with the baseline, with a reduction of 4.5 (CI: 4.0 to 5.0,  Neuropathic pain can be disabling, and is often difficult to treat ,2. GuideDue to the fast onset of pain relief after the application of creams containing such co-analgesics and the symmetrical distribution of pain intensity in case of a peripheral neuropathy , we were able to develop a test to identify those who responded to the cream within 30 min after application. During the first phase of data collection, we performed an open response test, applying the active cream on one foot. The patient was labeled a responder after a pain reduction of two points or more on the 11-point numerical rating scale (NRS) within a period of 30 min in the area where the active cream was applied. To control for the placebo effect, we developed a single-blind response test comparing an active cream with a placebo cream; the test takes only a minute to conduct. The single-blind response test could be performed when there was maximally one-point difference on the NRS between two painful areas  at baseline. Patients would then administer an equal amount of placebo cream and active cream on each foot using different hands to avoid contamination. Responders were defined as patients reporting (1) within 30 min; (2) ≥two-point pain reduction on the NRS in the active cream applied area; and (3) ≥one-point difference on the NRS between the active cream and the placebo cream area. A two-point reduction on the NRS was seen as clinically relevant .Although many patients were responders to compounded creams containing for example amitriptyline, ketamine, and baclofen, a number of patients remained treatment-resistant. We therefore introduced phenytoin as a new compound for topical neuropathic pain treatment based on its remarkable history and its various modes of action ,16,17. PData from those patients using phenytoin 5% or 10% creams were gathered from January 2014 to October 2017, and the pain intensity was measured on the NRS. Descriptive statistics were used for socio-demographic data, diagnoses, and pain characteristics. The screenings tool for neuropathic pain  was used to determine the pain characteristics . We calcp < 0.01).From January 2014 to October 2017, patients were treated with phenytoin 5% or 10% cream. Outcome from the 70 patients was documented in detail. The mean duration of neuropathic pain was 7.8 years (SD: 6.5). Thirty-four patients were male (48.6%), and 36 (51.4%) were female. The age of the patients ranged between 43–89 years, with a mean age of 67.7 years (SD: 10.4). The diagnoses of those patients treated with phenytoin 5% or 10% cream are summarized in An open or single-blind response test was performed on 10 or 12 patients, respectively. To date, the patients described in this cohort have been, and continue to be, treated over a period of a few weeks to 41 months, and most did not experience any side effects. Four patients have stopped using phenytoin cream, because their pain has been resolved.p < 0.01) and 1.1 , respectively. This difference was statistically significant (p < 0.01). While using phenytoin 10% cream during the open treatment phase, patients experienced a comparable pain reduction of 4.0 points on the NRS , with 7.3 (SD: 0.4) as baseline.Patients experiencing certain neuropathic pain characteristics as defined by the DN-4 are presented in t(16) = 2.4, p < 0.03), using the independent t-test. The onset of action after the phenytoin 10% cream application in CIAP patients is almost 14 min longer than in SFN patients. However, this difference does not reach significance using the independent t-test (t(15) = 1.7, p = 0.1). More than one third of the patients experienced a robust relief of pain (MPR70).t(66) = 1.2, p = 0.2) when using the independent t-test.The mean onset of action (onset to perceptible pain relief) after application was about 15 min for both phenytoin 5% and 10% creams. The mean duration of analgesia was almost 5 h for the phenytoin 5%, while patients treated with the phenytoin 10% cream reported a mean duration of meaningful analgesia of more than 8 h. However, the difference of 3.8 h between the two groups was not statistically significant  of 7.5 days and 36 days, respectively . AnotherThe percentage of patients experiencing a pain reduction of at least 50% and 70% on the NRS is around 65% and 35%, respectively. This high percentage of responders is most probably due to the open nature of this case series, and might also be related to the installment of the response test in 20 patients. However, topical analgesics are known to induce a high placebo response . That weThe average duration of the analgesic effect of phenytoin 10% cream is over 8 h, which corresponds with a mean daily application of 2.4 times. Patients can therefore apply phenytoin cream in the morning and evening, and if needed also at noon, to cover the whole day. The lack of a statistically significant difference in the duration of analgesia between the phenytoin 5% and 10% creams might be due to the small sample size.No systemic side effects have been reported. This finding is in line with the phenytoin plasma levels being below the limit of detection in 16 patients in our data pool. Previous studies did not show either detectable phenytoin plasma concentrations after applying the 2% and 5% creams on skin lesions due to epidermolysis bullosa simplex or sprinkling up to 400 mg of phenytoin sodium salt (100%) daily into wounds ,31. Only two patients reported local side effects: a transient aggravation of burning sensation, and in one patient, red papules after the administration of the phenytoin 10% cream, although in that case, not after the application of the phenytoin 5% cream. These local side effects were transient, and disappeared after stopping treatment.Phenytoin cream seems safe and effective in a cohort of 70 patients. As most patients were non-responders or partial responders to the oral analgesic interventions described in the guidelines, our data suggest that such a cream might become a new tool in our armamentarium of therapies for peripheral neuropathic pain. In most patients, the onset of analgesic action is fast, around 15 min. This is of particular interest, as most oral analgesics can take days to weeks before sufficient pain reduction sets in. Furthermore, the fast onset of action makes a single-blind placebo controlled response test possible. Thus, this test enables the clinician to identify responders directly at the first visit, and subsequently to prescribe the cream. Such an approach, together with the fast onset of action, might also enhance compliance. Side effects were rare. The open nature of this data collection limits the ability to make firm conclusions, and in the future, well-controlled studies are required to analyze the efficacy and safety of this topical phenytoin formulation in more detail. Furthermore, the statistically significant effects of the phenytoin 10% versus the placebo cream in the single-blind response test population supports further explorations. New studies are currently in the design phase, both in CIAP patients, as well as in patients suffering from painful diabetic neuropathy.


Preemptive analgesia has as its basic principle the administration of analgesics before the onset of painful stimuli, in order to reduce or prevent postoperative pain, but this question is little explored in implantology. Thus, this study was conducted in order to evaluate the clinical efficacy of ibuprofen in pain prevention after unit implant surgery. For this triple-blind, parallel, placebo-controlled and randomized clinical trial, 54 insertion surgeries of unitary implants were performed. Two groups have received two different protocols 1 hour before surgery: Ibuprofen group (IBU) 600 mg of ibuprofen; and (2) placebo group (maize starch). The intensity of the pain was evaluated through the visual analogue scale (VAS) in 6 times . Patients were instructed to take 750 mg of paracetamol as rescue medication, if necessary. The occurrence and the intensity of pain were analyzed by means of an analysis of variance ANOVA with repeated measurements using the general linear model procedure. p<0.001) and at all times in the intra, intergroup comparisons and time/group interaction than the placebo group (p<0.001). The use of rescue medication was significantly lower and the postoperative time was longer in the IBU group compared to placebo (p = 0.002). The IBU group had significantly lower VAS scores overall (IBU = 0.30, ± 0.57; placebo = 1.14, ± 1.07; The single use of ibuprofen was found to be significantly superior in reducing pain after unit implant surgery compared to placebo. Key words:Analgesia, dental implants, pain, surgery, oral. Pain is a factor hardly dissociated from dental treatment . Their pThe concept of preemptive analgesia (PA) to reduce the postoperative pain was based on a series of experimental animal studies , which dThree classes of analgesic drugs  have been used for this purpose alone or in combination ,6.Several studies have been conducted in PA, particularly in third molar extraction surgeries -12, periStudies have shown a high preference for the use of Ibuprofen in pain control related to dental problems or dental procedures ,16,19 IbIn this sense, the hypothesis for this study was that individuals who receive PA with the use of ibuprofen  1 hour before the implant surgery present lower postoperative pain in relation to individuals receiving placebo medication.Thus, the objective of this study was to evaluate and to compare by means of a randomized clinical trial, parallel-controlled and triple blind the efficacy of preemptive administration of Ibuprofen  1 hour before surgery for single insertion of implants osseointegrated in the control of postoperative pain.-Study sampleThis study was conducted from November 2018 to May 2019, in a private clinic of Implantology in the city of Belo Horizonte, Brazil. Fifty-four eligible individuals, both genders, non-smokers, aged 37 to 74 years were selected to participate in this randomized clinical trial, controlled, parallel and triple blind.The nature of the study was previously explained to each patient, who signed a consent form, and this study was approved by the Ethics Committee in Human Research of the Federal University of Minas Gerais, Brazil (83534618.5.0000.5149) and registered in Brazilian registry of clinical trials (ReBEC) under identifier RBR-4B5DSG (www.ensaiosclinicos.gov.br).The following inclusion criteria were adopted: 1) good systemic health status (ASA I or II); 2) absence of current pain or presence of any oral inflammatory process; 3) without analgesics in the 3 weeks prior to the study; 4) lack of continuous use of steroid and non-steroidal anti-inflammatory drugs; 5) need to install unitary implants not concomitant with maxillary and mandibular exodontia; 6) implants of 3.75 mm in diameter with 11 to 13 mm in length; 7) presence of compatible bone width and height determined by tomographic examination (cone-bean computed tomography). The following were excluded: pregnant or lactating women, use of some type of medication that could affect the perception of pain, history of allergy or intolerance to the drugs (ibuprofen and paracetamol) used in the research; and history of alcohol or drug abuse.-Sample CalculationUsing statistical power analysis software R , it was determined that 25 patients per group would be required to achieve 80% of power at 95% of confidence interval (CI), assuming moderate to intense changes in pain score 24 hours after surgery in at least one group and non-normal distribution data . In ordeRandomizationAll patients involved in this study were selected through a sequential non-probability method, that is, consecutive cases were drawn for each eligible intervention using, alternatively, envelopes denominated group I and II in consultation prior to surgery. Randomization in the groups was performed by a sequential stratified randomization process that consisted of the use of 54 opaque envelopes, where the identifications of the treatment groups (groups I and II) were placed. The envelopes were sealed and scrambled, and later numbered in sequential order. For each new entrant in the study, a subsequent numbering envelope was opened. The flow diagram is show in Figure -Medications usedThe following drugs were used in this research: Ibuprofen – Tablets 600 mg, a placebo containing maize starch and Paracetamol - Tablets 750 mg. All drugs used in the research were conditioned in white capsules, placed in bottles identified as group I or II medication by the researcher (G.M.P).-Instructions for the study and collection of variablesAll participants in consultation prior to surgery have received detailed instructions for the correct form filling and visual analogue scale (VAS) for postoperative pain assessment. They were advised to contact the operator in case of any doubt. Thus, following randomization procedures, the individuals received a vial containing a medicine capsule from Group I or a medicine capsule from Group II, which should be ingested 1 hour before the surgical procedure. In addition, Paracetamol 750 mg Tablets were made available to all individuals to be used as a rescue medication in case of pain. The use of rescue medication was at the discretion of the patient in case of pain. It is noteworthy that all patients registered in this consultation on mobile phones a reminder to take the drug 60 minutes before the scheduled time for surgery.The following information was collected in this consultation: age, gender, body mass index, educational level, family income expressed in minimum salaries, as well as additional information on health in general.-Visual Analog Scale (VAS)Participants have completed a visual analogue scale (VAS), where they indicated the presence and intensity of pain ,21. This-Surgical ProceduresSurgical procedures were performed by a single operator (F.O.C.) through a mucoperiosteal flap where unitary implants  were inserted according to the manufacturer’s instruction. The individuals were anesthetized with a local infiltrative anesthetic (Prilocaine hydrochloride 30 mg/ml) block using 2 to 4 anesthetic tubes at most. All surgical procedures were performed in up to 1 hour.-Statistical analysisThe analyzes were performed blindly by a researcher (LOMC) continuing to assign the groups as groups I and II. The variables of interest were reported for descriptive measures  and analyzed using the chi-square test and t-test when appropriate. The perception of pain over time (VAS 1 hour to 72 hours) between the groups (Placebo vs IBU) was analyzed separately by the Friedmam test  and subsequently by means of a 2-way analysis of variance ANOVA with measures repeated through general linear model procedure (GLM). Comparative analysis of the need for medication rescue for pain control and survival analysis for need of rescue were performed using the Manny-Whitney and Mantel-Cox tests, respectivaly. The data were analyzed using the statistical program (R software). Subsequently the analysis according to the initial knowledgeable investigator (G.M.P.) of the groups has revealed that group I used Ibuprofen (group IBU) and group II the capsule with maize starch (placebo group).p = 0.012). The mean age in the IBU group was 61.07 ± 8.01, while in the control group 55.63 ± 9.36 (p = 0.026)  . No majop<0.001). In addition, the IBU group also presented values significantly lower than those reported in the control group at all times in the intragroup, intergroup comparisons and in time and group interaction (p <0.001).p = 0.002).Regarding the need to use of the rescue medication to control postoperative pain, the IBU group has used significantly less rescue than that observed in the placebo group (p = 0.007).Corroborating these findings, In this study, the use of ibuprofen 1 hour prior to the surgical procedures for insertion of unitary implants has revealed, overall, a significant effect on reduction of postoperative pain, at all times evaluated, less need for rescue medication, as well as a longer time for the occurrence of the rescue event in relation to the individuals with the use of placebo medication. Thus our hypothesis of its beneficial effect on the reduction of postoperative pain was affirmative.Theoretically, PA is defined as an antinociceptive treatment , which aIn our study, the IBU and placebo groups differed significantly in age and gender, without differences in relation to the other variables studied, such as anatomical position of the implants, surgery time, BMI, family income and socioeconomic level.Analyzing the plurality of factors that may interfere with perceived pain , the absIn a review about orofacial pain  the dataFuture research needs to elucidate the influence of socio cultural, environmental, and psychological factors on pain as well as the effects of sex on factors that protect against the development of pain or that prevent pain from becoming debilitating . Thus, wSeveral studies have been conducted in PA in dentistry. Most studies focus on third molar extraction surgeries -10,12,28Moreover, in almost all different procedures using PA, the results are conflicting. In addition, studies with different types of drugs have been tested in PA but without a consensual definition of the best protocol for the drug, posology and period of exposure to the drug. Thus, there is a tendency in PA to test steroid and non-steroidal anti-inflammatory drugs with only one study testing the use of ibuprofen.In a systematic review  it was vAdditionally, in our findings, ibuprofen has proven to be very effective in reducing pain in the immediate postoperative period from 1 to 6 hours compared to placebo, significantly reducing the need for rescue medication and increasing the time required for rescue medication, thus according to the theoretical foundations of PA this initial reduction is very important because it has a positive effect on reducing pain at subsequent intervals of time ,23.In this context, our finding is supported by a systematic review  of the oet al. (Another point to be discussed refers to the extent and numbers of implants inserted in the surgical procedure. Low pain scores are related to implant surgeries and according to Kim et al.  pain andThe present study may be considered as a good starting point for future studies aimed at providing additional information on the use of ibuprofen in PA in implant surgeries. However, prospective multicentric studies, in different populations, with different surgical and dosing protocols, are necessary to confirm these findings and to establish a beneficial protocol for the control of pain in dental implant surgeries.The present study demonstrated that the use of ibuprofen 1 hour before to the surgical procedures for insertion of unitary implants has revealed a significant effect on the reduction of postoperative pain overall at all evaluated times has shown less need for the use of rescue medication and, when necessary, the time of use has been shorter when compared to individuals on placebo. Thus, its use can be considered a beneficial adjuvant for the control of postoperative pain in dental implant surgeries.