Appropriate pain management is essential to improve the postoperative recovery after total knee arthroplasty (TKA). There is a paucity of literature on ketamine for TKA procedures. The aim of this study was to evaluate the analgesic efficacy of ketamine in patients undergoing primary TKA.This study was designed as a prospective, double blind, single center, randomized controlled trial. The participants were randomly assigned to either the ketamine or placebo groups, using a set of random numbers for the allocation sequence. All patients underwent TKA without patella resurfacing under spinal anesthesia. Preoperative workup, surgical technique, and postoperative management were standardized for all the patients. The primary outcome of this noninferiority study is opioid consumption within the first 24 hours following surgery, pain scores, distance ambulated, patient satisfaction, length of hospital stay, and complications.The results of this study were expected to provide useful information on the effectiveness and safety of ketamine for immediate postoperative analgesia after TKA surgery.This study protocol was registered in Research Registry (researchregistry5575). Additionally, prolonged duration of hospitalization may increase more medical expenses. Therefore, pain management after TKA is an important issue for surgeons and patients to recognize.Total knee arthroplasty (TKA) is a common surgical procedure that can cause severe postoperative pain. Postoperative pain management in patients undergoing TKA is a challenging issue that can optimize the treatment plan, reduce side effects, save health care resources, and increase patient satisfaction.–7Opioids are effective for acute postoperative pain after TKA. Persistent opioid use frequently follows surgery, so reducing postsurgical pain via opioid-sparing techniques can have long-term benefit. Preventive analgesia aims to reduce postoperative pain and analgesic consumption by combining multimodal analgesic therapies. Ketamine inhibits N-methyl-d-aspartate (NMDA) receptor activation and attenuates wind-up and central sensitization associated with hyperalgesia, opioid tolerance, and chronic pain. Ketamine, given at sub-anesthetic doses, has been shown to modulate nociceptive hypersensitization through its antagonist effects on NMDA receptors by blocking pain signaling input. There is significant evidence supporting the use of ketamine as an adjunct, to elicit the reduction in hypersensitization specifically when combined with low-dose morphine.–12 Numerous publications state that adjuvant ketamine reduces pain and opioid consumption postoperatively.,14 Although there is a paucity of literature on ketamine for orthopedic procedures, there are a few studies on intraoperative subanesthetic ketamine that are either of small sample sizes or performed with general anesthesia. As general anesthesia has been largely replaced by neuraxial anesthesia, it is important to evaluate ketamine in this setting.Ketamine is a phencyclidine derivative, and acts as a noncompetitive NMDA receptor antagonist.The present study is a prospective, randomized, double blinded trial determining the efficacy of sub-anesthetic dosing of ketamine during TKA on postoperative pain and narcotic consumption in patients receiving spinal anesthesia. We hypothesized that the addition of intravenous ketamine to standard opioid analgesia would reduce pain scores and overall morphine equivalent consumption.2This study was approved by the Institutional Review Board in our hospital and written informed consent was obtained from all subjects participating in the trial. The trial was also registered at the Research Registry (researchregistry5575). It was carried out in accordance with the principles of the Helsinki Declaration. Data are presented according to the CONSORT statement.2.12 due to patient selection, contraindication or allergy to opioid pain medication, any preoperative ketamine, and chronic narcotic usage . Furthermore, patients with an ejection fraction less than 30%, creatinine clearance less than 30 mL/min, chronic liver disease, any neurologic or psychiatric disorder , and alcohol abuse were excluded as these are contraindications for the use of ketamine. Additionally, patients with prior surgery on the ipsilateral knee within 6 months, simultaneous bilateral arthroplasty, and those who received general anesthesia or a nerve block were excluded.Inclusion criteria were patients between 18 and 85 years old undergoing unilateral, primary TKA for osteoarthritis. Patients with the following conditions were excluded: body mass index greater than 40 kg/m2.2An equal number of envelopes for each treatment group were prepared using a computerized random number generator by a study assistant who did not take part in any subsequent part of the study, and was not in contact with the rest of the study team throughout the entire study duration. He prepared 100 identical sequentially numbered, opaque, sealed, and stapled envelopes; 50 envelopes contained instructions for mixing solutions for Group A, and the other 50 for Group B. The envelopes were kept in a file with the principal investigator  to the anesthesiologist in charge; thereafter, he did not partake in any subsequent part of the study. Both ketamine and normal saline study solutions had the same physical properties: clear liquids with no distinctive odor. Therefore, they could not be identified or differentiated by sight or smell by anyone in the operating theatre. The allocation sequence was concealed from both the study team and study assistants. The blinded study team labeled the data collection sheet with the patient identity code, and, in the operating theatre, verified the proper timing of study solution administration.2.3All TKAs in this study were carried out by either the senior author, or by fellows under his direct supervision. A tourniquet was used in all cases, spine anesthesia was administered to each patient before incision, and the operative knee was prepared and draped in a conventional sterile fashion. All components were cemented with a conventional technique using antibiotic cement without any patient-specific instrumentation or robotic aide. The implants utilized were beaded periapatite-coated femoral, tibial, and patellar components .2.4−1·min−1 of ketamine that was continued until the patient emerged from anesthesia. Subsequently, the infusion rate was reduced to 1.5 ug·kg−1·min−1 and maintained for 48 hours. Patients allocated to the Group B were given identical volumes of saline.In patients assigned to the Group A, 0.05 mL/kg of the blinded test solution  was given Intravenous (IV) over 2 minutes just after the orotracheal intubation and before the skin incision. The initial bolus was followed by a maintenance IV infusion of 3 ug·kg2.5The primary outcome of this noninferiority study is opioid consumption within the first 24 hours following surgery. Subjects receive standardized postoperative multimodal analgesics. Supplemental oxycodone 5 to 15 mg every 3 hours for pain is available to each subject. Nurses administer a 5-mg oxycodone tablet for numerical rating scale (NRS) scores of 1 to 3, 10 mg for NRS scores of 4 to 6, and 15 mg for NRS scores of 7 to 10. Oral hydromorphone is substituted for oxycodone in the instances of patient allergy or intolerance. Rescue analgesia is available with IV hydromorphone 0.5 mg every 1 hour as needed for pain of greater than NRS of 7 when refractory to oral opioids. Opioid consumption during the first 48 hours postoperatively is retrieved from the electronic medical record and convert to IV morphine equivalents for analysis. The average and worst NRS pain scores at rest and with activity are determined by blinded investigators at 24 and 48 hours postoperatively.Secondary outcomes included pain scores, distance ambulated, patient satisfaction, length of hospital stay, and complications. Length of hospital stay was calculated by measuring the time from the completion of surgery through discharge for each patient.2.6t test. If the numerical variable has a nonnormal distribution or unequal variance, the Wilcoxon Mann–Whitney U test was used (American Society of Anesthesiologists grade); Pearson Chi-squared test or Fisher exact test was used to analyze the qualitative variable (complications). The nature of the hypothesis testing was 2-tailed, and a P-value < .05 was considered statistically significant.The statistical analysis was performed with the Statistical Package for Social Sciences . Normal distribution was verified using the Kolmogorov–Smirnov test. Continuous variables were presented as median and interquartile range , or mean ± standard deviation according to distribution. Categorical parameters were expressed as number (%). The normal distributed numerical variables  were analyzed by Student 2.7The sample size was determined for the primary endpoint. According to the results of our previous study, the postoperative NRS score for nausea was 2.16 in the control group. We anticipated a difference of 0.72 in the NRS score. With a power of 0.90 and significance level of 0.05, the required sample size was calculated as 50 in each arm. Considering possible exclusion, we decided to include 60 patients in each group.3 Becke et al demonstrated that intraoperative low dose ketamine had no effect on pain relief and morphine consumption during the first 72 hour after surgery. However, recent published articles reflected mixed results in TKA patients. Therefore, we performed a randomized controlled trial to evaluate the efficacy and safety of ketamine for reducing pain after TKA.TKA generates substantial postoperative pain. Although various effective interventions including femoral nerve block, peri-articular injection, adductor canal block, nonsteroid anti-inflammatory drug, and epidural morphine have been used for pain control after TKA, the optimal analgesia still remains a subject of debate. Recently, the use of ketamine has been popularized in the surgical field and exhibits improved outcomes for analgesia. Singh et al reported that preemptive ketamine has a definitive role in reducing postoperative pain and analgesic requirement in patients undergoing laparoscopic cholecystectomy.The present research seeks to compare the effect of ketamine on the postoperative analgesic effect and early rehabilitation in patients undergoing TKA. Three potential limitations to this study were identified. First, NRS pain was recorded by nursing pain assessment records in hospital and thus pain measurements are based on the frequency and accuracy of documentation in the medical record. The second limitation was the small sample size used in this study. Replication of this study on a multi-institutional level would provide less variation between experimental groups and simultaneously increase the reliability and generalizability of the results. Finally, having the same surgeon for all procedures in this study was both an advantage and disadvantage. It is advantageous for consistency and internal validity; however, it may limit the reproducibility of this study.Conceptualization: Jing Chen, Wei Hu.Data curation: Shu-Ming Li.Formal analysis: Jing Chen, Wei Hu.Funding acquisition: Xiao-Lin Li.Investigation: Jing Chen, Wei Hu.Methodology: Zhan-Min Yang.Resources: Zhan-Min Yang.Software: Xiao-Lin Li.Supervision: Zhan-Min Yang.Validation: Shu-Ming Li.Visualization: Shu-Ming Li.Writing – original draft: Jing Chen, Wei HuWriting – review & editing: Zhan-Min Yang.


Little is known about pain and opiate use at home directly after total knee replacement (TKR). Due to adverse effects, low opiate use is desired. An electronic health app (PainCoach) was developed to guide patients in pain control and opiate use.The aim of this paper was to investigate the effects of the PainCoach app on pain control and opiate use in patients who underwent TKR during the first 2 weeks at home after surgery.In an unblinded randomized controlled trial, patients scheduled for TKR were offline recruited and randomized to a PainCoach group or control group. In the PainCoach group, the PainCoach app was downloaded on each patient’s smartphone or tablet. In response to the patient’s input of the pain experienced, the PainCoach app gave advice on pain medication use, exercises/rest, and when to call the clinic. This advice was the same as that received during usual care. The control group received usual care. The primary outcomes were opiate use and visual analog scale (VAS) pain scores at rest, during activity, and at night during the first 2 weeks at home after surgery, which were collected daily from day 1 until 14 postoperatively by online questionnaires. The actual amount of app use was recorded, and active use was defined as ≥12 total app uses.P=.02) and 14.6% more acetaminophen  when compared with the findings in the control group (n=33). The PainCoach app was used 12 (IQR 4.5-22.0) times per patient. In the active PainCoach subgroup (n=19), the following were noted when compared with the findings in the control group: 4.1 times faster reduction of the VAS pain score during activity , 6.3 times faster reduction of the VAS pain score at night , 44.3% less opiate use , 76.3% less gabapentin use , and 21.0% more acetaminophen use .The pain scores did not differ between the groups. The PainCoach group (n=38) used 23.2% less opiates (95% CI −38.3 to −4.4; The use of the PainCoach app contributes to reduced opiate use in the initial period at home after TKR. Active use of this app leads to a further reduction in opiate use and improved pain control.ClinicalTrials.gov NCT03961152; https://clinicaltrials.gov/ct2/show/NCT03961152 Total knee replacement (TKR) is a successful treatment option for patients with end-stage knee osteoarthritis (OA) . ModeratAlthough pain is usually under control during hospital stay, less is known about pain control in the initial period at home after TKR. Current pain management strategies include a combination of nonsteroidal anti-inflammatory drugs (NSAIDs), nonnarcotic medication, opiates, and exercise . AlthougWith this in mind, to manage pain better and potentially decrease opiate use, an eHealth app named PainCoach was developed. This app aims to help patients control their pain better in the initial period at home after TKR, including optimal use of the available pain medication. This study aimed to determine the effects of PainCoach on pain control and opiate use in TKR patients in the first 2 weeks at home after surgery. The hypothesis was that the use of this app would decrease pain and opiate use.An unblinded, randomized, controlled, single-center trial was performed at Kliniek ViaSana . Patients with an American Society of Anesthesiologists (ASA) score of I-II, a body mass index (BMI) of ≤35, and a plan to undergo primary TKR between February and June 2016 were enrolled. Four experienced high-volume knee surgeons performed all surgeries, and three experienced anesthesiologists administered spinal anesthesia. The same type of TKR implant was used in all patients . All surgeries were performed using a tourniquet. The pain management protocol consisted of preoperatively administered medication, LIA injections during surgery directly before cementing the implant, and a step-wise postoperative pain management protocol . PatientIncluded unblinded patients were randomly assigned to the PainCoach or control group using lots presented in sealed opaque envelopes during admission. All lots were created and sealed by a researcher in the ratio of 1:1. A blinded nurse presented the envelops to a patient, and the patient selected one to complete randomization. All patients received the usual pain management care including pre-, peri-, and postoperative pain medication , particiBeside the actual amount of app use, all the outcome measurements were assessed using a digital, online, automated collection system , which automatically sent an invitation by email to complete an online questionnaire preoperatively, daily from day 1 to 14, and at 1 month postoperatively. In case of nonresponse to the preoperative or 1-month questionnaire, an automatic reminder was sent after 3 days. The invitation to complete the daily questionnaire was sent at 5 pm, and patients had access to the questionnaire until midnight.The primary outcomes were opiate use and pain score of the operated knee at rest, during activity, and at night in the first 2 weeks at home after TKR. The pain score was measured on a VAS for pain, which ranged from 0 (no pain) to 100 (worst imaginable pain), preoperatively, daily from day 1 to 14, and at 1 month postoperatively -35. SeveThe secondary outcomes in the first 2 weeks at home and 1 month after TKR included other pain medication use , which was also recorded in quantities per 24 hours from day 1 to 14. Additionally, pain acceptance at rest, during activity, and at night was assessed with a happy smiley (acceptable pain) and a sad smiley (unacceptable pain) preoperatively, daily from day 1 to 14, and at 1 month postoperatively. Experiences with the executed recommended physiotherapy exercises were recorded daily from day 1 to 14 on a 3-item scale . Moreover, function and quality of life were measured preoperatively and 1 month postoperatively. Knee function was assessed using the Knee Injury and Osteoarthritis Outcome Score–Physical Function Short-form (KOOS-PS) on a scale from 0 (no difficulty) to 100 (extreme difficulty) . The OxfPreoperative opiate and other pain medication use, age, gender, ASA score, BMI, preoperative comorbidities, history of knee surgery on the same side, Charnley score, date of surgery, date of discharge, and complication data were collected from the electronic patient records. Pain coping, anxiety, education level, and marital status were determined preoperatively using an online questionnaire. Pain coping was measured using the pain coping and cognition list scored from 1  to 6 , and it had the following four categories: catastrophizing, pain coping, internal pain management, and external pain management .t-test, Mann-Whitney U test, likelihood analysis, Fisher’s test, or Pearson’s chi-squared test, depending on the type of data. Mixed linear models were used to analyze the overall rate of decrease or increase for continuous data, and generalized linear models were used to analyze the percentage decrease or increase for count and nominal data. Additional analysis was performed to compare the active PainCoach subgroup with the control group, with correction for differences in preoperative data. Statistical significance was set at P<.05, and trends were defined as .05<P<.10.Analysis was performed using SPSS version 25.0 . All measured outcomes from day 1 until day 14 after surgery were recoded into measured outcomes for days at home by subtraction of the admission period. Patient characteristics were analyzed using descriptive statistics, and data were checked for normal distribution. Differences in mean, median, or percentage were tested using the independent two-sample A total of 97 patients were included, and of these, 76 patients were randomized. Because of loss to follow-up, the final analysis was performed with 71 patients  . The resP=.02)  than in the control group (P=.02) .P=.02)  at rest, 20.0 (IQR 7.0-35.0) during activity, and 17.0 (IQR 4.0-37.0) at night. The control group had VAS pain scores of 20.0 (IQR 7.0-33.0) at rest, 21.0 (IQR 10.0-38.0) during activity, and 20.5 (IQR 8.0-40.0) at night. Pain was classified as severe on one or more days in 21% (8/38) of patients from the PainCoach group and 30% (10/33) of patients from the control group. No statistically significant differences were found between the two groups in terms of the VAS pain scores at rest, during activity, and at night . RegardiP=.02) . One monP=.02) .P=.02) (P=.001) (P<.001)  at rest, 12.0 (IQR 5.0-25.0) during activity, and 10.0 (IQR 2.8-28.0) at night during the first 2 weeks at home. Pain was reported as severe on one or more days in 16% (3/19) of patients from the active PainCoach subgroup. The VAS pain score during activity significantly decreased 4.1 times faster in the active PainCoach subgroup when compared with the finding in the control group  . The VAS(P=.001) . The mea(P<.001) . One mon(P<.001) .P<.001) and no statistically significant differences in NSAID use and gabapentin use when compared with the findings in the control group during the first 2 weeks at home (P=.02)  . At 1 mo (P=.02) .P<.001) during the first 2 weeks at home. Additionally, the active PainCoach subgroup had statistically significant 76.3% decreased gabapentin use when compared with the findings in the control group  (P=.048)  . In the  P<.001) . One mon(P=.048) .Among 28 patients who provided appropriate responses, 25 (89%) reported ease of app use, 22 (79%) found that the app added value, and 22 (79%) would recommend the app to friends and family. The PainCoach app was used 12 (IQR 4.5-22.0) times per patient on 7 (IQR 4.0-9.0) days at home. The number of patients with at least one entry in the PainCoach app ranged from 11 (30%) to 26 (70%) per day at home . The appThis study aimed to determine the effects of an eHealth app, the PainCoach app, on pain control and opiate use in patients who underwent TKR during the first 2 weeks at home after surgery. The hypothesis was that the app would decrease pain and opiate use. As indicated by the main findings, there was no statistically significant difference in pain scores between the two groups and opiate use was significantly reduced by 23.2% in the PainCoach group when compared with the finding in the control group. In the active PainCoach subgroup, however, pain during activity and at night significantly decreased 4.1 and 6.3 times faster, respectively, and opiate use significantly reduced by 44.3% when compared with the findings in the control group.Overall, low pain scores and high levels of pain acceptance were found in this study. Only 21% (8/38) of patients in the PainCoach group and 30% (10/33) in the control group classified their pain as severe during one or more days at home. Other studies have stated that the most painful period after TKR surgery was the initial period at home, with 23%-30% of patients rating their average pain as severe ,41. AsidOpiate addiction caused 74 deaths in the Netherlands in 2016, and this number is increasing each year . Using tA shorter hospital stay is associated with a higher burden among patients, who need to take responsibility for aftercare shortly after surgery. Recent studies have shown that patients feel uncertain and left alone after discharge, which could increase anxiety and affect their pain coping and subsequent management ,51. PatiTo our knowledge, this is the first randomized controlled trial to examine the effects of eHealth with regard to controlling pain and reducing opiate use after TKR. The strengths of this study are that the actual amount of app use was measured and because of the unique download codes adopted, it was not possible for the control group to use the PainCoach app. The shortcomings are that the additional analysis was underpowered and the cost-effectiveness of the PainCoach app was not investigated. Furthermore, as there is no short validated questionnaire in Dutch for measuring pain acceptance, an expert group decided to assess pain acceptance using happy and sad smileys as the best alternative. In the population of this study, opiate use was already low. The app might have a much stronger effect in patient populations where preoperative opiate use is much higher. It is questionable if the PainCoach app is effective in the overall TKR population, as this study investigated the effects in patients having ASA I-II and BMI ≤35, which represent around 80% of the total TKR population ,53. FutuThe use of the PainCoach app contributes to reduced opiate use in the initial period at home after TKR. Active use of this app leads to further reduction in opiate use and improved pain control.


While the evolution of technology provides new opportunities to manage chronic refractory pain using different waveform modalities of spinal cord stimulation in failed back surgery syndrome (FBSS), there is no randomized controlled trial available to compare the efficacy of these different stimulations waveforms to date. MULTIWAVE is a prospective, randomized, double-blinded, crossover trial study designed to compare the clinical efficacy of tonic conventional stimulation (TCS), burst stimulation (BURST) and high-frequency stimulation (HF) in FBSS patients over a 15-month period in SCS implanted patients.Twenty-eight patients will be recruited in the Poitiers University Hospital, in Niort and La Rochelle Hospitals in France. Eligible patients with post-operative low back and leg pain with an average visual analog scale (VAS) score ≥ 5 for low back pain are implanted and randomly assigned to one of the six arms (in a 1:1:1:1:1:1 ratio), where they receive a 3-month combination of TCS, BURST and HF including one treatment modality per month and varying the order of the modality received within the six possible combinations. Patients receiving intrathecal drug delivery, peripheral nerve stimulation and back resurgery related to the original back pain complaint and experimental therapies are excluded from this study. Patients included in the spinal cord stimulation group undergo trial stimulation, and they all receive a TCS treatment for 2 months, as the gold standard modality. Thereafter, patients are randomly assigned to one of the six arms for the total duration of 3-month crossover period. Then, patients choose their preferred stimulation modality  for the follow-up period of 12 months. Outcome assessments are performed at baseline (first implant), before randomization (2 months after baseline) and at 1, 2, 3, 6, 9 and 15 months post-randomization. Our primary outcome is the average global VAS of pain over 5-day pain diary period between baseline and after each period of stimulation. Additional outcomes include changes in leg and back pain intensity, functional disability, quality of life, psychological state, paraesthesia intensity perception, patient satisfaction and the number of adverse events.Recruitment began in February 2017 and will continue through 2019.NCT03014583. Registered on 9 January 2017.Clinicaltrials.gov  Failed back surgery syndrome (FBSS), defined by chronic back and/or leg pain after lumbosacral spine surgery –5, is reStudies have clearly demonstrated the clinical efficacy and medico-economic interest of spinal cord stimulation (SCS), which consists in delivering an electrical current to the dorsal epidural space via electrodes, as a way of managing refractory pain in FBSS patients , 10. HowRecent clinical trials provide evidence for the efficacy of BURST –17 and HThe MULTIWAVE study is an RCT comparing clinical SCS efficacy using TCS, BURST and HF modalities in a crossover design in implanted chronic refractory FBSS patients. Before randomization, all implanted patients receive TCS treatment for 2 months. Then, TCS, BURST and HF waveforms are randomly and alternatively administered for a 1-month period and a total duration of 3 months for the three different SCS waveforms. After the 3-month period, each patient selects his or her preferred stimulation modality with a follow-up period of 12 months.The primary objective of this study is to compare the efficacy of TCS, BURST and HF Stimulation on pain relief  in refractory FBSS patients. Secondary objectives are to compare changes in the following outcomes for each of the three treatment modalities: back pain intensity, leg pain intensity, functional disability, quality of life and psychological state.This protocol is reported in accordance with the SPIRIT 2013 guidelines for protocols of clinical trials .MULTIWAVE study is a prospective, controlled, randomized, crossover, double-blind trial comparing TCS, BURST and HF SCS treatments. Twenty-eight patients will be recruited in the Poitiers University Hospital, in Niort and La Rochelle Hospitals in France. Patients will be implanted with a 32-contact surgical lead and a Precision Spectra SCS System™  Internal Pulse Generator (IPG) enabling use of these different waveforms. After a period of 2 months following the surgical lead implant, patients will be randomized 1:1:1:1:1:1 to various SCS modalities. During this period, patients will receive a 3-month specific set of 3 combinations of TCS, BURST and HF amongst 6 possible combinations, delivering each treatment modality during a 1-month period. Patients will be unable to switch from one waveform to another modality until the end of the crossover period. After completion of the 3-month post-randomization period, patients will be asked to choose their preferred SCS modality. Starting with this visit, patients will be able to switch from a waveform to another depending on daily activity within a day. In case the choice of waveform is not obvious, to assist decision making, the patient will be allowed to see his VAS score and pain mapping. Reasons for modality choice will be collected. Patients are monitored up to 15 months post-randomization. The study design is presented in Fig. The study population comprises patients suffering from chronic significant low back and leg pain following spinal surgery . A patient must meet all the inclusion criteria and none of the exclusion criteria to be eligible for the study. Inclusion/exclusion criteria will be checked by the Principal Investigator, who is an expert neurosurgeon specialized in surgical SCS implantation.The patient is an eligible candidate for SCS, according to the French guidelines for SCS selection and implantation . The pain should be refractory despite well-conducted conservative management and no further spine surgery required. For the purposes of this study, FBSS is defined as persistent or recurrent low back and leg pain of at least 6 months’ duration, following at least one decompression and/or fusion procedure –5. The pThe patient is treated or has previously been treated with SCS, subcutaneous or peripheral nerve stimulation, treated with an intrathecal drug delivery system or requires back surgery at the location related to his/her original back pain complaint or receives/had received experimental therapies; had most recent back surgery less than 6 months ago; presents low back pain accessible to etiological “mechanical” surgical treatment ; is < 18 years or > 80 years of age; presents a surgical, anaesthetic or psychiatric contraindication to implantation of a SCS system; is pregnant or planning to become pregnant during the course of the study; would be unable to operate the SCS equipment, based on the opinion of the principal or sub-investigator; and is a member of a vulnerable population.A patient is considered enrolled in the study upon completion of the informed consent process. The subject records his/her global, back and leg pain scores during a 5-day pain diary period prior to randomization. FBSS diagnosis and candidacy for SCS is confirmed based on appropriate imaging according to usual practice. In addition, in cases where psychological and anaesthetic evaluations are standard of care and/or required, the evaluations must take place prior to randomization.Subjects who meet the inclusion criteria and none of the exclusion criteria undergo a 7-day SCS screening trial period with a CoverEdge 32-contact surgical lead™ implantation  allowing patient feedback or general anaesthesia. A CoverEdge 32-contact surgical lead will be implanted empirically at T8/T9 vertebral level, using a minimally invasive technique according to our usual practice. The projection of the conus medullaris over L1-L2 will be assessed on pre-operative MRI, previously to lead implantation to ensure optimal localization of the surgical lead. Immediate fluoroscopic control of the vertebral projection, the lateralization of the lead and lead impedance check will be performed.After radiological assessment of the lead positioning by X-rays, preliminary lead electrophysiological testing will be performed and the lead will subsequently be navigated longitudinally through the epidural space, to determine the best vertebral level and implantation site, using patient feedback and objective quantitative measurements by tactile interface mapping data (NeuroMapping Tools Software) , 25. TheSome TCS patterns will be tested using various predetermined combinations, in order to achieve good pain coverage, by targeting the sweet spot location with objective quantitative measurements by tactile interface mapping data (NeuroMapping Tools Software) , 25. ThiAfter completion of lead programming testing, the lead will be permanently implanted and secured with appropriate anchoring, at its final vertebral level. A final X-ray check will be performed to ensure that the lead has been adequately secured and will not be subject to displacement, once the lead programming and the patient coverage are optimal , 25.Subjects, who succeed in the TCS SCS screening test , receive a Precision Spectra SCS System™ IPG. At this stage, subjects receive TCS during 2 months before the randomization to avoid any period-related bias due to the pain scar. After the 2 -month period, the subject is randomized to one of the six arms. After the crossover period, subjects choose their preferred modality for a follow-up period of 12 months. Subjects who fail the screening test are excluded from this study.Supported by Multiple Independent Current Control (MICC) hardware, Illumina3D™ is a model-based anatomically guided 3D Neural targeting programming algorithm, designed to precisely calculate anodic and cathodic current distribution at each lead contact. The resulting field shape  is then used as the target for the delivery of various waveforms, including paraesthesia-based stimulation waveform, BURST and HF using Illumina3D™ Algorithm Fig. .TCS patterns are tested thanks to patient cooperation, using various predetermined combinations, in order to achieve good pain coverage and validate the sweet spot location. TCS operates at frequency range of 10–100 Hz for every patient with pulse width of 10–500 μs and amplitude 0.1–25 mA. TCS significantly increases the spontaneous activity of neurons in the gracile nucleus, which are known to project to the primary somatosensory cortex in the brain. This increased spontaneous activation of the spinal nucleus may account for the sensation of paraesthesia that typically occurs during TCS .BURST stimulation consists of closely spaced, high-frequency stimuli delivered to the spinal cord. The stimulus paradigm consists of a 40-Hz burst mode of constant-current stimuli with 5 spikes at 285–332 Hz per burst, pulse width of 10–500 μs, interspike intervals of 3 ms and amplitude corresponding to 50–70% of the sensitive threshold. The differences between TCS and BURST stimulations could be due to more selective modulation of the medial pain pathways by BURST stimulation, as evidenced by activation of the dorsal anterior cingulated cortex . Recent While HF is generally operated with a range of 500 Hz to 10 kHz, new SCS systems have been developed and make it possible to deliver stimulation up to 10 kHz. The device allows delivery of HF stimulation from 650 to 1200 Hz with pulse width of 10–500 μs, and amplitude corresponding to 60–65% of the sensitive threshold. HF may offer several distinct benefits over TCS. The first would suggest that this therapy could address axial back pain more effectively, which often does not respond as well to traditional SCS. The second is based on the fact that HF, as BURST SCS, appears capable of delivering pain relief without inducing any paraesthesia. This last observation could have obvious benefits for patient acceptance of SCS therapy and could also simplify system implantation by avoiding intraoperative paraesthesia mapping, required to ensure proper lead positioning . The effOutcome measures selected for this trial are based on a review of the previous RCTs of SCS and consideration of IMMPACT recommendations . The visThe primary outcome is the variation of average global VAS score, assessed over a 5-day pain diary, between baseline  and after each treatment period . PatientSecondary outcomes are variation of leg and back pain relief, as measured by VAS ; proportFurther, pain surface, pain intensities and paraesthesia surface are quantified with objective quantitative measurements (Neuro-Pain Software) to compare Global Pain Surface reduction, pain intensity reduction and paraesthesia coverage surface between arms groups , 25.Staphylococcus aureus decolonization (2 days prior to visit until 2 days after). Subjects who proceed to device implantation have the following information collected: pain/paraesthesia by tactile interface mapping data (NeuroMapping Tools software), lead programming parameter settings, electrode location and device implant information. The NeuroMapping tool is a validated quantitative tactile interface allowing the patient to delineate painful zones in the back and legs and to precisely map objective changes in pain coverage and SCS performance [At the screening and baseline visits, the following additional pieces of information are collected: subject demographics  and a neuropathic pain assessment by clinician-administered diagnostic questionnaire (e.g. Douleur Neuropathique en 4 questions) to discriminate neuropathic pain components of low back pain , surgicaformance , 25.Unscheduled patient visits could occur between scheduled study follow-up visits due to patient discontinuation from the study or device reprogramming and management of any complication.12 + SD22 − SD2change)/(2 × SD1 × SD2) where SD1 = 3.0 and SD2 = 2.5 are the standard deviations of the two time points/treatments. Based on data from Kapural et al. [To calculate the sample size of our study, we started by focusing on the pairwise comparison of HF stimulation and TCS (using a Wilcoxon signed-rank test) while taking into account the Bonferroni correction. BURST and HF stimulation did not show any differences in the literature , which wl et al. , we esti12 + SD22 − 2 × corr × SD1 × SD2 = the square root of 3.02 + 2.52–2 × 0.6 × 3.0 × 2.5), a significance level of 0.0167 (Bonferroni correction) and a power of 0.8, a total sample size of 23 is required and stepped up to 24 in order to ensure a balanced number of subjects per arm. To consider 15% dropout, we decided to include 28 patients.Assuming a mean difference of 2 points, a standard deviation of the difference of 2.5  vs 3.0/10 (SD = 3.0)), no difference between BURST and HF stimulation (3.0/10 (SD = 3.0) vs 3.0/10 (SD = 3.0)), a correlation of 0.60 between every two treatments  and a significance level of 0.05. We obtain an estimated power of 96.1% for 28 patients and 90.9% for 23 patients, for detecting the hypothesized difference between the three groups.https://www.dirc-hugo-online.org/csonline) dedicated to the study and accessible to investigators by username and personal password. Once given, the randomization assignment for the subject cannot be changed. Early departure from the study does not give rise to replacement or reassignment of the rank of inclusion.To minimize selection bias, randomization sequence is prepared using a random selection programme developed under SAS V9.3. Randomization numbers are assigned in strict sequence, i.e., when a subject is confirmed eligible for randomization, the next unassigned randomization number in the randomization sequence is given. Randomization allocation is hidden from the clinician and subject, using a centralized automatic web-based data management system  with the optimal coverage of pain surface is selected. Once the optimal programme is chosen, the minimal threshold allowing paraesthesia perception is identified. Based on it, the patient device remote control is adapted so that patients can modulate stimulation intensity (BURST or HF) only from 20 to 50% of this reference amplitude. By following these recommendations of the manufacturer, patients do not feel paraesthesia with BURST and HF stimulations, which ensures the patient-blinding trial. Double-blind is ensured by conducting patient evaluation and SCS programming by two different agents. Unblinding is made according to the sponsor site procedure. The randomization list is held by the Pharmacy of the CHU of Poitiers.p value adjustment method will be conducted for pairwise comparisons. Ordinal outcomes will be compared between groups using the same previously described procedure. Quantitative normally distributed endpoints will be compared between groups using repeated measures ANOVA. Pairwise comparisons will be conducted after the repeated measures ANOVA indicate significance. Binary outcomes will be compared using the Cochran Q test and a McNemar test will be conducted for pairwise comparison after the Cochran Q test rejects the null hypothesis.Categorical variables will be described by numbers and percentages while quantitative variables will be described by the mean and its confidence interval or median and interquartile range based on the skewness of the variable. The study sample will be described by age, gender, BMI, duration between pain appearance and device implantation, number of spinal surgeries and type of pain . The primary hypothesis of the difference between TCS, BURST and HF will be verified using the Friedman test or repeated measures ANOVA depending on the normality of the global pain VAS (average VAS over the 5-day diary period). Shapiro-Wilk test will be used to test for non-normality of distributions. In case the Friedman test indicates significance, a post hoc test using the procedure described by Conover  and the t test or Wilcoxon signed-rank test depending on the variables’ distribution. All comparisons will be two-sided with a level of significance of 0.05. Missing data will be described. Patients with missing data on the primary outcome will be excluded from the analysis. The blind analysis is aimed to be conducted in per-protocol analysis. A robustness analysis including all available data will be conducted on the primary outcome using a Skillings-Mack Test. R software will be used for statistical analysis.After the end of the crossover design, patients will choose a preferred waveform and will be followed for 1 year. The proportions of waveform preference will be compared using a chi-square goodness of fit test. The categorical variables will be compared between visits M6, M9 and M15 and baseline using the McNemar test while the continuous variables will be compared between baseline and the post crossover visits using the paired This study received funding in 2016 from Boston Scientific grant programme ISS agreement (Investigator Sponsored Study).Each patient provides informed consent and approval from the Poitiers University Hospital Ethics Committee (CPP Ouest III), the French National Agency for Medicines and Health Products Safety (ANSM) and the General Data Protection Regulation (GDPR) No. 2016-679 of April 27, 2016.Prior to site initiation or subsequent involvement in study activities, the sponsor provides study training that is relevant and pertinent to the personnel conducting study activities, including investigator responsibilities and device training .Monitoring visits are conducted periodically every 4 months. Monitors may work with study personnel to determine and recommend appropriate corrective action(s) and to identify trends within the study.Throughout a 30-year period, SCS has been developed with TCS modality of stimulation as the main treatment method. In two seminal studies published by North et al.  and KumaAs indicated in a recent review of Head et al. , the choThe MULTIWAVE study design described herein is not free of limitations.First, our design presents some limitations, notably for blind comparison between TCS involving paraesthesia effect versus the two other waveforms (BURST and HF), which are paraesthesia-free. However, this design will provide the opportunity to blindly compare BURST and HF for the first time.Second, the crossover design in comparison with a parallel-arm design does not allow us to determine the long-term efficacy of each modality. While we will be able to document the use of each modality between the 3- and 12-month follow-up periods, long-term efficacy will be determined in a non-controlled design. This limitation could nonetheless be considered as a plus-value for the patient, who will be able to use the whole potential of the SCS with modality choice within a day, while adherence of the treatment is reinforced.Third, it is not possible to guarantee/claim that each stimulation modality might impact, significantly or not, on the outcomes of the modalities used during the randomization phase. A 1-month wash-out period might be relevant to solve this problem, and we strongly believe that it will allow us to avoid any contamination effect. We agree that the feasibility of a wash-out design is challenging and our study design is not intended for this purpose.This study represents the first randomized controlled, crossover, double-blind trial comparing TCS, BURST and HF treatments. Beyond any waveform comparison, the ability of this new generation SCS system to independently or simultaneously deliver the three SCS modalities to the patients depending on their needs, in real time, should enhance adherence to the treatment. In the future, the concept of therapy choice within a day can be transposed to cylindrical leads enhanced by the multisource concept. Further studies are also needed to determine the underlying physiological mechanisms for each SCS waveform modalities according to clinical outcomes.The MULTIWAVE trial began patient recruitment in February 2017 and recruitment was completed in December 2019. Follow-up measurements will be closed in May 2021.


Pain is the principal symptom in knee osteoarthritis (OA). Current non-operative treatment options have only moderate effects and often patients experience persistent pain or side-effects. Novel advances in the field of cryoneurolysis applies low temperatures to disrupt nerve signaling at the painful area, providing pain relief. The primary aim of this randomized controlled trial (RCT) is to investigate if cryoneurolysis is superior to sham at decreasing pain intensity 2 weeks after the intervention in patients with knee OA. Secondary aims are to explore effects on pain, quality of life and functional performance over 24 months.n = 94) to a cryoneurolysis intervention group + standardized education and exercise (CRYO) or a sham group + standardized education and exercise (SHAM) (1:1 ratio). Both groups will be assessed at baseline, 2 weeks post intervention, post education and exercise and at 6, 12 and 24 months after cryoneurolysis. The primary outcome is the NRS knee pain intensity score assessed 2 weeks post the intervention. Secondary outcome measures include functional performance , patient reported outcomes , Knee and osteoarthritis outcome scores (KOOS), among others), use of analgesics, and adverse events over 24 months.This two-arm, parallel-group RCT, approved by the Regional Ethics Committee, will randomly allocate patients (Cryoneurolysis could potentially provide an effective, safe and non-pharmacological therapeutic option to treat pain in OA patients. The potential benefits include increased functional capacity and quality of life as a result of significant pain relief and improved benefits of physical exercise.NCT03774121, registered 3 March 2018, http://www.clinicaltrials.govClinicaltrials.gov,  Chronic pain represents a major challenge worldwide, with significant clinical, social and economic implications. In Denmark and the rest of Europe, 20% of all chronic pain conditions is related to osteoarthritis (OA) . There aThe treatment of knee OA typically focuses on pain relief, however, the effects of current conservative treatment options remain small to moderate and most are associated with side effects . In manyIn Denmark, a standardized education and neuromuscular exercise program (GLA:D) has been implemented in the national clinical guidelines by the Danish Health Authority, for the treatment of knee and hip OA in clinical practice . Recent The primary objective of this RCT is to investigate if cryoneurolysis is superior to sham at decreasing pain intensity 2 weeks after the intervention in patients with painful knee OA.The secondary objective is to explore the safety and effectiveness of cryoneurolysis followed by GLA:D and to assess long term effects.This study protocol describes the design of an ongoing parallel-group RCT conducted at the Department of Neurology, University Hospital of Southern Denmark, Esbjerg, Denmark. The study protocol conforms to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)  and electrical nerve stimulation followed by a diagnostic genicular nerve block. If patients experience a ≥ 50% decrease in knee pain intensity (NRS) as a result of the nerve block, they will be randomly allocated to either a cryoneurolysis intervention group (CRYO) or a sham group (SHAM).Referred to GLA:D  by a phyAge ≥ 18 yearsChronic knee pain for a minimum duration of 6 months.Pain intensity ≥4 on the Numeric Rating Scale (NRS).Radiographic confirmation of osteoarthritis; Grade 2-4 changes according to the Kellgren-Lawrence classification system.A decrease of ≥50% in NRS scores with diagnostic genicular nerve block.Written and oral understanding of Danish.History of systemic inflammatory conditions such as rheumatoid arthritis.Previous recipient of cryoneurolysis for the knee.Use of hyaluronic acid within the previous 30 days.Injection of corticosteroid within the previous 3 months.Clinically significant structural abnormities affecting locomotion and knee function aside from osteoarthritis and which might cause chronic knee pain.Body mass index ≤18 and ≥ 40 kg/m2.In treatment for other pain conditions.PregnancyCoagulopathyUncontrolled serious disease Disease associated with reactions to cold, such as cryoglobulinemia, cold urticarial and Renaud’s syndrome.Randomization is performed as computer-generated block randomization with a 1:1 allocation ratio using random block sizes of 2, 4 and 6. The randomization restrictions will not be disclosed to ensure allocation concealment and the sequence will be performed by an external co-investigator. To account for the placebo effect and reduce the risk of bias, the patients, therapists and data-manager will be blinded to the allocation. Blinding will be assured using a sham trial that includes the same procedures as cryoneurolysis treatment but without any freezing temperatures.The allocation code is concealed in a sealed envelope, that will be available for the surgeon performing the cryoneurolysis procedure only. In case of unexpected issues and if deemed absolutely necessary by the investigators and physician, unblinding will occur according to emergency unblinding procedures that will maintain the integrity and confidentiality of the study.The interventions involve two visits.Radiographic confirmation and clinical determination of knee OA as pain generator followed by the identification of the infrapatellar branch of the saphenous nerve (IBSN) and anterior femoral cutaneous nerve (AFCN). Predefined areas for each nerve are marked directly on the patient , 36. Thereversible destruction of nerves, also known as Wallerian degeneration, that prevents nerve signaling and potentially alleviate pain and motor dysfunction in a number of medical conditions.Ropivacain (5 mg/ml) is injected before treatment, locally at the insertion-point, 4-6 cm from target nerve locations. This allows for continuous patient feedback during the following procedures. The cryoneurolysis probe  is inserted in proximity of the target nerve, guided by ultrasound visualization to accurately determine the location of the nerve and to account for adjacent neurovascular structures and variations in anatomical structures. Cryoneurolysis are performed with a single freeze cycle; 30s at an effect of 20%, and 2 min 30s at 60% effect. After each freezing cycle, 1 min active thaw and 1 min passive thaw is used. The machine used for cryoneurolysis is a VisualICE, , which utilizes Argon as a coolant and Helium to thaw. This technology allows for The sham intervention includes the same procedures as described above but using a sham probe that does not allow for any freezing temperatures. Thus, visible marks as a result of the procedures will be similar in both groups.Following the cryoneurolysis intervention, both groups will participate in GLA:D  for a duThe patients will be assessed at baseline, 2 weeks post intervention, after completion of GLA:D and 6, 12- and 24- months post cryoneurolysis. The tests will include both patient-reported outcomes (PRO) and objective functional performance tests. The effects of group CRYO and group SHAM will be compared at each timepoint  from baseline to 2 weeks post cryoneurolysis compared between group CRYO and SHAM. NRS consists of an 11-point scale between 0 and 10-, anchored by two verbal descriptors, “no pain” for the score of 0 and “worst pain imaginable” for the score of 10. Respondents are asked to rate their pain intensity on average within the past 24 h. The NRS instrument has been validated in diverse populations and has been widely applied in clinical and research settings .Functional performance will be evaluated by the 30 s chair-stand test, the 40 m fast-paced walk test, the 9-step stair-climb test and isometric knee MVC force .The 30 s chair-stand test [and test  consistsThe 40 m fast paced walk test [The 9-step stair-climb test [imb test  consistsMVC force of the knee extensors . Patients will be seated in a chair with knee and hip flexed at 90° and with the pelvis and chest restrained by straps. A non-extensile chain attached to the back of the chair and connected to a force transducer will be placed just proximal to the malleolus. The patient will then be asked to perform three knee extensions pushing as hard as possible against the chain, with 1 min rest in between. The highest peak value out of the three MVCs will be taken as the MVC force.Quadriceps strength will be assessed measuring isometric Knee Injury and Osteoarthritis Outcome Score (KOOS). To assess patients’ opinion about their knee and associated problems .EQ-5D. To assess generic quality of life .Pain Catastrophizing Scale. To assess the extent of catastrophic thinking .Patient Health Questionaire (PHQ9). To assess the extent of depression .Generalized Anxiety Disorder (GAD7). To assess the extent of anxiety .Pain intensity (NRS) and location (electronic drawing on a 2D model).Self-reported use of analgesics.In addition to pain intensity, PRO-data will be collected using PainData, which is an electronic questionnaire system and database with multiple integrated questionnaires, including:Adverse events will also be reported and are defined as any undesirable experience during the trial leading to contact with the healthcare system . All adverse effects will be assessed during follow-ups using both pre-specified symptom inventories and open-ended questions.The planned number of trial participants is based on the null-hypothesis, assuming no difference between cryoneurolysis treatment and sham. Estimating the sample size for a two-sample means test with a level of significance at 0.05, assuming a common standard deviation (SD) of 3 in NRS pain intensity scores indicates that for the intention-to-treat (ITT) population, 74 individuals is required to obtain a power of at least 80% to establish a minimal clinically important difference (MCID) of 2 in NRS pain scores . The MCITo evaluate the distributions of the continuous outcomes, visual inspection of the studentized residuals will be applied to evaluate whether the assumption of normality is reasonable. Data will be reported as differences between group means  if normal distributed, otherwise as medians with interquartile ranges. Categorical data will be reported as numbers and proportions. An Intention-To-Treat (ITT) analysis will be used for all allocated patients. Mixed linear regression with the assumption of unstructured covariance will be used to model the effect of the cryoneurolysis treatment over time and to take into account the repeated measures by including individuals as random variables. Time, group of treatment (cryoneurolysis or SHAM) and the Group, time interaction will be used as fixed effects to estimate different patterns of change over time. The results will be illustrated using marginal effects that will be calculated using the margins command of STATA16. If the 95% CIs do not overlap, data will be considered statistically significant. A statistically significant difference of at least two in NRS scores between groups, will be interpreted as a MCID.The current project will not require a formal data monitoring committee. This decision is based on the minimal known risks associated with the intervention and little expected disturbance to the clinical equipoise. Any adverse effects will be recorded and reported according to the guidelines to the Regional Committee on Health Research Ethics for Southern Denmark within 7 days. Once a year the lead investigator will report all expected and unexpected adverse effects that have occurred during that period, with an evaluation of patient safety.The leading investigators will review the trial processes and data continuously. In addition, a status report will be sent for approval to the Danish Health Authority each year.All data will be kept electronically and filed according to a participant code. Data entry will always be handled by the same investigator, who will use unambiguous and standard terminology based on predefined study forms. Complete back-up of all data will be performed regularly and stored on OPEN’s servers in the Region of Southern Denmark, using Research Electronic Data Capture (REDCap). REDCap store data via an encrypted connection with restricted access and fulfil the demands for data security. Data will be stored for a duration of 10 years. The project will be reported to the Danish Data Protection Agency and will be handled according to the regulations of the Act on Processing of Personal Data. The full data set will be available to the lead investigators only.The study is conducted according to the declaration of Helsinki and is approved by The Regional Committees on Health Research Ethics for Southern Denmark (S-20180089) and registered in ClinicalTrials.gov (NCT03774121). Given the study design, eligibility criteria and safety measures, the current project does not include special risks for the participating patients. The majority of risks does not require medical attention and serious adverse effects as a result of local anesthetics and cryoneurolysis are very rare. In contrast cryoneurolysis could potentially provide an effective, safe and minimally invasive option to treat pain in OA patients.The inclusion of a sham group is necessary to test the hypothesis because of the large reported placebo effects in invasive interventions . In addiCurrent pain-relieving therapies show small to moderate effects and a significant portion of patients who receive surgery (TKA) report unchanged pain intensity levels post-surgery. This indicates that there is a need for additional therapies that could supplement or improve the existing therapies. A significant difference in the change in pain intensity between sham and intervention post cryoneurolysis treatment would indicate that cryoneurolysis is an effective non-pharmacological therapeutic option to treat pain in OA patients. Outcome measures include both pain, social and psychological factors and functional capacity, which allows for a thorough understanding of treatment effects. The novel addition of GLA:D in combination with cryoneurolysis will elucidate whether feasibility and effectiveness of exercise increase if pain is attenuated and if the potential pain-relieving effects of cryoneurolysis can be extended. The potential benefits include increased functional capacity and quality of life as a result of significant pain relief and improved benefits of physical exercise, ultimately postponing or making surgical intervention unnecessary. This could have a significant impact on patients’ lives as well as significant socioeconomic consequences and could change the clinical landscape in the treatment of OA. Finally, an important perspective, is the application of cryoneurolysis in other areas – such as managing pain, related to surgery, to improve rehabilitation.If the results indicate that cryoneurolysis does not elicit additional pain relief when compared to sham, it might indicate that cryoneurolysis treatment is not suitable for the treatment of OA related pain or at least not in the way it is applied in the current study.Importantly, the freezing protocol in this study results in reversible nerve damage, allowing for the reinnervation of the sensory receptors over time , 16. It This study is a blinded randomized controlled sham trial that includes long-term follow ups allowing for an evaluation of the long-term effects of treatment. The sham intervention includes the same procedures as in cryoneurolysis treatment, emulating both physical marks and sensory experiences such as sound and vision. Despite of this, some performance bias cannot be excluded, and some attrition bias might occur, due to patients seeking treatment elsewhere – expectedly from the sham group. The inclusion of a sham group is necessary to test the hypothesis because of the large reported placebo effects in OA trials . TreatmeThe obtained results will be made publicly available within 1 year after the end of the project. This will include publication of the obtained results in international scientific peer-reviewed journals - adhering to the recommendations of the Vancouver convention. Published papers will have open access to ensure a broad distribution and the results will be presented at international scientific conferences. The results will also be presented for the general public and distributed across public platforms  if copyright allows.


Post-thoracotomy pain syndrome (PTPS) is reported with a prevalence ranging between 33% and 91% in literature. However, the difference between open (TT) and video-assisted thoracic surgery (VATS) concerning the prevalence and neuropathic character of PTPS has not yet been systematically investigated. Furthermore, knowledge on analgesic treatment and its efficacy is limited.Structured telephone interviews were conducted with 488 patients 6 to 30 months after TT and VATS. In case of pain, patients received a structured questionnaire including the Leeds Assessment of Neuropathic Symptoms and Signs and Brief Pain Inventory.P < 0.05) and in patients younger than 65 years . TT resulted more often in neuropathic pain . Forty six percent of PTPS patients received analgesics: 30.3% nonopioids, 25.2% opioids, 10.9% anticonvulsants, and 1.7% antidepressants. Antineuropathic agents were used in 17.4% of patients with neuropathic pain. In 36.7% of patients, the reported reduction of pain was less than 30.0%.Prevalence of PTPS was 28.6%. 13.2% of patients had a pain intensity Numeric Rating Scale >3, and 4.6% of patients had a pain intensity Numeric Rating Scale >5. In case of PTPS, 63% of patients suffered from neuropathic pain. Post-thoracotomy pain syndrome was more frequent after TT than after VATS (38.0% vs 29.3%, Post-thoracotomy pain syndrome is not as common as estimated. In most cases, pain intensity is moderate, but patients suffering from severe pain require special attention. They are often heavily disabled due to pain. Tissue-protecting surgery like VATS is beneficial for the prevention of PTPS. Analgesic medications are often underdosed, unspecific for neuropathic pain, and insufficient. Apart from intraoperative nerve damage and subsequent postoperative neuropathic pain, operation techniques, age, sex, pre-existing pain, genetic and psychosocial factors, severe postoperative pain, and analgesic management are suspected to have an impact on the development of PTPS.16 Considering the widespread use of minimal invasive surgical approaches, video-assisted thoracoscopic surgery provides an alternative to open thoracotomy for lung resection. However, its implications on the prevalence of PTPS have not yet been systematically investigated.Chronic pain is a common complication after thoracic surgery. The prevalence of post-thoracotomy pain syndrome (PTPS) ranges from 33% to 91%.Our study aims to investigate the prevalence of PTPS in patients receiving open thoracotomy (TT) in comparison with video-assisted thoracic surgery (VATS). In case of PTPS, the presence of neuropathic pain as well as the use and efficacy of analgesic treatments was investigated.The study was approved by the ethics committee of Witten/Herdecke University. The local hospital information system was used to identify all patients who underwent TT or VATS between 2009 and 2011. Chest wall resections were not included. After erasing duplicates, we applied our inclusion and exclusion criteria: Patients older than 18 years who received TT or VATS within the past 6 to 30 months and gave informed consent were included in the trial. We excluded patients who participated in other studies, had missing or invalid contact data, or were deceased.29 As there were no data of PTPS after VATS available to us, based on our clinical experience, we expected that the prevalence would be lower compared with TT, due to decreased surgical trauma. For the purpose of our sample size calculation, we estimated the prevalence of PTPS for VATS to be <30%. Assuming this effect size in a one-tailed test for the difference between 2 independent mean values with alpha risk of 5% and beta risk of 20%, a sample size of 456 patients would be required. Thus, our aim was to contact 500 patients by telephone (250 TT and 250 VATS). The survey period was 6 to 30 months postoperatively.All eligible patients were contacted by phone. The maximal number of attempts was 3. We performed a sample size calculation at the beginning of the study. After review of literature, prevalence of PTPS after TT was estimated to be 40%.3 According to the IASP classification of chronic pain, 6 months was chosen as the point of division for acute and chronic pain.18 In case patients did not report any pain or discomfort, no further investigations ensued. In case of persisting pain or discomfort, written informed consent was obtained to include patients in a questionnaire-based survey containing the Brief Pain Inventory and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS). Brief Pain Inventory is a comprehensive and validated instrument for pain assessment.22 Pain was determined by Numeric Rating Scale (NRS 0–10). Pain-related disability was also assessed by the Brief Pain Inventory and categorised according to NRS scores. NRS scores are presented as mean (SD). After the initial telephone interview, all personal data were removed; the data set was collected and stored anonymously with a patient identification number.All patients gave informed consent to participate in a short-structured telephone interview inquiring about current level of pain and discomfort. Chronic pain was defined as pain persisting past the normal time for healing.The standard approach for TT was anterolateral thoracotomy. The incision was made on the level of the fourth or fifth intercostal space. The latissimus dorsi muscle was visualized and spared. The serratus anterior muscle was divided only when needed parallel to the muscle fiber direction, and the intercostal place was opened at the lower edge of the fourth or fifth rib. The vascular nerve bundle was carefully detached from the upper rib, and the intercostal nerve was resected at the level of the thoracotomy just laterally from the intervertebral foramen. A rib retractor was placed and gradually widened . In case of VATS procedures without anatomical resection, three 1-cm ports  were used. In case of VATS with anatomical resection (lobectomy and segmentectomy), two 1-cm ports and an axillary 3- to 4-cm incision in the fourth intercostal place were used. Rib retractors were not used in the VATS group. The opened intercostal space was closed using a continuous suture (thoracotomy and axillary incision in VATS group) sparing the intercostal nerve. VATS converted to TT was processed as TT in the statistical analysis.Patients after TT received a paravertebral single-shot analgesia in landmark technique after closure of the operation wound by the anaesthesiologist combined with systemic analgesia based on the department's standard operating procedures for the management of acute pain after thoracic surgery. Patients after VATS received the same systemic analgesia. Regional anaesthesia was not used.Pain medications were categorised according to the following active agents: “nonopioid analgesics,” “opioid analgesics,” “anticonvulsive agents,” and “antidepressant agents.” Within the groups, the dosage was classified with respect to the recommended minimal and maximal dosage: “underdosed,” “low dosed,” “middle dosed,” “high dosed,” and “overdosed” Table . For opi2 test. Continuous variables were calculated using the Mann–Whitney U test. For analysing predictors of PTPS, logistic regression analysis was performed. The occurrence of pain was considered a dependent variable, while age (<65 years/≥65 years), sex, surgical procedure (TT/VATS), presence of malignant primary disease, and postoperative period were considered independent variables. The significance threshold was α = 0.05 .Professional statistical consulting services were provided by the university. Missing variables were completed if possible. Differences in categorical variables were calculated using the χAn overview of the enrolment process is outlined in Figure P < 0.05). After TT, PTPS was reported more often than after VATS . There were no significant differences in rates of PTPS with regard to sex, presence of cancer, or time since the operation , 10.9% anticonvulsants, and 1.7% antidepressants. For details, see Table P < 0.05). The more different analgesic agents were prescribed, the higher the mean pain  of nonopioids and opioids or of opioids and anticonvulsants (40.9%). The majority (70.9%) of patients receiving analgesic agents had no prescription for medication on demand. Average pain in patients with analgesic agents was significantly higher than in patients without analgesic agents . In 36.7% of patients, the reported reduction of pain was less than 30.0%.P < 0.05; Fig. P < 0.05). In case of PTPS, pain intensity was significantly higher in patients with neuropathic pain than in patients without  had no impairment in any category. Patients with a low rating (NRS ≤3) were significantly less disabled due to pain than patients with an NRS rating >3 in all categories  may have been potential confounding factors. A Danish nationwide questionnaire study determined a rate of 31.7%, as did a similar investigation in the United Kingdom (45.0%).29 Both studies had a response rate of 41.1% and 52.0%, respectively. It is tempting to speculate that affected patients may be more likely to respond to a survey, which could be a potential source for bias contributing to an overestimation of prevalence rates. We tried to reduce the impact of this potential confounder by performing telephone interviews. We assumed that patients without pain would be less likely to answer a questionnaire than patients suffering from pain. Subsequently, the use of a questionnaire might pose a risk for selection bias and might overestimate the prevalence of pain. We tried to minimise the risk for bias by contacting everyone by telephone and assess persistent pain or discomfort after the operation. Studies with higher prevalence rates are frequently associated with several methodical limitations, such as short postoperative survey periods, inclusion of elderly patients, routine performance of rib resections during thoracotomy, and postoperative analgesic management by morphine analgesia or by patient-controlled intravenous analgesia.27 At the time our study was performed, there was no consistent systematic classification of chronic postoperative pain available. We adhered to the IASP classification of chronic pain from 1994 and decided to include patients 6 months after surgery, as we wanted to ensure that pain-related disabilities of daily life had enough time to manifest. In the upcoming ICD-11 classification, chronic postsurgical pain will be defined as pain persisting >3 months.23 This may limit the comparability to our findings. In addition, most previously reported prevalence rates result from surveys after posterolateral TT, which would be expected to lead to higher rates of PTPS than anterolateral TT, which was used in our investigation. In light of new developments in surgical and anaesthetic techniques, such as single-port VATS or regional anaesthetic techniques  might limit the external validity of our findings. By now, PTPS prevalence was estimated in synopsis of all data to be 30% to 40%.10Our data showed that the prevalence of PTPS was not as common as estimated by previous studies. The prevalence of PTPS reported in the literature ranges from 33% to 91%.29 Another study assessed the severity of PTPS after posterolateral thoracotomy by telephone interviews.21 It found the overall prevalence of PTPS to be quite high (52%); however, patients reported moderate pain in 16% and severe postoperative pain in only 3% of cases. These results were confirmed by another study with an equally high prevalence of PTPS (61.0%) recorded 1 year after thoracotomy performed without epidural or paravertebral catheters, which reported an equally low rate of 5% for severe pain.20 Overall, the prevalence for severe PTPS seems to be low, although rates for moderate PTPS differ significantly.While PTPS is a frequent sequel of thoracic surgery, severe forms of PTPS occur less frequently. In a multicentre questionnaire-based trial, similar rates of moderate and severe PTPS were found: NRS >3 11.0% and NRS >5 4.0%.15 In a registry analysis, TT and VATS were compared with a trend towards lower prevalence rates of PTPS after VATS, yet without statistical significance.29 In both trials, only patients with lung cancer were included and postoperative analgesia was provided by thoracic epidural anaesthesia for both TT and VATS. In other studies, the sample sizes were too small to draw valid conclusions.12 According to our data, age is a relevant predictive factor for developing PTPS with young patients (<65 years of age) being at a higher risk for chronic pain. This is in line with other investigations.29 Although the reason is unclear, limited inflammatory processes and higher pain tolerance in older patients may be possible explanations.Minimally invasive VATS reduces tissue and nerve damage during surgery. Investigations comparing the prevalence of PTPS after TT vs VATS are rare. According to our data, TT leads more frequently to chronic post-thoracotomy pain than VATS. Once PTPS occurred, there was no difference in pain intensity with regard to the surgical technique used. One survey investigating chronic pain after TT and VATS found no differences 1 year after surgery; however, details on postoperative analgesia and response rates were not provided.1 The impact of sex on the incidence of PTPS, however, remains uncertain. Similar to previous results,17 we found a higher rate of PTPS in women. These differences were not statistically significant. An analysis of a larger cohort is required to further investigate the impact of patient sex.We could not detect any additional statistically significant predictive factor. Female sex is a known risk factor for developing chronic pain syndromes.27 Paravertebral block seems to be effective as well.13 It is unclear, if the protective effect is based on effective postoperative pain management or on the regional anaesthesia technique itself.9 The use of regional anaesthesia in our study was affected by the surgical technique. Paravertebral single-shot regional anaesthesia was only used in patients with TT. Patients with VATS received systemic analgesia only. Thus, we cannot assess the impact of regional anaesthesia on the development of PTPS.Performing regional anaesthesia has shown beneficial effects regarding the development of chronic pain. Compared with intravenous PCA, patients with thoracic epidural analgesia developed PTPS less frequently.29 No further details are provided. 46.2% of our patients regularly used analgesics. Although 63.0% of patients suffered neuropathic pain with subsequently increased pain levels, antineuropathic medication was prescribed in only 17.4% of cases. By contrast, recommendations of national guidelines and current literature support systemic and topical antineuropathic treatment,5 which could improve pain therapy.Knowledge on the analgesic management and its efficacy in case of PTPS is limited. Current investigations reported that between 33.0% and 53.0% of patients use analgesic medications.Dosing of analgesic agents was frequently inadequate because it was often underdosed or low dosed. Comparing average pain levels between patients being underdosed or low dosed and middle or high dosed, pain reduction in middle- or high-dosed patients tended to be better.Specific and high-dosed antineuropathic medication could lead to better pain reduction. Pain management could be improved by adding short-acting analgesic agents on demand. However, 70.9% of all patients with analgesic medication had no additional medication on demand.7 and nerve damage may occur in thoracic surgery,2 neuropathic pain is a potential explanation for the development of PTPS. However, the exact role of neuropathic pain in PTPS is not entirely understood. Almost 2 thirds of our patients with PTPS suffered from neuropathic pain, according to questionnaire. LANSS is an established screening tool for neuropathic pain, which was also validated for the purpose of a questionnaire survey with high sensitivity and specificity.28 Patients reported neuropathic pain more frequently after TT than after VATS. Our high rate of neuropathic pain might be influenced by the extent of tissue and especially nerve damage. Another reason may be standard neurotomy performed in case of TT. The exact role of neurodestructive procedures like neurectomy or kryoneurolysis in the development of PTPS is unclear. Several studies failed to detect a beneficial effect of neurodestructive procedures on acute and chronic pain.19 Some patients even developed long-term neuralgia. This is in contrast to other studies showing less acute and chronic pain rates after neurodestructive procedures.24 Most studies used relatively short observation periods, which may not detect the late onset of long-term neuropathic pain.Considering that many patients suffering from PTPS report neuropathic symptoms26 All rates are in accordance with our findings. However, the presence of neuropathic symptoms was associated with increased pain intensity and more impact on daily life activities, according to our data.17Using other screening tools for assessing neuropathic pain does not significantly alter the prevalence of neuropathic pain.PTPS is not as common as previously estimated. In most cases, pain intensity is moderate; nevertheless, patients suffering from severe pain have to receive special attention, as they are often heavily disabled by chronic pain. For the prevention of PTPS, tissue and nerve protective surgery seem beneficial. Accordingly, VATS should be performed if possible. Analgesic medication is often underdosed, unspecific for neuropathic pain, and insufficient.The authors have no conflicts of interest to declare.Presented in part as a poster at the Congress of the European Federation of IASP Chapters (EFIC), Florence, Italy, October 2013.


First-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients.NCT03342950.This is a study protocol for a randomized, double-blind, placebo-controlled, phase II clinical trial with a cross-over design. It is a single-centered, 5-week study that will enroll a total of 32 patients with post-traumatic peripheral neuropathic pain. Patients will be treated topically with either a combination of clonidine and pentoxifylline or placebo for a period of 2 weeks each, in randomly assigned order across patients, with an intervening washout period of 1 week. The primary outcome measures of the study are the intensity of spontaneous pain recorded daily in a pain diary with a visual analog scale, and the degree of mechanical allodynia evoked by a brush stimulus. The secondary outcome measures of the study include scores of pain relief and change in the area of punctate hyperalgesia. This trial has been prospectively registered with ClinicalTrials.gov on November 1, 2017. ClinicalTrials.gov Identifier: The analgesic use of topical treatment with clonidine and pentoxifylline in combination has not been investigated in post-traumatic neuropathic pain. This study could generate the first evidence for the efficacy and safety of the formulation in alleviating pain in patients with neuropathic pain. Furthermore, this trial will provide objective grounds for the investigation of other agents that enhance tissue oxygenation in the topical treatment of peripheral neuropathic pain.This trial has been registered with ClinicalTrials.gov owned by NIH’s US National Library of Medicine.NCT03342950. Registered on November 1, 2017 .ClinicalTrials.gov This is protocol version 5, dated June 2018. McGill University Health Center (MUHC) Reaseach Ethics Board (REB) identification number: TTNP 2018-3906. Peripheral neuropathic pain is a chronic pain condition that is a direct outcome of damage to the peripheral nerves . The damPeripheral neuropathic pain of varying etiologies involves microvascular changes that result in ischemic hypoxia of the affected nerves. Functionally, deficits have been reported in the endothelial production of vasodilatory nitric oxide (NO), which normally acts to counteract the basal vasoconstrictive sympathetic tone . Structu2-adrenergic receptors and reducing the release of norepinephrine both centrally and at peripheral sympathetic nerve endings  or hormonal methods .Patients will have to fulfill all the following inclusion criteria:Diabetes mellitus necessitating antihyperglycemic treatment or any other endocrine diseaseAny liver disease, resulting in liver transaminase enzyme levels greater than three times the normal valuesChronic renal failure or kidney disease, resulting in serum creatinine levels > 133 μmol/lHypertension or taking of anti-hypertensive medicationMalignant disease or taking of chemotherapeutic agentsKnown diagnosis of angina pectoris, arrhythmias, congestive heart failure, or peripheral arterial diseasePregnancy or breastfeeding. Female patients of childbearing age must have a negative urine pregnancy testKnown allergic reaction to clonidine or pentoxifyllinePresence of a medical condition known to affect peripheral circulation Medication that interacts with clonidine or pentoxifylline Any medical condition that might be impacted by clonidine or pentoxifylline, such as cardiovascular disease, cardiac rhythm disorders , orthostatic regulation disturbances, and disorders of cerebral perfusionA cerebral and/or retinal hemorrhage (in the last 5 years)Any of the following conditions will exclude patients from this study:All participants will be randomized to treatment with either active drug or placebo in one of the two 2-week-long treatment blocks of the study. The active drug is an anhydrous topical solution containing 0.1% (W/V) clonidine and 5% (W/V) pentoxifylline. The placebo is a blank version of the anhydrous solution with constituents identical with the active drug except omitting the therapeutic agents, i.e., clonidine and pentoxifylline. The stability of the topical solutions at room temperature has been ascertained with mass spectrometric studies done upon the request of Health Canada. The exact composition of the active drug and placebo is as outlined in Table Both the active drug and placebo solutions are colorless and will be packaged in identical Topi-Pump® dose-metered applicators that dispense 1 ml of topical solution with each pump. Participants will be instructed to apply one pump or 1 ml of the topical solution three times daily on an eight-hourly basis. They will also be asked to return the emptied pumps after use so adherence to treatment can be monitored.The average daily pain intensity level is recorded by the patient at home in an REB approved pain diary that contains a visual analog scale (VAS) displaying the words “no pain” and “worst pain possible” on the left and right of a 100-mm line, respectively.The degree of dynamic mechanical allodynia (DMA) is determined by stroking the most painfully sensitive area of the skin once at a velocity of 1–2 cm/s with a soft brush (bristle length by width: 20 × 15 mm). The patient then indicates the amount of pain evoked on an REB approved data collection sheet with a 100-mm VAS. This test will be stopped immediately at the request of the patient if it is too painful.Primary outcome measures of the study are as follows:Pain relief scores are recorded on a 6-point categorical pain relief scale (0 worse pain to 5 complete pain relief).Area of punctate hyperalgesia (PHA) is measured using punctate stimulation with a 26-g von Frey monofilament . Stimulation commences from outside the sensitive area toward the center of the sensitive area, along eight approximately evenly spaced radii, while asking the subject to report when the sensation becomes unpleasant or frankly painful. The points at which the sensations change will be marked and the markings gently transferred onto a lightweight transparent plastic sheet. The marked sheet is subsequently photographed with a ruler to calibrate the number of pixels per unit length during image analysis and area calculation.Secondary outcome measures of the study are as follows:d = 0.8, alpha = 0.025 corrected for multiple testing; power = 95%). Based on a power calculation for two groups using a cross-over design, the estimated required sample size is 27, and we expect that a sample size of 32 is sufficient to detect changes in pain levels even if up to 18% of patients do not complete the study.Thirty-two patients will be recruited for this trial. This number of patients is chosen based on the assumption that during the active topical drug treatment period patients will experience a reduction of either of the primary outcome measures (spontaneous pain or intensity of DMA) of 20 mm or more on the 100 mm VAS  and the Alan Edwards Pain Management Unit at the Montreal General Hospital.The thirty-two patients, females and males, with post-traumatic peripheral neuropathic pain will be recruited from the Quebec Pain Registry  clinical research training certification by the Research Institute of the McGill University Health Centre. Also, the research study staff will receive training on general standard operating procedures for clinical trials and specific tasks for conducting the study.Randomization for treatment order (placebo–active drug/active drug–placebo) is performed by a coin flip done by a research coordinator assigned for this task who is not involved in patient interaction and outcome assessment. The same coordinator also ensures blinding by assigning a three-digit number code, from a computer-generated random list, to the Topi-Pumps used in each treatment block. The list of number codes and the identity of their corresponding treatment is only shared with the compounding pharmacy. The blinding applies to the patient, the study coordinator performing patient assessments, and the dispensing pharmacy.The sequence of treatment for each patient will be determined based on the randomized treatment order assigned by the research coordinator described above. The enrolment and evaluation of eligible patients will be performed by two other research coordinators with the assistance of research nurses at the pain clinic. The two research coordinators and research nurses will be strictly blinded to the treatment allocations of the patients.Data will initially be collected on paper-based source documents filled out at every visit. Data will then be transferred promptly into a spreadsheet stored in a password protected drive. Data entry and management will be completed by one of the study coordinators and the sponsor will not have access to the data. All source documents and data sheets used in the clinical trial will not have patient identifying information; instead, patients will be assigned a study code number with the key securely stored to ensure confidentiality. All information pertaining to the study will be retained by the principal investigator for 25 years after completion as per guidelines of Health Canada.The MUHC-REB will perform an annual review of the study activities and progress before issuing a renewal of authorization to resume the study. The review will require a detailed report of the number of recruited and enrolled participants; a tally of participants that completed, dropped out, or withdrew from the study with explanations; and a description of the nature and frequency of adverse events recorded during the study. Regular inspections and audits are expected to be performed by delegates from the MUHC-REB and Health Canada. The study coordinators will facilitate the process by granting access to all paper and electronic study records and data. The coordinators will also accompany the auditor on any tours and inspections of the study area.t-test to evaluate between-group differences in the 2-sequence groups, as is recommended for analyses in cross-over designs [t-tests to assess carry-over effects by comparing baseline and washout period measures. DMA pain scores at the end of each treatment period will also be compared between treatment periods. Secondary analyses of pain relief and the area of punctate hyperalgesia will also be conducted using unpaired t-tests.Statistical analysis will be performed using an unpaired  designs . The sumBoth clonidine and pentoxifylline have a history of safe systemic use in humans, and there is evidence that topical application of these agents produces extremely low to undetectable plasma levels . As no nAccording to the FDA, rare events in patients taking pentoxifylline  include anaphylactic reactions . SubjectRisks involved in taking clonidine orally are dizziness, light-headedness, drowsiness, tiredness, and vision problems, which are caused by a decrease in blood pressure . PatientAll adverse events will be tabulated, summarized, and reviewed by the study physician. Serious adverse drug reactions, i.e., reactions causing hospitalization; persistent or significant disability; that is life-threatening or resulting in death, will be immediately reported to the study sponsor who is the primary investigator and the research ethics coordinator for the study site. Serious adverse drug reaction reporting will follow International Council for Harmonization (ICH) guidelines.Eligible patients are expected to have stable disease with no alteration to their treatment regimen in the 5 weeks preceding enrollment. If a patient develops uncontrolled pain with a clinical indication for a new treatment during the study period, the participation of the patient in the trial will be discontinued and the new treatment commenced. If any subject’s systolic pressure is found to drop below 80 mmHg during any section of the trial, they will be asked to stop the treatments and they will be removed from the study. Finally, in the event of an anaphylactic reaction to any of the topical treatments used in the study, the patient’s participation in the study will immediately be terminated. In both instances, the coordinator performing the randomization will send the study physician the information required to unblind him to the study drug the patient was taking so the information can be transferred to the medical team that will care for the patient.Patients will be instructed to contact the study coordinator and/or physician if symptoms of clonidine withdrawal occur during washout or the week following completion of the study. In such an event, the study physician will perform a clinical evaluation of the patient and appropriate medical care will be provided. Unblinding and termination of participation in the study will depend on the study physician’s assessment of the patient’s clinical status.Participants will receive reimbursement of travel expenses up to a sum of 100 Canadian dollars. If participants fail to complete the study, the compensation they receive will be pro-rated amounts based on the duration of participation.The peripheral neuropathic pain patient population is composed of a sizable number of patients that can benefit from avoiding the systemic anticonvulsants and antidepressants that are first-line treatments of the condition –5. GivenAs a phase II clinical trial, this study is a proof-of-concept step to evaluate the potential efficacy and safety of the topical combination of clonidine and pentoxifylline in peripheral neuropathic pain . To optiThe cross-over design of the study was another step taken to increase the efficiency of the initial screening of the formulation’s analgesic effects. The design allows the use of a relatively small number of patients by minimizing between-subject data variability thereby reserving resources and time , 36. We Clinical trials with cross-over designs with relatively few patients have been used to successfully detect the efficacy of analgesics in painful diabetic neuropathy, post-herpetic neuralgia, and post-traumatic neuropathic pain –40. The With randomization and blinding, we have tried to maintain the internal validity of the study. Outcome measures were chosen to pointedly assess the analgesic efficacy and solely focus on discovering the degree of relief from spontaneous and evoked pain . A broadThe outcome measures used as comparators in this study are kept the same as what has been used in the healthy volunteer human-study performed with the topical combination . The meaTo the best of our knowledge, this study is the first randomized, double-blind, and placebo-controlled clinical trial to assess the analgesic efficacy of the topical combination of clonidine and pentoxifylline in neuropathic pain. Topical clonidine on its own has been investigated in this manner for the treatment of painful diabetic neuropathy and a positive outcome has been reported . In compLastly, relevant clinical data is required to affirm the abundant preclinical evidence on the role of poor nerve oxygenation and blood supply in the genesis of peripheral neuropathic pain , 46–48. The study is currently actively recruiting and enrolling eligible participants. Recruitment started in January 2019 and the study is forecasted to be completed by January 2021. This is protocol version 5, dated June 2018. MUHC-REB identification number: TTNP 2018-3906. If significant changes requiring the modification of this protocol are required, the changes will be submitted for approval to the MUHC-REB through its web-based platform Nagano.