Pain after surgery is normal, and treatments, including both pharmacological and psychological components, are fundamental for proper postoperative care. While several trials have investigated the analgesic effect of traditional non-pharmacological treatments, such as cognitive behavior therapies, the newer ways of delivering psychological interventions for pain after surgery are scarcely investigated. The aim of this randomized controlled trial (RCT) is to determine if delivering the psychological content through virtual reality (VR) along with the standard pharmacological treatment return better pain relief outcomes than standard care in adult patients following surgery.This is a protocol of a parallel RCT conducted in one community hospital. In order to test the efficacy of VR environments for reducing pain intensity, in the following day after surgery, adults (18 to 65 years) will be randomly assigned to either (1) standard treatment after surgery (control group) or (2) VR based intervention along with standard treatment. It is intended that a minimum of 30 patients be recruited in each group. For estimating the intensity of pain, both self-report and physiological measures will be used. Repeated measures of pain outcomes will be taken before and after the intervention. Moreover, for allowing an in-depth investigation of the effect of VR environments, the primary outcome will be complemented with measures of the adverse effects, level of immersion, and level of presence in the VR environment.The online version contains supplementary material available at 10.1186/s13063-021-05196-7. As defined by the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and an emotional experience associated with actual or potential tissue damage or described in terms of such damage . Often, g = 0.31, 95% confidence interval (CI) 0.14 to 0.48) as for improving recovery . However, these CBT interventions were delivered into face to face format and consequently associated with several threats regarding their applicability on a large scale. Specifically, one of the biggest challenges of the face to face interventions is to synchronize the hospitalization time and patients’ availability, as some were designed to be implemented in pre-surgical settings. Likewise, other interventions need several sessions to be implemented before producing positive effects, and often patients did not have this amount of time during their hospitalization. As a consequence, most of the CBT interventions are applied only in the management of chronic pain while the treatment of acute pain remained mainly pharmacological [Despite that in the last years pain management gained a lot of attention in both research and practice areas with enormous gains, the management of postoperative pain remains a tremendous challenge with high costs for patients and health care providers . Currentological . Furtherological , 8 whichOne potential approach for increasing the applicability of CBT interventions in cases of acute pain during short hospitalization could be to develop shorter protocols, respectively to deliver the psychological content through technology, such as virtual reality (VR). The VR technology already proved its effectiveness in the case of adults in other hospital settings, such as burn units –15 or ca= − 0.49, 95% CI − 0.83 to − 0.14). Moreover, a subsequent meta-analysis [g = 1.09, 95% CI 0.25 to 1.92) and after the medical procedures . Moreover, comparable results were founded when interventions aimed to reduce the cognitive  or affective components of pain . However, these promising results of VR interventions integrated into acute pain management are hampered by the fact that none of the analyses includes studies on post-surgical patients. In spite that the VR technology could be effectively exported in medical care settings [By using a combination of technologies , VR environments create immersive  and multanalysis  relying settings , to datesettings  which shsettings  comparinsettings  althoughsettings , 29 had settings . In addiThe aim of this study is to assess whether exposure to relaxing VR environments is associated with decreased levels of pain after surgery after varicose veins, hernia repair, or gallbladder surgeries. Surgeries of varicose veins, hernia repair, and gallbladder were aggregated due to similarities across (1) the incidence rate –34, (2) This study is a prospective, randomized controlled trial with two parallel groups. After randomization, participants will receive either (1) standard care after surgery (control group) or (2) VR-based intervention along with standard care treatment .The study protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)  instructα = 0.05 and power = 0.80. The expected effect size of 0.49 was chosen in the light of the results found by the most recent meta-analyses [g = 1.08, 95% CI 0.46 to 1.70) for studies with parallel design aiming to decrease pain at hospitalized patients. However, as we expected some dropouts  and somAll the participants were recruited from one community hospital from Romania. Starting October 2018, each patient admitted to the hospital for surgery was screened for eligibility criteria to this trial.The below criteria had to be cumulative met in order that a participant be included in the trial.❖ Adults aged 18–65 years, after surgery of varicose veins, hernia repair, or gallbladder surgery.❖ Patient in the acute care units, 1–3 days following surgery.❖ Willing and able to provide informed consent and participate in the study visit and study follow-up questionnaire.Presence of any criteria listed below will conduct at the exclusion of the participant from the trial.❖ Patients with neoplastic pathologies.❖ Patients with a history of motion sickness.❖ Patients with severe visual impairment .❖ Patients with severe/profound cognitive impairments measured with Six-item Cognitive Impairment Test (6CIT).❖ Use of strong opioids ❖ Other reasons for exclusion Some of the exclusion criteria were dependent on the VR device or were designed as a precautionary measure for not harming participants after using VR technology. Particularly, we excluded the participants with profound visual impairments  due to the incompatibility with the VR device which was not equipped with the eyes glasses spencer. Similarly, patients with a history of motion sickness were excluded for preventing any severe dizziness or injury.Randomization was conducted within the type of surgery using a random number generator, with an equal number of participants in the control and experimental group. An independent researcher had conducted the randomization sequence and the allocation sequence was stored on a secured computer until the participants were assigned to one of the interventions. The medical personnel and trial assessors were blind to the group allocation, but the study participants and research assistant were aware of the allocations. Precaution strategies to prevent the blind from breaking up included a limited number of persons interacting with the patients (i.e. only the research assistant) and a reminder to the patients not to talk about research allocations and study procedure. In addition, the treatment room was a different room of the patient hospital room. In the treatment room patients from the experimental group was exposed to the VR content and psychological respectively physiological measured. For the patients from the control group, only psychological and physiological measures were taken without exposing them to the VR content. After this, each participant was conducted to their hospital room. In the case that a participant explicitly requests to end the study procedure for any reasons, the procedure was stopped and counted as a dropout. Those patients who ask to end the procedure earlier were asked to respond at a short interview to quantify the reasons.The recruitment process and data collection are presented in Fig. https://www.oculus.com/experiences/go/1723271804396968/), promoting relaxation through fifteen highly immersive environments. Each environment recreates a different natural scene  which can be explored by the patients through a controller. Concomitant with the activities  environmental effects are changing smoothly to create a vivid experience. Additionally, in some environments , patients can freely explore the scenes in 360 degrees for enhancing the feeling of presence and immersion.Patients allocated to the VR-based intervention followed the standard protocol after surgery as prescribed by the current medical personnel and exposed for 15 min to an interactive virtual environment . This application is a commercially available app from the Oculus store (available at https://www.oculus.com/). This device is the premium device from Oculus, equipped with a highly immersive headset, one controller, and integrated headphones.As previous studies testing the efficacy of the analgesic effect of VR  showed tFive minutes before and during the VR exposures, the fluctuations of skin conductance (SC) were measured for all patients. Before and after the intervention, pain intensity, relaxation, and VR adverse effects were assessed. Additionally, the catastrophizing level, anxiety, and depression related to health and presence in the VR environment were quantified.Patients allocated to the standard of care group followed the treatment after surgery as prescribed by current medical personnel. In addition, they followed the same protocol as the patients in the intervention group regarding psychological and physiological measures. Specifically, they were conducted in the treatment room and asked to indicate the non-dominant hand for setting up the equipment to SC measures. After that, the SC was measured continuously for 20 min without exposure to the VR environments. At the end, they completed de psychological measures and were conducted in their hospital room.Figure The present study assesses the efficacy of a Nature Track© VR to decrease pain intensity in surgical patients. The primary outcome is pain intensity measured right before the exposure to the VR content and after. The secondary outcomes measure the effects of the application on relaxation and the amount of time spent by each patient thinking about pain. Also, the primary outcome was complemented with measures of the adverse effects, level of immersion, and level of presence in the VR.The pain intensity was measured using the Numerical Rating Scale (NRS)  by askinConcomitantly, as a physiological indicator of postoperative pain were measured the fluctuations of the SC –48. The As the level of relaxation could affect the perception of the pain intensity, the state of relaxation was measured using the NRS from 0 (“extremely stressed” to 10 (“relaxed”) before and after the intervention. We chose to measure by using NRS rather than other scales designed to measure relaxation due to his factual effect and similarities with the pain intensity measures.Another factor which can contribute to an increased perception of pain intensity is the amount of thinking time spent by a patient at pain . ConsequPotential adverse effects were evaluated using the Simulator Sickness Questionnaire (SSQ) . As someThe presence in VR was assessed using Igroup presence questionnaire (IPQ). This is a 14 items questionnaire assessing different aspects of presence and immersion into VR world through items such as: “In the computer generated world I had a sense of being there” or “How aware were you of the real world surrounding while navigating in the virtual world? ?”. In the end, once the IPQ completed, the patients will be instructed to answer an additional question  with dichotomous response developed by the authors for assessing the willingness for further sessions with VR system.The amount of analgesic used will be extracted from the medical records. The usage of opioids will be coded as present and absent. The mean drug metabolism time will be calculated in order to determine if an opioid agent is active, coding 1 if the opioid agent is active and 0 if is out of his action range.Level of catastrophizing was measured through the Pain Catastrophizing Scale (PCS) . This scAnxiety and depression levels were assessed through the Hospital Anxiety and Depression Scale (HADS) . This scCognitive abilities were measured through the Six-item Cognitive Impairment Test (6CIT) , a screeDemographic characteristics and psychological measures will be explored for missing data, and distribution abnormalities. Means and standard deviations will be used to characterize the sample. Preprocessing of skin conductance measure will be performed using AcqKnowledge 4.1 first through the visual inspection of the raw signal, and then applying the smoothing function with a smoothing factor of three samples. This function has the same effect as the low pass filter by replacing the high-frequency signal with the mean values across three milliseconds to subtract the artifacts, without changing the wave form.t-test statistic or the non-parametric equivalent. Physiological data will be processed using the AcqKnowledge 4.1 software, and for each patient, a difference score in the area under the curve between the last 5 min of measurement and baseline level of SC will be extracted. Pearson correlation will be employed to examine the relationship between the level of SC and pain intensity (as a difference score between pre-post intervention). A P value will be used to estimate statistical significance for all analyses.Behavioral data will be analyzed using STATA 16.1 in accordance with the intent to treat principal . DescripAs virtual reality technology is not known to be associated with severe adverse events and because the present intervention is designed for one session, 15 min length, there has no planned interim analyses or stopping rules.From the study group, RG and HS were responsible for the supervision of data acquisition. In this vein, they had weekly meetings with the research assistant responsible for data collection to monitor the entire process. A Data Monitoring Committee was not employed as the study implementation was designed in one site and the intervention has a low risk for adverse effects. Any change from the protocol will be reported to the ethical committee of the Babeș-Bolyai University and will be updated in the ClinicalTrials.gov (NCT03776344).Treating pain after surgical interventions is an overly complex and challenging process , and the integration of non-pharmacological approaches has been one of the priorities of healthcare reform in the last years . AdditioShould the hypotheses suggested in this study be proven, this would add empirical evidence about the benefits and feasibility of VR for the pain treatment in surgical patients. Our expectation is to obtain greater pain relief compared with studies employing non-technological interventions. Moreover, we expect that the results of the present study to be in line with the ones conducted by Mosso-Vazquez and colleagues  as well However, the present protocol is exposed to several threats. First, by recruiting participants from o single hospital is possible to affect the external validity of the study. Will be unknown if the characteristics of our participants will be representative for a broader population of surgical pain suffers. Moreover, our results cannot be extrapolated to other VR environments, being strictly linked to Nature TreksVR®. Second, the present protocol uses self-reported measures to asses pain intensity, level of relaxation, mood, pain catastrophizing and an open-label design, thus is possible that some of the reports be affected by the knowledge of the group assignment. Nonetheless, the trial assessors and researchers conducting data analysis will be blinded in order to improve the internal validity of the study and maintain a low detection bias (63). Not lastly, our results will be subtracted in the absence of other non-pharmacological treatment, thus, in the case of hypothesis confirmation we can conclude that the Nature TreksVR® produce significant reductions in pain intensity but we cannot know the effects when other non-pharmacological interventions are applied or when VR-based interventions are integrated in more comprehensive treatments of pain intensity.Concluding, although several threats exist, this study is to our knowledge, the first to test the efficacy of a modern, market-ready VR application for the treatment of pain after surgery, and his results will assist in the development of a new method for the delivery of evidence-based treatments.During data collection, all the data will be safely stored at the Municipal Hospital. After the implementation phase is completed, all the data will be transferred in a secured PC at the International Institute of Psychotherapy, accessible only by the principal investigator (RG) and the corresponding author (AD).Following the recommendations of the Consolidated Standards of Reporting Trials (CONSORT)  statemenThe trial started patient recruitment in October 2018 and completed in September 2019. At the date when the first draft of the present protocol was submitted (March 2019) the status of data collection was “on going.” Currently, the data for opioid consumption were not extracted from the patient medical records, and data analysis was not performed. A trial paper with the results should be submitted for publication around the beginning of 2021. The present version of the protocol is 1.5 (March 2021).Additional file 1. Informed consent.


The presence of opioid receptors around the peripheral nerves offers the possibility of providing postoperative analgesia, thereby encouraging the study of the effect of opioids in combination with local anesthesia (LA). Studies have also reported the efficacy of peripherally administered opioids in achieving adequate analgesia in regions with inflammation. Applying the concept of peripheral opioid receptors, our study aimed to evaluate the effectiveness of opioid analgesia in managing postoperative pain. The split-mouth study was carried out to evaluate the efficacy of buprenorphine added to lidocaine 2% in providing postoperative analgesia after the surgical extraction of the impacted mandibular third molar.  We conducted a randomized, double-blinded, split-mouth trial among 21 patients with impacted mandibular third molars bilaterally. In all patients, bilateral impacted mandibular third molars were extracted at different periods. The primary outcomes assessed were postoperative analgesia by the VAS score and the number of rescue analgesics consumed by patients at 24, 48, and 72 hours of interval via a questionnaire. P = 0.012) and 48 hours (P = 0.024), respectively, between the test and control group. Even though the mean number of rescue analgesics consumed by the test group was less than that of the control group, no significant difference was seen.  There was a statistical significant difference in postoperative analgesia duration at 24 ( Buprenorphine added to lidocaine 2% showed a minimal decrease in the pain score and duration of postoperative analgesia with no difference in the frequency of rescue analgesics consumed between the test and control. The impacted mandibular third molars in the oral cavity requiring surgical removal predispose the patient to pain and discomfort. While surgical extraction of the third molars of the lower jaw is a common procedure, pain management is the biggest apprehension for the patients. While intraoperative pain is well managed under local anesthesia (LA), the major problem lies postoperatively when the effect of the anesthesia dissipates . The paiµ-agonists with no direct organ damage offer an effective alternative for pain management. However, opioids may also cause central effects such as dizziness, fatigue, respiratory depression, hypotension, mental clouding, and vomiting [Extraction of teeth is generally done under the effect of a local anesthetic agent, commonly being lidocaine 2% with epinephrine 1 : 2,00,000. The duration of the effect of the local agent is approximately 40–60 minutes which is the duration of the surgical procedure. As soon as the effect of the local anesthetic agent has dissipated, the patient begins to develop pain. To overcome this, the patient consumes analgesics postoperatively [vomiting .µ-agonistic, κ-antagonistic, and antihyperalgesia effects. The pharmacological effects of buprenorphine are generally alike to morphine (μ-opioid receptor agonist) and are said to be 20–25 times more potent than morphine (buprenorphine 0.3mg is as equipotent as morphine 10mg) with a rapid onset and longer duration of action [This led to the understanding of a drug, buprenorphine hydrochloride, with a potent analgesic effect and close to no adverse systemic effects. Buprenorphine hydrochloride is a synthetic opioid having f action .μ-receptors is their upregulation with change in pH of the surrounding environment, such as the areas of inflammation, making these opioid agents more effective in the intraoral surgical sites which are generally inflamed and infected [In contrast to the other opioids, buprenorphine appears to have far fewer adverse effects such as tolerance and hyperalgesia. The use of systemically suboptimal dose of buprenorphine in the area of peripheral nerve endings resulting in analgesic effect has helped prove the theory of peripheral action of opioids –10. It hinfected , 14.Previous trials on the use of buprenorphine with LA have shown a marked reduction in postoperative analgesia –18. ThesThe study followed the Declaration of Helsinki on the medical protocol and ethics, the institutional ethics committee of Kasturba Hospital, Manipal (KH-IEC: 97/2019), approved the protocol, and prior informed consent was obtained from all patients. The trial was registered with the Clinical Trial Registry of India (CTRI/2019/08/020631). A prospective, randomized, double-blind, split-mouth trial was conducted in 21 patients who required bilateral impacted third molars' removal. The study was conducted from January 2019 to December 2020 at the Department of Oral and Maxillofacial Surgery.Patients who required bilateral impacted mandibular third molar extractions by the transalveolar method and aged between 18 and 40 years without any comorbidities with Pederson's difficulty index ≤6 were included . PatientThe study had a split-mouth design; each patient served as their own control. However, randomization was used using the coin toss method to determine which side received test or control intervention. The patient was unaware of the intervention being done, and the operator who administered LA was also blinded.Two solutions were prepared as a double-blinded study; solution A contained a modified solution of lidocaine 2% with epinephrine 1 : 20,000 mixed with buprenorphine, and solution B contained lidocaine 2% with epinephrine 1 : 2,00,000. The concentration of buprenorphine added to lidocaine 2% was 1 ml of 0.3 mg in a 30 ml vial (0.01 mg/ml). The dental nurse prepared the solution after she was handed over the coin by the respective patient. The maximum amount of LA administered was 3 ml. The amount of buprenorphine in 3 ml of LA administered was 0.03 mg (0.01 mg/ml × 3 ml).The standard technique for the inferior alveolar nerve (IAN) block was used to administer the LA by a single operator, NJ. All patients received a maximum of 3 ml of the solution . The side of the mouth which received solution A was categorized as the test group, and the side of the mouth which received solution B was categorized as the control group.The position of the tooth to be extracted was classified as per Pederson's difficulty index of the impacted third molar, which was assessed on a preoperative OPG of the patient . The difThe extraction was performed under LA under aseptic precautions as per the standard protocol by a single operator NJ. The onset and effect of the anesthesia were assessed as per the objective signs and symptoms for the inferior alveolar nerve block. Sutures were placed after completion of the extraction and achieving hemostasis. After extraction, the patient was prescribed antibiotic amoxicillin and potassium clavulanate (500 + 125 mg) combination three times per day for three days and an anti-inflammatory-analgesic combination of diclofenac 50 mg with paracetamol 325 mg as per the requirement, subject to not exceeding three tablets in a day.The primary outcomes assessed were postoperative analgesia and the frequency and number of rescue analgesics consumed by the patient. Pain was quantified using the Visual Analogue Scale (VAS) and documented by the patient before taking the rescue analgesic. A 10 cm VAS assessed the postoperative pain, ranging from 0 to 10, with 0 indicating no pain and 10 indicating the most severe pain. In addition, the patient documented the frequency and number of rescue analgesics consumed, which was collected on their follow-up visit. For this, the patients were given the preprinted forms and were instructed to mark their VAS score for pain at 24, 48, and 72 hours of intervals. Similarly, the number of analgesics consumed along with time was also mentioned on the provided form. A follow-up reminder was sent to each patient telephonically.p value <0.05 was considered statistically significant. Comparison of pain scores and the number of rescue analgesics between the test and control was done using Wilcoxon's signed-rank test.The analysis was done using SPSS version 20 . A Effect on the Pain Score. The mean pain score on the test side was significantly lower than on the control side at 24 and 48 hours (P = 0.012 and 0.024). Similarly, lower pain scores were noted on the test side than the control side at 72 hours; however, at 72 hours, the difference was not statistically significant (P = 0.064) ( = 0.064) .Frequency of Rescue Analgesics Consumed. The mean number of rescue analgesics was lower on the test side than on the control side. However, on comparing the test with the control, there were no significant differences between 24, 48, and 72 hours  ( d 0.058) .The initial 28 patients had five patients excluded because they underwent only single-side extraction. Additionally, two patients were excluded because of an incomplete questionnaire. The final study comprised 21 patients, of which 11 were males and 10 were females . The meaThe surgical procedure involves a mucosal incision to raise a mucoperiosteal flap, exposing the underlying impacted tooth, thus making it an invasive procedure. Tissue damage initiates the release of inflammatory mediators such as bradykinin and histamine. These inflammatory mediators act on nociceptors. Consequently, pain, inflammation in the submandibular area, and the submasseteric region with trismus are likely the outcomes .Postoperatively, analgesics and anti-inflammatory drugs are prescribed, the most common being NSAIDs . Despite their analgesic effect, they potentially cause side effects, including GI disturbances and renal toxicity, making them undesirable. Opioid analgesics, on the contrary, are a primary line of treatment for managing debilitating conditions. They are not known to cause direct harm to organs in low doses . Howeverδ-opioid receptor and antagonist of the κ-opioid receptor and shows lesser systemic side effects. Buprenorphine, a weak μ-receptor agonist and κ-receptor antagonist, was compared with morphine and produced a longer duration of analgesia with lesser side effects [The presence of opioid receptors around the peripheral nerves exposed the possibility of achieving postoperative analgesia, thereby encouraging studies of the effect of opioids in combination with LA . However effects –25.Recent advances allowed for the supplementation of LA with adjuvants such as steroids, which prolonged its postoperative analgesic effect without unduly extending the anesthetic effect and were efficient in inflammatory conditions , 27. SimNumerous studies have shown a beneficial effect of adding buprenorphine to various local anesthetic agents while administering regional blocks , 11, 28.Our study showed a significant pain reduction score over a 48-hour period in the test group, in which buprenorphine was administered along with lidocaine 2% for the IAN block compared to the control group in which unmodified local anesthetic solution was administered. This finding was consistent with the findings in the other two studies. Chhabra et al., in their study, reported that patients remained pain-free for 12 hours on administering buprenorphine-mixed LA solution , while KAnother parameter assessed in our study was the number of rescue analgesics consumed by the patient postoperatively. Even though the mean number of rescue analgesics was lesser in the test group, it was not statistically significant. In contrast, in both studies conducted by Chhabra et al. and Kumar et al., a significantly lesser number of rescue analgesics were consumed by the patients in the test group , 17. ThiThe systematic review had considerable heterogeneity in both studies conducted regarding the study design and parameters assessed . ChhabraKumar et al., in their study, included all the patients undergoing any form of intraoral surgical procedure which required nerve block administration. Furthermore, there was no mention regarding blinding of patients or operators in their study . Both thPain is a subjective experience, and perception of its intensity can vary with different patients. We designed a split-mouth study that included patients with the bilateral easy to moderate grade of mandibular third molar impaction to overcome this. The same patient was included in both test and control groups and assessed for their pain by the VAS chart. We tried to minimize or negate this subjective evaluation of pain perception and psychological differences between the tested individuals, affecting the results.No adverse effects were reported; this could be attributed to the low concentration of buprenorphine, i.e., 0.03 mg used peripherally. These results were similar to the other documented studies on the use of buprenorphine with LA for intraoral use. However, these reports regarding systemic side effects are in contrast to the one published in the systematic review regarding the use of buprenorphine for regional blocks, which had been attributed to a comparatively higher dose of buprenorphine which was administered . Thus, wIn our study, addition of buprenorphine to lidocaine reduced the pain severity postoperatively and extended the postoperative analgesia duration; the study was constrained by not including patients allergic to LA and limited to patients with a narrow range of the difficulty index between bilateral impacted third molars.Administration of local anesthetic solution mixed with buprenorphine for intraoral block-related procedures effectively reduces postoperative pain, with no significant side effects. The current study demonstrated a significant reduction in the mean pain score in the first 48 hours, in patients who were administered lidocaine with buprenorphine. However, there was no significant difference in the number of rescue analgesics consumed between the test and the control interventions. Furthermore, addition of buprenorphine for administration at the local site did not show any significant adverse effect. Hence, we can conclude that administration of local anesthetic solution mixed with buprenorphine has beneficial effects in prolonging postoperative analgesia after mandibular third molar extraction. Similar studies can be carried out to assess its efficacy in various other intraoral minor surgical procedures.


The influence of the stimulation frequency on the outcomes of dorsal root ganglion stimulation (DRG-S) to treat pain is not well understood. It is assumed that specific neural components dedicated to different tasks in the DRG can be preferably influenced at specific frequencies. The identification of frequencies designed for the type of pain and the ratio of neuropathic versus nociceptive pain might improve overall pain control and open new indications in DRG-S.We report on a randomized double-blind clinical trial with a crossover design. Patients with a permanent DRG-S system underwent phases of stimulation with 20 Hz, 40 Hz, 60 Hz, 80 Hz, and sham in a randomized order. Each phase lasted for 4 days and was followed by a 2-day washout period. Pain intensity and quality of life were assessed with visual analog scale (VAS), McGill Pain Questionnaire (MPQ), EQ-5D, and Beck Depression Inventory (BDI). Analgesics intake was assessed.Overall 19 patients were included in the study. CRPS was the most frequent pain etiology (7). Five patients had a PainDetect score of 12 or lower at baseline. The mean VAS before the system was implanted was 8.6 and 3.9 at the baseline. Pain intensity was reduced to 3.7 by the stimulation with 20 Hz but increased with higher frequencies reaching 5.8 at 80 Hz. A significant difference among the groups was shown over all variables examined . The best results were seen at 20 Hz for all variables, including the smallest increase in pain medication consumption.The choice of the stimulation frequency shows a clear influence on pain reduction and quality of life. Lower stimulation frequencies seem to be most effective in neuropathic pain. Further studies are required to determine whether specific frequencies should be preferred based on the condition treated. Dorsal root ganglion (DRG) stimulation has been effectively used in the treatment of neuropathic pain of different etiologies. In neuropathic pain, spontaneous firing as a consequence of lower action potential thresholds can be observed in the DRG neurons . DiffereIt is assumed that specific neural components of the DRG can be influenced in a targeted manner by the selection of different frequencies and that different pain patterns can be optimally treated with different frequencies. Little is known about the effect of stimulation frequency over the clinical outcomes of DRG-S. We report on the first randomized double-blind clinical trial testing mid-frequency DRG-S in patients with neuropathic pain.Patients aged above 18 years old with a DRG stimulation system implanted and followed-up at the Department of Neurosurgery of the Heinrich-Heine-University Düsseldorf were invited to participate in the study. Written informed consent was obtained. Individuals were excluded from the trial in case of further significant pain that might confound the study assessments. Nineteen patients participated in the study. The study was approved by the Ethics Committee of the Medical Faculty under the number 2020–1120 and was registered at the German Clinical Trials Register (DRKS) under DRKS00022557.Patients were evaluated for neuropathic pain with PainDetect (0–38 points) at the baseline. All patients tested five different stimulation parameter settings in a randomized order: stimulation frequencies of 20 Hz, 40 Hz, 60 Hz, 80 Hz, and sham stimulation. Sham means amplitude set at 0.025 mA, the minimum amplitude allowed, so that the IPG indicates to the patient stimulation on, but delivers only ineffective stimulation. Patients were programmed at subthreshold for each tested frequency; amplitude was corrected in each case. Patients and investigators were blinded, and a study nurse had access to unblinded data. Each stimulation parameter setting was tested for 4 days and was followed by a 2-day washout period. The stimulation parameters were programmed in advance by a study nurse and were randomly changed by the patients each week at home. The stimulation amplitude was programmed to subthreshold levels individually for each frequency. At the end of each phase, the patients were interviewed by phone and completed numbered questionnaires.At baseline, VAS and clinical parameters were assessed, and pre DRG-S pain data was collected from charts. During the study, patients underwent assessment of pain intensity and quality using the visual analog scale and McGill Pain Questionnaire , of quality of life using EQ-5D (Index 0–1), and of the prevalence of depression using the Beck Depression Inventory . Any additional intake of analgesics was documented by the patients.Patients’ demographics were analyzed using descriptive statistics and presented as frequency and percentage for categorical variables, and as numbers, means, minima, maxima, and standard deviations (SD) for continuous variables. Statistical analysis was performed using SPSS 19 software  and GraphPad Prism 8.0.2.Repeated measurement one-way ANOVA was used for comparison between baseline data and measurements at the different frequency settings applying Tukey’s multiple comparison test. An alpha error of 0.05 was considered significant, and 0.01 was considered highly significant.A total number of 19 patients participated in the study. The mean age was 53 years (range: 25–80) and the patients were using DRG-S for a mean of 17.2 months (range: 4–102). The most common pain etiology was chronic regional pain syndrome (CRPS) (7 subjects), followed by postsurgical pain after implantation of joint prosthesis (4), postherpetic neuralgia (3), nerve injury after resection of neurinomas (2), traumatic nerve injury (2), and diabetic polyneuropathy (1). Fourteen patients had a PainDetect Score of 12 or higher (76.7%), indicating higher probability of neuropathic pain. Patients reported a mean VAS of 8.6 (SD 1.0) before the implantation of the DRG-S system and a mean baseline VAS of 3.9 (SD 1.9). All patients had already been programmed in the clinical routine and had reached a stable therapeutic response. All patients had a stimulation frequency of 20 Hz at study start.Even at subthreshold level with corrected amplitude, some patients experienced at higher frequencies a change in the paresthesia field. Amplitude was reduced in these cases. No patient had painful paresthesia nor motor stimulation.p = 0.004) and any other tested stimulation parameters (p < 0.001). 40 Hz did not result in significantly better results than 60 Hz (p = 0.086), nor did 60 Hz have lower pain intensities than 80 Hz (p = 0.695) , 4.9 (SD 2.2), 5.8 (SD 1.9), 5.8 (SD 1.9), and 8.6 (SD 1.3) respectively . When analyzing quality of life, EQ-5D indexes were 0.76 (SD 0.16), 0.69 (SD 0.26), 0.59 (SD 0.30), 0.58 (SD 0.30), and 0.24 (SD 0.37). The index for 20 Hz was not significantly higher than for 40 Hz (p = 0.071), but than for 60 Hz and 80 Hz (p = 0.001).The same trend was seen with the McGill Pain Questionnaire, which resulted in 30.8 (SD 15.8), 33.1 (SD 17.3), 35.9 (SD 16.9), 36.3 (SD 14.2), and 46.5 (SD 17.2) points. In this case, statistical significance was only achieved when comparing MPQ results of 20 Hz and 80 Hz (p = 0.19), but under 60 Hz (p = 0.033) and 80 Hz (p = 0.005). Table Beck Depression Inventory resulted for the same groups 9.9 (SD 7.8), 10.8 (SD 7.1), 11.9 (SD 8.9), 13.6 (SD 8.7), and 15.5 SD 10.2) points. Under 20 Hz, BDI was not significantly lower than under 40 Hz ( points. Although only assessed in a very basic fashion (increase in medication yes/no), the lowest number of patients reported an increased need for analgesic medication during 20 Hz stimulation (9 subjects), and 13 patients referred increased analgesics intake during 40 Hz stimulation and 16 subjects under 60 Hz and 80 Hz, whereas all 19 patients reported an increase during sham stimulation.When stratified by PainDetect, a higher overall VAS and a higher mean difference in the VAS between stimulation frequencies were observed in the patients with a score > 12 without reaching statistical significance. The overall observation regarding better pain control with lower frequencies was still observed.Dorsal root ganglion stimulation is an effective form of treatment for chronic, especially neuropathic, pain conditions. The choice of stimulation frequency shows a clear influence on pain reduction and the associated quality of life. Lower stimulation frequencies seem to be most effective in the examined pain etiologies, which is explained by the pathophysiology of pain processing.A possible mechanism of action of DRG-S involves the activation of low-threshold mechanoreceptors, which are Aß-, Aδ-, and C-fiber afferents transmitting fine touch sensation. These fibers play an important role also inhibiting painful stimuli at the level of the dorsal horn . Animal The reason why low- and high-frequency stimulations may work differently is probably the phase locking of low-threshold mechanoreceptors. This occurs when neurons fire at the same frequency as the stimulation and it is only possible at certain stimulation frequencies depending on neurophysiological properties of each fiber. As shown by Arcourt et al. in a study with optogenetically modified rats, low-threshold mechanoreceptors in these animals were subject to phase locking for frequencies up to 20 Hz, after which neurons start asynchronous firing . AssuminThe frequency effect was less evident in patients with a PainDetect score under 12, which indicates a less pronounced neuropathic component in the overall pain. Dichotomizing the group by the PainDetect score did not result in a statistically significant difference but in a trend. This study might simply be underpowered to clearly reveal this difference. These subjects with an important nociceptive pain, which did also benefit from DRG-S in this trial like patients with classic neuropathic pain, seem not to rely exclusively on the endogenous intraspinal opioid inhibitory pathway for pain relief. This interesting finding is yet to be confirmed with further studies and could help extending neuromodulation for the much larger population with nociceptive pain.In our study, we used a 2-day washout period. In most patients, DRG-S elicits fast to immediate response regarding pain control, but some effects of DRG-S go beyond pain control, e.g., autonomic symptoms in CRPS. These commonly take longer to become effective and are therefore likely underestimated in this study. For studies investigating only pain control, the washout period could even be shortened. In studies investigating autonomic effects, the stimulation interval and washout periods should be extended. This is especially important in studies looking into the efficacy of neuromodulation to modulate the function of immune system, e.g., to treat CRPS, osteoarthritis, and similar disorders .This trial is the first to investigate the influence of stimulation frequencies in DRG-S in a double-blind, randomized, prospective setting. We tested frequencies down to 20 Hz—a mid-frequency stimulation. We recognize the potential of even lower stimulation frequencies down to 4 Hz, as shown by Chapman in his important case series .The study results are limited by the fact that all the subjects were using 20 Hz of stimulation frequency for a long time prior to the beginning of the study.The choice of the stimulation frequency shows a clear influence on the pain reduction and the associated well-being and quality of life of the patient. Lower stimulation frequencies seem to be most effective for neuropathic pain. As soon as larger similar studies are available, conclusions will be drawn regarding the functioning of the DRG in different pain etiologies and the pathophysiology of pain processing.


With the improvement of cystic fibrosis (CF) patient survival, the prevalence of long-term complications increased, among them rheumatologic disorders.The aim of this prospective study was to evaluate the prevalence of spinal and joint pain, and their impact on disability, anxiety, depression, and quality of life in CF adult patients.2 and a mean FEV1% of 63%. Twenty-two patients (47%) described rheumatologic pain either spinal  and/or joint pain . Patients with spinal and/or joint pain were shorter (p = 0.023), more frequently colonized with Staphylococcus aureus (p < 0.008), had more frequent ΔF508 homozygous mutations (p = 0.014), and a trend for more impairment of the 6-min walking distance (p = 0.050). The presence of rheumatologic pain tended to be associated with disability according to the Health Assessment Questionnaire (HAQ) and anxiety. Compared with patients with no pain patients with both spinal and joint pain exhibited a more pronounced impact on the St George's Respiratory Questionnaire (SGRQ).Forty-seven patients were analyzed, 72% of men, mean aged 28 years, with a mean body mass index of 22 kg/mRheumatologic pain is frequent in CF adult patients, and may affect daily living, anxiety and quality of life. Systematic assessment of rheumatologic pain should be included in the management of CF patients. Cystic fibrosis (CF) is the most common life-threatening genetic disease in Caucasian populations. Morbidity and mortality depend mainly on chronic respiratory failure and malnutrition. Beside usual clinical and spirometrics parameters and sweat chloride concentrations, emergent tools including biomarkers measured in blood, sputum or bronchoalveolar lavage , rheologWith improving survival, the prevalence of long-term complications increased . In CF aThe definition of CFA is not fully accepted. Clinical manifestations are heterogeneous, usually characterized by recurrent transient episodes of painful mono- or polyarthritis lasting 1 day to several weeks and not classifiable as any of other rheumatic diseases , 14, 15.Pain is a common symptom in CF that impacts the quality of life –18, moodThe aim of our study was to determine the prevalence of rheumatologic pain  in a cohort of CF adult patients. In addition, we evaluated the impact of pain on patient's disability , anxiety and depression , and quality of life by Cystic Fibrosis Questionnaire for teenagers and adults (CFQ 14+), St George's Respiratory Questionnaire (SGRQ) and Medical Outcome Study Short Form 36 health survey (MOS SF-36) usually used in CF studies.ClinicalTrials.gov (NCT02924818) on 5th October 2016. Each patient signed a written informed consent form.This monocentric study was prospectively conducted in the Department of Respiratory Diseases  between November 2016 and December 2019. Patients were included in the RINNOPARI study (Recherche et INNOvation en PAthologie Respiratoire Inflammatoire), an observational cohort of inflammatory chronic lung diseases. The study was approved by the Ethics Committee of Dijon EST I on 31st May 2016 (N°2016-A00242-49) and by the French National Agency for Medicines and Health Products (ANSM) on 25th April 2016. The protocol was registered on CF patients were included if they were at least 18 years of age. Exclusion criteria were previous or planned lung transplantation and patients requiring an urgent visit. Anonymized data including demography, clinical characteristics, pulmonary function tests, and sputum microbiology were collected and registered on an electronic medical record.Pseudomonas aeruginosa and by extension chronic infection by Staphylococcus aureus was defined according to Leeds criteria , and one question assessed joint pain (“Did you have joint pain?”). Patients were classified as either “no pain” (answering “no” to the two questions) or “pain” (answering “yes” to at least one question). Patients with “pain” were classified as “both pain”  or “isolated pain” .Two additional questions assessed arthritis (“Did you have swelling joints? Did you have morning joint stiffness more than 30 minutes?”). Arthralgia associated with swelling joints and/or morning joint stiffness suggested inflammatory joint pain.Patients' functional disability in the past week was assessed by the Health Assessment Questionnaire (HAQ), a validated scale consisting of eight sections: dressing, arising, eating, walking, hygiene, reach, grip and activities. The final score ranged between 0 (no assistance) and 3  , 22.Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HAD) , 24.The quality of life of CF patients was evaluated using dedicated questionnaires: (1) the Cystic Fibrosis Questionnaire for teenagers and adults (CFQ 14+) assessing the quality of life, symptoms, and disease effects. The score ranges from 0 to 100, the highest score corresponding to a better quality of life ; (2) theThe primary endpoint was the prevalence of rheumatologic pain . Secondary endpoints were to evaluate the impact of rheumatologic pain on the patient's functional disability, mental health, and quality of life .p-value <0.05 was considered statistically significant. Results were analyzed with SPSSv27.Data were described as numbers (percentages), mean ± standard deviation. Given the limited number of patients, differences in all variables were assessed using Fisher's exact tests for qualitative variables and Mann–Whitney U-tests for quantitative variables. A correction was applied for multiple comparisons according to the Benjamini Hochberg procedure. A The Cronbach's alpha value for each quality of life scores  was calculated. A value > 0.7 was considered as a high level of consistency.n = 3 for clinical rheumatologic missing data; n = 1 for previous lung transplantation), 47 patients were analyzed.Fifty-one consecutive CF patients were included in the study. Four patients were excluded , tramadol  and non-steroidal anti-inflammatory drugs .Demographic, clinical, bacteriological characteristics, and rheumatologic assessment of patients are detailed in n = 15, 32%) and/or joint pain ; seven patients (15%) reported both spinal and joint pain. Inflammatory joint pain appeared uncommon . Of note, there was no difference in terms of painkillers treatment in patients with pain or no pain (Twenty-two patients described rheumatologic pain (47%), including spinal ( no pain .p = 0.022), had more frequent ΔF508 homozygous mutations , more frequent colonization by Staphylococcus aureus , and had a trend to an impaired 6-min walking distance . The prevalence of rheumatologic symptoms didn't increase with age (data not shown).Patients suffering from spinal and/or joint pain were significantly shorter . HAQ was impaired in patients with both spinal and joint pain when compared with patients with no pain   .p = 0.058) whereas no difference was observed for depression . It included spinal pain (32%), joint pain (30%), with 15% of patients suffering from both spinal and joint pain. Inflammatory joint pain appeared uncommon (6%). For the first time, our study focused on the impact of rheumatologic pain on disability, anxiety and depression, and quality of life.During the past few years, many studies investigated pain in adult CF patients. The prevalence of painful symptoms varies between 89% in the past week , 82–89% Joint pain concerned 30% of our cohort, similar to the previous reviews reporting arthralgia between 20 and 41.4% , 19. In p = 0.023) and more frequently colonized with Staphylococcus aureus . The comparison is difficult with other specific studies concerning musculoskeletal and arthropathy in CF . By contrast, two previous studies didn't find an association between cystic fibrosis transmembrane conductance regulator (CFTR) mutations and CFA . To our knowledge, no previous rheumatologic CF study assessed the 6-min walk distance. Second, our results suggest that patients with both spinal and joint pain had a more important impairment on HAQ scale. Their functional disability is probably more important to those of the young general population . Second, we have not assessed the consequences of rheumatologic pain on asthenia, sleeping disorders, family life and study or work absenteeism. Third, the four questions used to detect rheumatologic pain do not fully cover the characteristics of pain . Lastly, the absence of additional tests for this study carried out in current practice not allowed to identify the origin of pain. A larger study should be conducted to elucidate the potential mechanisms of rheumatologic pain and its therapeutic management.Staphylococcus aureus and had more frequent ΔF508 homozygous mutations. The prevalence of rheumatologic symptoms didn't increase with age. No study had previously specifically assessed the impact of rheumatologic pain on patient's disability, anxiety and depression, and quality of life. The impact of both spinal and joint pain seems to be more important, in particular on disability and on quality of life, in comparison with patients with no pain. However, there is no evidence for more painkillers rescue. Our results highlight that the health care team should carefully assess patients and undertake additional tests in collaboration with rheumatologists to identify the cause of pain and therapeutic management.Our study confirms that rheumatologic pain is frequent concerning near half of cystic fibrosis adult patients. Patients with spinal and/or joint pain were more frequently colonized with The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.ClinicalTrials.gov (NCT02924818) on 5th October 2016. The patients/participants provided their written informed consent to participate in this study.The RINNOPARI (Recherche et INNOvation en PAthologie Respiratoire Inflammatoire) study was approved by the Ethics Committee of Dijon EST I on 31st May 2016 (No. 2016-A00242-49) and by the French National Agency for Medicines and Health Products (ANSM) on 25th April 2016, and declared on AS, CL, BR, GD, J-HS, and SD: substantial contributions to the conception. AS, CL, BR, FL, GD, J-HS, and SD: design of the work. AS, J-MP, BR, MG, SC, PM, JA, JH, J-HS, and SD: acquisition and analysis of the data. J-MP: software. AS, CL, J-MP, BR, MG, SC, PM, JA, JH, FL, GD, J-HS, and SD: drafting the work or substantively revising the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Reims University Hospital and Champagne Ardennes University .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Persistent pain after spinal surgery can be successfully addressed by spinal cord stimulation (SCS). International guidelines strongly recommend that a lead trial be performed before any permanent implantation. Recent clinical data highlight some major limitations of this approach. First, it appears that patient outco mes, with or without lead trial, are similar. In contrast, during trialing, infection rate drops drastically within time and can compromise the therapy. Using composite pain assessment experience and previous research, we hypothesized that machine learning models could be robust screening tools and reliable predictors of long-term SCS efficacy. We developed several algorithms including logistic regression, regularized logistic regression (RLR), naive Bayes classifier, artificial neural networks, random forest and gradient-boosted trees to test this hypothesis and to perform internal and external validations, the objective being to confront model predictions with lead trial results using a 1-year composite outcome from 103 patients. While almost all models have demonstrated superiority on lead trialing, the RLR model appears to represent the best compromise between complexity and interpretability in the prediction of SCS efficacy. These results underscore the need to use AI-based predictive medicine, as a synergistic mathematical approach, aimed at helping implanters to optimize their clinical choices on daily practice. Failed back surgery syndrome (FBSS), now known as persistent spinal pain syndrome type 2 (PSPS-T2), is characterized by persisting back and/or leg pain despite one or several spinal surgical procedures ,2,3,4. PWith a legitimate determination to bring some medico-economic rationale to technological evolution, healthcare systems provide strict rules of SCS implantation since its initial diffusion; following international recommendations, a lead trial must be performed and validated before any permanent device implantation ,17,18,19-First, one can observe a lack of homogeneity among practices, making comparisons and recommendations regarding lead trialing very difficult: a patient can be trialed with a surgical lead (requiring an invasive approach) vs. a percutaneous trial, where one, two or three percutaneous lead(s) are placed in the spinal canal, under local sedation or general anesthesia ,18; the -Lead trial outcomes have been reported using the Visual Analogue Scale (VAS) or Numeric Pain Rating Scale (NPRS). Based on these assessments, guidelines recommend that a refractory PSPS patient can be eligible to permanent implant, if a 30–50% pain decrease is observed during the trial ,16,17,19-Third, it appears that patient selection, final implantation ratio and patient outcomes, with or without lead trial, are similar . Indeed,-Fourth, it has been shown that infection rates during SCS trials increase logarithmically within time, after 14 days of trialing, and can compromise the therapy [However, recent clinical data highlight some major limitations of this approach: To date, we can conclude there is no consensus on the usefulness of the screening trial phase due to the invasiveness of the procedure and potential complications such as lead migration, dural puncture during lead placement and/or infection ,28. AimiUsing our experience of multidimensional composite pain assessment and previous predictive research ,23, we hData from two different prospective comparative studies were used to conduct this work. https://clinicaltrials.gov/ct2/show/NCT01628237 (accessed on 12 March 2021). The primary objective of this study was to compare the efficacy of multicolumn SCS programming to the efficacy of monocolumn SCS programming. As part of the ESTIMET study, all subjects provided informed consent and enrolled in the following ethical committee approval (CPP-Ouest III) [The first study is ESTIMET , which iest III) . The stuhttps://clinicaltrials.gov/ct2/show/NCT02821897 (accessed on 12 March 2021)), which is a monocentric comparative study, including 15 patients implanted with SCS under general vs. awake anesthesia at Poitiers University Hospital (France), with a 1-year follow-up. This study examines the effect of target-controlled intravenous infusion on SCS implantation, lead placement optimization using patient intra-operative feedback and SCS efficacy on back pain coverage. Patients in this study were randomized to either be implanted using general anesthesia during lead implantation or to be implanted using target-controlled intravenous anesthesia with active patient–implanter cooperation during the surgery. Three patients were lost to follow-up. The 12 remaining patients who underwent 12-month follow-up from the AIVOC study were used for external validation. The second study is AIVOC , health-related quality of life (EuroQol with five dimensions and three levels (EQ5D-3L)) , functioTo avoid any bias induced by variable selection based on statistical significance, no primary variable selection was conducted. We used the 14 variables that were the most widely studied in the SCS literature. They included age ,30, sex The statistical analyses were performed using R 3.6.0 software .Categorical variables were described by numbers and percentages, while quantitative variables were described by their means and standard deviations (SD) or by their median and interquartile range (IQR) depending on the skewness of the variable. No missing data imputation was performed.n = 91) were used as a training set, and AIVOC study data (n = 12) were used as an independent testing set to confront model predictions and to compare model performances to the 5- to 10-day trial results. Leave-one-out cross-validation and Monte Carlo cross-validation were used to assess internal validity and performance variability.For this analysis, we developed several algorithms based on logistic regression (LR), regularized logistic regression (RLR), naive Bayes (NB) classifier, artificial neural networks (ANN), support vector machines (SVM), classification and regression trees (CART), random forest (RF) and gradient-boosted trees (GBT) to test our hypothesis. Commonly used model performance metrics ROC curve and area under ROC curve (AUC) were used to evaluate model accuracy. ESTIMET study data  stepwise variable selection procedure was used in order to identify the best LR model based on the Akaike information criterion (AIC). To avoid overfitting, no interaction terms were included in the model.LR: This model was developed using the glmnet package. Regularization is a technique used to shrink or reduce insignificant effects in the logistic regression to zero. This technique enables the model to avoid overfitting because it reduces model variance. As our data contain few variables, we opted for the use of ridge regularization.RLR: This regularized generalized linear model  was devesvm function available in the e1071 R package [SVM: Support vector machine models are known for their classification capability, since SVM algorithms are computationally stable and generalize well, giving a sufficient number of training examples . Besides package . The opte1071 R package.NB: This classifier  was devekeras package [ANN: The neural networks model  was deve package , which irpart function available in the package with the same name [CART: The classification tree model was developed using the ame name . In a CArandomForest function available in the R package with the same name [RF: The random forest  was traiame name .xgboost package [GBT: This gradient-boosting-based model  was deve package .Both RF and GBT are tree-based ensemble models, which are a type of models based on the principle that averaging the predictions of several small models could help to obtain a better model. Each of the two models uses a different ensemble learning technique. RF uses bagging (bootstrap aggregating), which can be described as follows: for each iteration, a decision tree model is created using data from a bootstrap sample drawn from the training set, independently of other iterations. After growing all the trees, each tree casts a unit vote for the outcome (good or non-responder) of a new observation. The final prediction for this observation is the average of predictions obtained from all the trees.GBT, as the name suggests, uses a technique called boosting, whereby weighted combinations of decision trees are constructed into a stronger classifier in an iterative way . The strongest classification tree is weighted to count more substantially in the prediction of outcome. A tree that most accurately classifies examples that were misclassified by the first tree is grown next. This procedure allows the trees that are weak on some examples to be compensated by another tree, which performs better on the same examples.Cross-validation was used to identify optimal hyperparameters of the models and to assess their internal validity. Our cross-validation procedure goes as follows: We divide our training dataset into 10 separate datasets . One subset is kept for model assessment. Nine-fold cross-validation is conducted on the remaining nine subsets to identify the optimal hyperparameters, which are then used to develop the models. The final models are then tested on the 10th subset. This process is conducted for all of the 10 folds. This procedure allows us to reduce evaluation bias associated with identifying optimal hyperparameters and evaluating the models on the same subset.The models and screening trial efficacy (percentage of pain decrease) were evaluated using sensitivity, specificity, accuracy, and area under ROC curve (AUC). The cross-validation means of these evaluation measures and their standard deviations are reported.An independent dataset of the 12 remaining patients from the AIVOC study was used for model assessment and external validation. Similarly, models were evaluated externally using sensitivity, specificity, accuracy, and area under ROC curve (AUC). Descriptive statistics of our training and testing data can be found in The results of this PCA leading to the development of our composite outcome can be found in We developed our models using the eight different binary classification methods described in The results of our models using the external validation set can be found in We also evaluated patients for whom the model predictions deviate heavily from their true outcome. Among patients with a prediction smaller than 20% (the model is very confident in their negative response to SCS), none had a positive outcome, which coincides with their predictions. On the other hand, among patients with a prediction greater than 80% (the model is very confident in their positive response), two patients had a negative outcome. The first patient is a female (aged 70 years) with back and leg pain. Following spinal cord stimulation, the patient observed a significant decrease in leg pain and a moderate decrease in back pain. At 12-month follow-up, the leg pain relief was still significant but her back pain was not (severe pain). The patient kept focusing on her back pain, which altered her patient-reported outcomes. The patient was very satisfied with her stimulation device efficacy, in general. We understood that the residual back pain component was mechanical and implanted her with a subcutaneous lead after the end of the study, as a salvage therapy. She achieved significant back pain relief. The second patient was a 39-year-old female who was implanted with spinal cord stimulation 2 years after pain onset to treat back and leg pain. Similarly to the first case, this patient observed moderate leg pain relief without sufficient back pain relief. The patient was implanted with a subcutaneous lead, as a hybrid therapy, to address her back pain component, after the end of study. She started professional retraining for a new job.The majority of the models discussed and analyzed in this paper are black box models, meaning that it is difficult to extract useful information on how the variables interact with SCS outcomes. However, this interpretability is sometimes disregarded in order to achieve more complexity. In this section, we will show the role of explanatory variables in decision making for the logistic regression model. p-value = 0.002). Depressive patients have a reduced chance of having a good outcome 1 year after the implantation of SCS device. Interestingly, we observed a greater probability of achieving a successful outcome not only in patients with hypoesthesia related to back pain  but also in those with positional back pain symptoms . Patients who achieved a 50% pain decrease after TENS therapy before SCS had a better chance of successful SCS therapy at 1-year follow-up .Based on the logistic regression model results , the basThe goal of this paper was to investigate the comparative performance of machine learning models vs. recommended lead screening trials to predict SCS efficacy. Our results show that machine learning techniques offer the opportunity to predict patient SCS long-term outcomes with higher accuracy than SCS trialing . Compared to previous research works aiming to identify SCS outcome predictors, the originality of this mathematical approach is based on computing these predictors in a multivariate statistical model in order to transpose this predictive model to PSPS-T2 patient real-life conditions . This stApplying invasive therapeutic strategies to vulnerable patients implies empiric choices for the implanting physician. To develop a strong therapeutic alliance, when convinced, the physician also has to convince his patient that the benefits/risk ratio is in favor of applying a new technique. In that sense, a lead screening trial appears very comfortable, not only for the patient but also for the physician, as described with humor by an internationally renowned implanter: “The beauty of SCS is that you try it before you buy it…!”.Conversely, it is now well documented that lead trialing is associated with substantial complications ,26, inclReconsidering back the benefits/risks balance, one should examine the benefits of lead trialing carefully, if risks are considered as substantial. Eldabe et al.’s recent study leads to implanter disappointment, by showing that SCS outcomes remain similar, whether using lead trialing to select patients for permanent implantation or not . MoreoveTherefore, an original mathematical predictive approach could aspire to replace SCS trial procedure with a more objective, noninvasive and accurate strategy based on AI, using machine learning models to reduce the risks of complications associated with invasive surgical procedures by more efficiently selecting the patients who may benefit from spinal cord stimulation. We more accurately predicted the efficacy of SCS than the screening trial . As a starting point, easy to transpose in daily practice, we recommend the use of RLR model, as it achieved a remarkable performance for both internal and external validation. In contrast with NB, RF and GBT showing even greater performance, the RLR model is also easily interpretable (it can be interpreted similarly to a logistic regression model), and variable selection is included in the model estimation procedure, which can simplify the creation of an automated decision tool. Few authors have proposed models predicting SCS efficacy. The most recent and relevant paper was published by Goudman et al. . In theiUsing a different strategy, Thomson et al.  proposedOur logistic regression model shows that patients with higher levels of depressive symptoms are less likely to benefit from SCS, whereas patients with a higher perceived health-related quality of life (EQ-5D) are more likely to achieve a good outcome following SCS. This corroborates our findings from a previous work identifying two distinct patient profiles , for whiTENS efficacy was also significantly associated with SCS efficacy. This has been shown since 2011 in a prospective predictive study published by Mathew et al. Lastly, back pain hypoesthesia and changes in pain depending on patient position are associated with a greater likelihood of a good outcome following SCS. These findings are complex to extrapolate. Back pain hypoesthesia is one main criterion of the DN4 (Douleur Neuropathique en 4 questions) questionnaire , confirm-A double dataset, extracted from prospective comparative studies, comprising a large sample size, to reduce biases typically associated with this type of research and to ensure the maximal potential of generalization of our predictive models.-The multicenter nature of our sample also helps to ensure generalizability and applicability to clinical practice.-The development of a composite outcome, based on objective methods, which might lead to optimize patient satisfaction evaluation and, therefore, more precisely capture patient needs and expectations so as to define what should be considered as a positive outcome. However, two patients presented positive predictions related to significant “negative” results. While these patients had good outcomes for leg pain, back pain still remained unrelieved, altering the results of the global pain assessment. This highlights the relevance of assessing both global pain and individual pain areas in order to avoid misinterpretation of the overall assessment .Apart from the originality of combining several machine learning models to reach our objectives, this study has several strengths, such as: We also observed substantial limitations, which could be addressed by further research.One of the reasons patients might fail a conventional tonic SCS trial is their inability to tolerate SCS-induced paresthesia. Patient potential intolerance to SCS-induced paresthesia was not taken into consideration in these study outcomes. In contrast, it has been shown that there is a high correlation between intolerance to tonic SCS and intolerance to TENS-induced paresthesia . TherefoEven though our data were extracted from several studies, including one multicenter national study with 12 centers, a main limitation would concern the relative homogeneity of practices across countries, such as lead choice, permanent trialing available in France and Europe, lead positioning and lead programming, depending on local cultures, which might not offer global extrapolations. An interesting way to overcome this limitation would be to pool and analyze data from large international registries, applying our machine learning model strategy, in further collaborative works. Although we have shown that our model’s predictive power is superior to the screening trial in this sample of 103 SCS implanted PSPS patients, it will remain necessary to conduct a more robust comparative study to assess the overall superiority of utilizing machine learning models as opposed to screening trial on a larger cohort of patients. The evaluation criteria of such a study should include not only the comparative evaluation of lead screening trial vs. mathematical models, but also medico-economical evaluations, extrapolated from models through healthcare-based medicine and prospectively reported SCS implantation-related adverse events. Machine learning and statistical models appear to show potential interest to put traditional SCS lead trial clinical outcomes into perspective with AI-based predictions of SCS efficacy. The regularized logistic regression, random forest and gradient-boosted trees models have demonstrated the best performance and provided a good model fit to the testing data and a relatively good performance on training data. Almost all the proposed models show a better prediction power than lead trial outcomes for this specific population of PSPS patients. On a general aspect, these results reinforce the need for AI-based predictive medicine, with no other ambition than helping physicians to optimize their clinical choices, based on a synergistic mathematical approach. SCS applications are at an early stage and, by essence, remain limited. This deserves further study, based on high-fidelity composite multi-dimensional pain assessment and data extracted from large cohorts of implanted patients, to take this debate to another level. More specifically, in echo with recent clinical data, this study can be depicted as a seminal mathematical substrate to reconsider SCS lead trial utility.


Cancer involves numerous physical, psychological and emotional changes and has a negative impact on patients. Although there are a wide variety of questionnaires for general use in patients with cancer, very few are available that assess the pain, disability and craniomandibular functionality of patients with head and neck cancer (HNC) in a more specific manner. The purpose of this study is to present the preliminary behavior of the CF-PDI in its reduced version adapted for patients with HNC. A total of 61 patients with HNC were included in a study to preliminarily analyze the internal consistency of the instrument, the convergent validity and the floor and ceiling effects. All the patients completed the informed consent document and a battery of 5 questionnaires: The Numerical Rating Scale (NRS), the Tampa Scale for Kinesiophobia for Temporomandibular Disorders (TSK-TMD), the Pain Catastrophizing Scale (PCS), the Quality of Life Questionnaire in patients with HNC (QLQ-HN) and the reduced version of the Craniofacial Pain and Disability Inventory (CF-PDI-11). Patients also performed 2 physical tests: measurements of the pain threshold on the masseter muscle and on the distal phalanx of the first finger; and the maximum mouth opening in neutral head position.p <0.01). Cronbach's α coefficient showed a very high internal consistency of 0.92. In terms of convergent validity, a statistically significant correlation was found between the CF-PDI-11 and the following variables: NRS, TSK-TMD, PCS, QLQ-HN, the threshold of pain in the distal phalanx of the first finger and the maximum interincisal opening. However, 21.3% of patients obtained the lowest possible score. The strongest correlation was found between the CF-PDI-11 and the QLQ-HN (r = 0.85,  The preliminary version of the CF-PDI-11 shows that it could be a valid and reliable instrument to measure pain, disability and quality of life in patients with HNC. Key words:Questionnaire, psychometric validation, head and neck cancer, pain, disability. Head and neck cancer (HNC) includes multiple functional , physical  and psychosocial  impairments . Many ofThe main risk factors are tobacco use, alcohol consumption and viral infections, such as infection with human papillomavirus and Epstein-Barr virus, which correspond to oropharyngeal and nasopharyngeal cancer, respectively . OropharThe loss of basic function generates disability in the patient and deterioration of their quality of life, limiting their food and drug intake as well as causing lifestyle changes, affecting their interpersonal relationships . Pain isThere is evidence of a significant association between psychological factors and cancer, with fear being a common problem among these patients. Furthermore, a strong association between poor quality of life and disability has been observed with higher levels of fear. Along these lines, an association was found between age, the presence and severity of physical symptoms  and certain psychological symptoms  . In addiCurrently, there is a shortage of questionnaires in Spanish that assess pain, disability, and craniomandibular functionality in patients with HNC in a more specific manner, such as the Craniofacial Pain and Disability Inventory (CF-PDI) . HoweverThe purpose of this study is to present the preliminary behavior of the CF-PDI in its reduced version adapted for patients with HNC.- DesignThe study employed a preliminary validation design of the short version of the Craniofacial Pain and Disability Inventory (CF-PDI-11) for patients with HNC. This design aimed to verify the psychometric characteristics of the questionnaire in an initial sample of 61 patients from the Medical Oncology and Maxillofacial Surgery Department at La Paz University Hospital (LPUH).The study followed the ethical procedures according to the rules of the Declaration of Helsinki and has the acceptance of the LPUH Ethics Committee for Research with Drugs (code: PI-1923). All patients signed the informed consent document before their inclusion.- Sample descriptionThe inclusion criteria were age older than 18 years and being diagnosed with primary HNC by a medical specialist. The exclusion criteria were presenting a traumatic history causing craniofacial pain, chronic craniofacial pain of another etiology, impossibility or difficulty in understanding the questionnaires, pregnancy, patients diagnosed with cancer other than HNC or a diagnosis of neurological diseases, chronic systemic diseases or previous rheumatic diseases.- ProcedureAfter selecting the patients by means of a consecutive sampling, they were provided with all the necessary information and the informed consent was signed. A battery of questionnaires was completed and 2 physical examinations were performed. This battery of questionnaires included a sociodemographic information sheet and 5 evaluation questionnaires: the Numerical Rating Scale (NRS) , the Tam- Description of the instrumentsPain intensity: To measure pain intensity, the NRS was used, which consists of a 10-cm line, with values from 0 to 10: 0 represents "no pain", and 10 "the worst pain imaginable" .Kinesiophobia: The TSK-TMD assesses the fear of relapse of an injury in the craniomandibular area due to movement. Composed of 11 items, it consists of 2 factors: avoidance of activity and harm. It has been shown to have reliable psychometric characteristics .Catastrophism: The PCS in its Spanish version seeks to measure the degree of catastrophizing associated with pain. It consists of 13 items and assesses 3 factors: rumination, magnification and hopelessness. Lower scores indicate less catastrophizing. It has been shown to have accepTable psychometric characteristics .Quality of life: The QLQ-HN is one of the QLQ-Core-30 specific HNC modules used by the European Organization for Research and Treatment of Cancer. It consists of 35 items, with higher scores corresponding to a poorer quality of life. It presents 3 subscales, directed to the functionality, symptoms and global condition of the patient .Development of the reduced version CF-PDI-11: The original CF-PDI consists of 21 items, with 4 multiple-choice responses, evaluating the factors of pain, craniofacial disability and functionality during activities of daily living . The criteria for discarding the items were those questions that could not be answered by patients with HNC or that did not make clinical sense for these patients.Pressure pain thresholds: Pain thresholds were measured in 2 locations: on the masseter muscle of the affected side  and on the first finger . A digital algometer (Wagner FDX 25) with an area of 1 cm2 was used, applying it with a pressure increase of 0.5 Kg/cm2/seg and perpendicularly . Three mMaximum interincisal opening: The maximum oral opening was measured in the neutral position of the head while recording the maximum opening measured from the lower edge of the upper incisors to the upper edge of the lower incisors .- Statistical analysisp<0.05 were considered statistically significant. The confidence interval was estimated at 95%.The statistical analysis was performed using the SPSS statistical program, version 20.0. The Kolmogorov–Smirnov test (over 50 participants) was used to verify the normal distribution of the variables. Descriptive statistics were presented as mean and standard deviation and maximum-minimum range for quantitative variables. The qualitative variables were presented by frequency and percentage. The statistical inference used to check the psychometric properties was performed using the following tests: (a) for reliability, internal consistency of the instrument was analyzed with Cronbach's α and the total correlation of items. Adequate internal consistency was considered when Cronbach's α was ≥0.70; (b) convergent validity between the CF-PDI-11 questionnaire and the TSK-TMD, PCS, QLQ-HN and its 3 subscales was assessed with Pearson’s correlation coefficient. The following correlations were considered: very weak between 0 and 0.3; moderate between 0.31 and 0.59; and strong from 0.60; (c) the ceiling and floor effects were analyzed according to the percentage of patients with the lowest (floor) and highest (ceiling) score in each dimension, considering that they are present if more than 15% of those surveyed achieved this score. Values of - Description of the study sampleThe sample consisted of 61 patients diagnosed with HNC with a mean age ± standard deviation of 60.5 ± 12.5 years. The percentage of men was 67.2% of the sample. Regarding the level of study achieved by our patients, 6.6% had no previous studies, 21.3% primary studies, 34.4% secondary studies, 36.1% university studies and 1.6% data lost.Regarding the treatment received for cancer, 49.2% did not receive any treatment, 19.7% received radiotherapy and 26.2% received radiotherapy plus chemotherapy. Related to employment status, 15% were active, 16.7% unemployed, 46.7% retired and 21.7% on leave due to disability. The descriptive statistics are shown in - Internal consistencyCronbach's α coefficient presented a value of 0.92, showing a very high internal consistency. All the data related to the internal consistency of the questionnaires are presented in - Convergent validityp <0.01). The CF-PDI-11 was also significantly correlated with the pressure pain threshold, the maximum interincisal opening and the NRS, but not between the CF-PDI-11 and the pressure pain threshold in the masseter . All the correlation data are presented in Convergent validity was assessed with Pearson’s correlation coefficient. For this, the CF-PDI-11 was correlated with the TSK-TMD, PCS, QLQ-HN and its 3 subscales. All the data obtained statistically significant correlations with the CF-PDI-11. The strongest correlation was found between the CF-PDI-11 and the QLQ-HN  of the 61 patients obtained the lowest possible score (0 points). The minimum and maximum ranges reported by the patients were 0 and 29 points, respectively.The present study was designed to develop the reduced draft version of the CF-PDI-11 for patients with HNC. Specifically, internal consistency, floor and ceiling effect, as well as convergent validity were evaluated, demonstrating a fast, reliable instrument, without ceiling effect and with good convergent validity. It is an inventory that can be validated internationally, given it does not contain items specifically related to Spanish culture.The study design had a biopsychosocial approach, because patients with HNC can present social and psychological factors caused by the anxiety related to their symptoms, diagnosis and the adverse effects of the treatment. The development of various inventories and questionnaires, such as the Cancer Needs Distress Inventory , in whicVarious questionnaires are available to evaluate oncology patients in general; however, very few are specific for patients with HNC. Furthermore, a large number of the existing questionnaires are not validated in Spanish. Reviewing the available literature, we found certain questionnaires related to quality of life, such as the Functional Assessment of Cancer Therapy, Head and Neck  and the Our sample consisted of a higher percentage of men (67.2%), which coincides with the literature that shows a higher prevalence in males. This higher prevalence could be associated with a greater amount of substance abuse by men, such as alcohol and tobacco, although the HNC caused by this is decreasing due to increasing awareness of the harmful health effects of these substances . On the On the other hand, 49.2% of the patients were not receiving treatment, given their recruitment was performed prior to treatment initiation. We should therefore consider that the literature indicates that both pain and disability often manifest themselves after the completion of treatment in these patients .- AssociationsThe CF-PDI-11 showed important associations with other questionnaires and tests performed, except in the pressure pain threshold on the masseter muscle. The majority of these associations was observed between the CF-PDI-11 and the QLQ-HN in quality of life. It should be considered that beyond the mortality that patients with HNC present, quality of life is by far the most valued variable , which iA strong association with fear has also been observed. This fear is especially present in the young population, in those who are undergoing complex surgery, chemotherapy or radiotherapy treatments and in those who in most cases believe that there will be a recurrence at some point in their life; so much so, that there are even specific questionnaires to assess fear of recurrence .- Clinical implicationsIn patients with HNC, physical and psychosocial conditions of various kinds develop, with pain, disability and dysfunction throughout the evolution of the disease. Unfortunately, there is evidence of insufficient pain management in these patients; thus, the development and use of inventories such as the CF-PDI-11 are necessary to achieve a better approach by measuring and recording the variables involved in this disease.The authors of the present work consider that the CF-PDI-11 could become a valid and reliable instrument in the Spanish-speaking population to measure the variables of pain, disability, functionality and/or quality of life in patients with HNC. In addition, the CF-PDI-11 aims to cover aspects that the patient demands in a fast and efficient way, given the time of its completion is estimated at approximately 1 minute and 30 seconds.- LimitationsFirst, this is a preliminary study; although the development of a study with these characteristics could be promising and of interest, it has some limitations associated with the size of the sample. That is why we were unable to perform a factor analysis of the instrument. For a definitive sample size, at least 100 participants will be necessary for a factor analysis to be performed with sufficient guarantees in accordance with data stability and variability criteria. Furthermore, various authors have suggested that a sample of 10–15 participants per item might be adequate for this type of statistical analysis. In this case, 100 to 110 participants would be necessary.On the other hand, there was no reevaluation to check the reliability of repetition by means of the Intraclass Correlation Coefficient by means of test-retest, given a large portion of the patients were about to begin treatment and their responses might be different after the intervention. We must also emphasize that a considerable number of patients did not want to participate in the study due to their poor general condition due to the disease itself. Also, it should be considered that the sample was made up of patients with a variety of HNCs and therefore they had differing characteristics. Cronbach's α coefficient was quite high in its result, which, although it is still too early to determine, could suggest the possibility of some redundant questions. Furthermore, although the study is preliminary, another limitation could be the appearance of a 21.3% floor effect. In the definitive study, it will be necessary to determine whether any of the questions did not apply to a significant part of the population and whether the selection of the sample was optimal.Future research with a minimum sample of 100 patients would allow a factor analysis and validation of the usefulness CF-PDI-11 in patients with HNC.The preliminary version of CF-PDI-11 shows that it could become a promising, valid and reliable instrument for use in patients with HNC. This preliminary questionnaire has shown a high association with the QLQ-HN of quality of life in patients with HNC. A future study with more than 100 participants is required for its final validation.