Overall, these reductions were of comparable magnitude between treatments. However, the modality most preferred by patients was low frequency (55% or 10 patients). Conclusions: The pain-relieving effects of SCS reached significance and were comparable across all modes of stimulation including sham. Sub-perception stimulation was not superior to supra-perception. SCS was characterised by a high degree of placebo effect. No evidence of carryover effect was observed between subsequent treatments. Contemporary neuromodulation procedures should be tailored to the individual preferences of patients.Background: The introduction of modern sub-perception modalities has improved the efficacy of spinal cord stimulation (SCS) in refractory pain syndromes of the trunk and lower limbs. The objective of this study was to evaluate the effectiveness of low and high frequency SCS among patients with chronic pain. Material and methods: A randomised, semi-double-blind, placebo controlled, four period (4 × 2 weeks) crossover trial was conducted from August 2018 to January 2020. Eighteen patients with SCS due to failed back surgery syndrome and/or complex regional pain syndrome were randomised to four treatment arms without washout periods: (1) low frequency (40-60 Hz), (2) 1 kHz, (3) clustered tonic, and (4) sham SCS . The primary outcome was pain scores measured by visual analogue scale (VAS) preoperatively and during subsequent treatment arms. Results: Pain scores (VAS) reported during the preoperative period was M (SD) = 8.13 (0.99). There was a 50% reduction in pain reported in the low frequency tonic treatment group (M (SD) = 4.18 (1.76)), a 37% reduction in the 1 kHz treatment group (M (SD) = 5.17 (1.4)), a 34% reduction in the clustered tonic settings group (M (SD) = 5.27 (1.33)), and a 34% reduction in the sham stimulation group (M (SD) = 5.42 (1.22)). The reduction in pain from the preoperative period to the treatment period was significant in each treatment group ( Patients with chronic pain who are not effectively treated with standard conservative medical therapy are candidates for neuromodulation therapy. Spinal cord stimulation (SCS) is an important neuromodulation tool for the management of chronic pain conditions, such as failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), peripheral diabetic neuropathy (PDN), and other types of chronic low back and/or lower limb pain syndromes ,2,3,4. TThe information about comparative efficiency of different modes of stimulation is scanty despite several published reports in this area ,15,16,17The objective of this study was to evaluate the effectiveness of currently available types of SCS. We tested three available waveforms: (1) low frequency (LF), (2) 1 kHz, and (3) clustered tonic. We additionally tested sham stimulation to assess the placebo effect. We aimed to examine the effects of various stimulation modes on levels of pain and disability, as well as, assess the amount of analgesic medication required during each mode.This study was conducted according to the rules of the Helsinki Declaration and requirements of the local ethics committee. Permission nr 629/2018 has been given by Bioethics Committee of the Nicolaus Copernicus University in Bydgoszcz. Each patient was informed about the details of the study and provided written informed consent. The trial was registered in the appropriate registry .Key inclusion criteria consisted of (1) patients with FBSS or CRPS with neuropathic and mixed pain in the low-back and/or legs that is refractory to conservative therapy, (2) chronic pain reported for at least 6 months, and (3) 18–80 years of age. Exclusion criteria were (1) active malignancy, (2) addiction to alcohol and/or medication, (3) evidence of an active disruptive psychiatric disorder, (4) local infection at the site of surgical incision, and (5) pregnancy.Twenty-three subjects (11 women) with chronic pain were enrolled in the study. Patients ranged in age from 35 to 74 years see . EighteeTM) electrodes on levels Th7–Th10 for low back and limbs pain. Surgeries were conducted in two stages. The first stage was performed using local anaesthesia with intraoperative testing followed by 2 weeks of trial stimulation. During the trial period, tonic LF stimulation was used to check the coverage of pain area with paraesthesia induced by an external stimulator by adjusting the optimal settings of active electrode’s contacts. After a successful 14-day trial period, participants who achieved at least a 50% reduction in pain were qualified to the second stage of the study, which involved the placement of a permanent internal pulse generator (IPG) implantation under general anaesthesia. Patients received a non-rechargeable IPG (Precision NoviTM) and in one case (patient 11), a rechargeable IPG (MontageTM) that was produced by Boston Scientific Co., Boston, MA, USA. The other group consisted of patients who could not undergo percutaneous implantation. These patients were qualified to receive a one-stage surgery that included the implantation of a surgical paddle electrode (ArtisanTM) with central flavectomy on the thoracic level and simultaneous implantation of a permanent IPG in the subcutaneous pocket. Examined patients underwent percutaneous implantation of either one or two linear lead 8- or 16-contact ; three participants  did not agree to further evaluation; and in one participant, feedback data were deemed irrelevant and unreliable (patient 12).Thus, 18 participants entered the randomisation phase two weeks after last surgery. All 18 participants were evaluated for a minimum of eight weeks in a prospective randomised trial. Participants were asked to rate their pain intensity using a visual analogue scale (VAS) upon trial entry and as a primary outcome measure. Participants also completed the Oswestry Disability Index (ODI) as a secondary outcome measure. Patient 11, who had the rechargeable IPG, was asked to charge it once per week, for half an hour each charge, despite the battery status. Ultimately, a total of 13 subjects who underwent assessment during the trial and 5 additional participants who received permanent implants without the trial period were randomised to one of four treatment arms: (1) LF tonic, (2) 1 kHz, (3) clustered tonic, or (4) sham stimulation.The study was conducted according to the rules of observational, randomised, semi-double-blind, crossover, controlled study in line with recommendations presented in CONSORT 2010 statement . All subStatistical analyses and data manipulation and visualisation was conducted using R 3.6.2 statistical environment . To deteIn Bayesian statistics, the goal is to estimate posterior probability distribution of model parameters by integrating likelihood with prior probability distribution of the values of the parameters. We used default priors implemented in brms, which are weakly informative and do not exert much influence onto parameter estimates . Inferent tests were used on difference scores . Bonferroni correction was applied to p values to control for multiple comparisons. To test changes in self-reported pain from baseline, we first computed average VAS scores separately for each treatment and subject. Pain levels were averaged across treatment day given that no effects of treatment day were observed. We then subtracted these individual means from individual VAS ratings measured during baseline—hereafter ΔVAS. Due to missing data, for some treatment types between participants, mean ΔVAS scores for each treatment were tested against zero using separate t tests.To test the change in average pain from baseline levels, one sample Change in Oswestry scores were tested using the nonparametric Wilcoxon test.To investigate changes in daily pain during the four tested treatments, we analysed average daily pain for each. Average daily pain was computed by averaging the ratings provided in the mornings, afternoons, and evening, separately for each day, treatment, and subject. Using descriptive analyses, no daily trends were evident in the data on the individual subject level . We did ME-Null = 0.55 (2.34), and ΔLOOICFull-Null = 8.04 (3.31), respectively. These results indicate that average pain did not differ significantly between treatments and was relatively stable throughout the entire trial. Parameter estimates for the ME model are presented in We found that neither the ME model nor full model had a better fit to the data than the null model, ΔLOOICWe observed a significant reduction in self-reported pain for each treatment type, and the magnitude of the observed effects were large .The LF mode appeared to result in a slightly greater degree of pain reduction, but this may be driven by two participants who reported unusually low levels of pain (see n = 7); and clustered tonic mode was most effective for 5% (n = 1) of patients.After the four-period randomisation, LF stimulation was most preferred by 10 patients (55%); 1 kHz stimulation was most effective for 38% . These results indicate that the treatments did not significantly differ from each other in terms of total number of medications taken. However, we observed credible differences in total number of pills taken between medications ), opioids were taken by nearly half of participants ) and NSAIDs were taken by approximately two thirds of patients ). Estimated marginal mean number of taken anticonvulsants was M = 5.35, , for NSAIDs it was M = 9.41, , and for opioids M = 5.46, .The ME1 model consisted of the main effect of drug type; the ME2 model consisted of the main effects of drug and treatment types; and the full model consisted of main effects and interactions between drug and treatment types. We found that the ME1 model had the best fit to the data. The ME1 model was also the only model that had better fit than the null model, ΔLOOICp = 0.056. This may be because complete data were available only for eight participants.Finally, we tested for significant changes in Oswestry scores after participants completed the study. Although the median Oswestry score was noticeably higher after the trial, Me (IQR) = 30.5 (10), as compared to before the trial, Me (IQR) = 19 (15), this effect did not reach significance, Z = −1.96, n = 3) of patients: (1) female, age 74 after 17 months; (2) male, age 72 after 10 months; and (3) male, age 65 after 12 months. Electrodes and IPGs were removed due to unsatisfactory pain relief in 13% of patients. In 1 case , the IPG had to be replaced due to depleted battery after 10 months, and in another case , the electrodes had to be replaced after 15 months due to electrode dysfunction (9.5%).In one patient , a delayed allergic reaction with a negative wound culture at the site of the implanted stimulator was observed after 13 months. The unavoidable removal of IPG occurred in 4.7% . Furthermore, the crossover design allowed for each subject to be exposed to each modality, which allowed for individual subjects to serve as their own control. A benefit of the crossover design is an increase in statistical power even in this relatively limited sample size. Moreover, the physician examining each patient was not aware of the type of stimulation used, which mitigated any performance bias. Patients only felt paraesthesia during the tonic LF stimulation condition. Therefore, the present trial can be considered to be semi-blinded. In tonic mode patients were always aware of active stimulation and knew when it was switched off. Unfortunately, it has been demonstrated that the conventional mode of stimulation predominantly covered limb areas with insufficient pain relief in axial regions .The primary goal of the study was to establish the type of stimulation was the most effective for relieving pain, and to establish which type was the most preferred in long-term stimulation. Patients did not report annoying paraesthesia during sub-perception modes. Patients were not aware of the type of stimulation that had been programmed and were not aware of whether the stimulation was on or off because they were informed that they could not perceive any sensations. There were no washout periods between subsequent treatment arms. Thus, each treatment arm ended the same day that the next arm was initiated.The design of this cross-over study could be burdened by carry-over effects, but the analysis revealed that average pain was relatively stable through the entire study periods. A previous trial used a similar double-blind placebo-controlled design and examined preferred frequencies and waveforms . That stIn the present study, average values of pain intensity after each type of stimulation were not shown to be superior to sub-perception stimulation. The observed reduction in pain was modest across all modalities. During the sham arm, devices showed that the IPG was on. It is possible that a small leaking current with maximal amplitude of 0.1 amp could have some therapeutic effect; however, the magnitude of this effect is likely negligible. The outcome can be attributed to the awareness that IPG was active to a greater extent than the real analgesic effect coming from stimulation with maximal amplitude of 0.1 Amp, f = 2 Hz, PW =10 μs. Nevertheless, we observed a strong placebo effect in this study. To exclude the potential influence of carryover effects from the previous treatment arm, average daily trends were assessed. We observed no significant difference in these daily trends. Results of the present study demonstrated a lack of persistent effects of earlier interventions. Probably there was a strong connection between implantation of SCS and improvement in psychological perception of pain presented in high placebo effect.M ± SD = 6.44 ± 2.04. In contrast VAS scores recorded in the present study during the 2-week trial period without stimulation were 5.43 ± 2.01. In the study by Wolter et al., there was no washout period [The reduction of pain after the application of all modes was statistically significant in relation to baseline values. Differences between various waveforms did not reach significance. LF tonic SCS had, however, the most robust analgesic effect of 50%. At the end of the randomised phase, the majority of subjects (55%) chose tonic stimulation as their preferred mode for SCS. Further, we found that LF tonic SCS was associated with the highest level of relative pain relief. Comparable results were reported in another study in which over 70% patients reported relief of low-back and/or limbs pain following tonic stimulation with 3D neural targeting . In a rat period .In our study, we applied clustered tonic stimulation as a “burst stimulation” with 450–550 Hz in a cluster activated with f = 40–60 Hz. The main difference between BurstDR SCS invented by de Ridder and clustered tonic stimulation is that the former was designed to mimic burst neuronal firing. BurstDR also has the ability to activate medial pathways whereas clustered tonic stimulation likely does not . It is pIn contrast to prior studies, we did not find clustered tonic stimulation  to be superior to other forms of stimulation. A prior randomised, placebo-controlled study demonstrated higher effectiveness of burst stimulation in comparison with 500 Hz tonic stimulation at subsensory amplitude and placebo stimulation . AnotherPoor outcomes following clustered tonic and 1 kHz stimulation can be caused by insufficient coverage of the pain area and suboptimal electrode lead placement. In our sample, most patients had percutaneous lead placement with intraoperative trial stimulation to verify the coverage of pain areas. Therefore, we assume that electrodes were placed in an optimal location. In general, we did not observe migration of electrodes nor loss of paraesthesia in the area of pain. However, there was one case where electrode leads required replacement due to dysfunction. Furthermore, Van Buyten et al. observed that generators were explanted in 14% of patients with HF stimulation due to inadequate pain relief . We did The true efficacy of SCS can be described by the number of therapy-related explants due to inadequate pain relief. In a multicentre study, the explant rate after SCS was 7.9% per year. Over half of these explants were due to failed analgesic effects, with 14.2% of those related to HF (10 kHz) rechargeable SCS . UnfortuThe period of assessment stimulation lasted 2 weeks and may not be not long enough to assess longevity and effectiveness of each modality. Longer assessment periods may result in different scores. For example, in the SUNBURST study, the treatment arms lasted 12 weeks ; in the The present study demonstrated that the application of SCS had an impact on pain relief. The pain-relieving effects reached significance and were comparable across all modes of stimulation including sham. Sub-perception stimulation was not superior to supra-perception stimulation. In this study, SCS was characterised by a large placebo effect. The most preferred type of stimulation was the LF tonic modality, given that perceptions may reflect active stimulation. No evidence of carryover effect was observed between subsequent treatments with different frequencies. Contemporary neuromodulation procedures should be tailored to the individual preferences of patients to achieve satisfactory effects. Patients are encouraged to actively participate in selection of the most effective mode of stimulation.


With the benefit of six years of observation, this study supports buprenorphine/naloxone as a safe and efficacious component of comprehensive chronic pain treatment in patients with SUD or high-risk of opioid overuse or misuse.Patients with chronic pain managed with opioid medications are at high risk for opioid overuse or misuse. West Virginia University (WVU) established a High-Risk Pain Clinic to use sublingual buprenorphine/naloxone  plus a multimodal approach to help chronic pain patients with history of Substance Use Disorder (SUD) or aberrant drug-related behavior. The objective of this study was to report overall retention rates and indicators of efficacy in pain control from approximately six years of High-Risk Pain Clinic data. A retrospective chart review was conducted for a total of 78 patients who enrolled in the High-Risk Pain Clinic between 2014 and 2020. Data gathered include psychiatric diagnoses, prescribed medications, pain score, buprenorphine/naloxone dosing, time in clinic, and reason for dismissal. A linear mixed effects model was used to assess the pain score from the Defense and Veterans Pain Rating Scale (DVPRS) and daily bup/nal dose across time. The overall retention of the High-Risk Pain Clinic was 41%. The mean pain score demonstrated a significant downward trend across treatment time ( Originally approved by the U.S. Food and Drug Administration (FDA) for out-patient use in 2002, buprenorphine rose to the forefront of the short list of medications for opioid use disorder (MOUD) with the rise of America’s opioid epidemic . RepeateAs one of the hardest-hit states in the nation, West Virginia began developing a comprehensive approach to the treatment of OUD in the early 2000s, focusing on the use of combination buprenorphine/naloxone  as the medication for OUD. This program has since developed into the Comprehensive Opioid Addiction Treatment (COAT) program that treats over 400 patients with eight prescribers spread over three locations ,10. The Both pain and SUD are complex and challenging clinical conditions. They are often so intertwined that each can make the other more difficult to treat. A relatively high prevalence of comorbidity has been reported in many previous studies. Even if there is no consistent estimate of an iatrogenic substance use problem, “aberrant medication-taking behaviors”  have become a public health concern . Every dThere is no doubt that such patients cannot be appropriately managed with traditional approaches. Integrated treatment models and comprehensive care management have shown promise ,16,17,18As a partial agonist of μ-Opioid receptor (MOR), buprenorphine has different formulations and is used to treat OUD as well as acute and chronic pain . While tThe present study is a retrospective chart review of patients enrolled in the High-Risk Pain Management Clinic of WVU Medicine. The clinic is located in the Pain Management Center of WVU and the patients are managed by a multidisciplinary team comprised of an addiction psychiatrist, a pain psychologist, an addiction counselor, and a case manager. The team works closely with pain specialists and other medical professionals to provide comprehensive pain treatment, including buprenorphine-related products. Because of lower abuse potential, bup/nal film is the first and main option offered to patients unless there is a clear documentation or observed allergic reaction to the combined formulation. The criteria for admission to this clinic include being age 18 and older, chronic pain diagnosis plus SUD, or high-risk opioid use including prescription opioid misuse or overuse, or being identified as high risk by a screening questionnaire such as the Screener and Opioid Assessment for Patients with Pain (SOAPP-R). This clinic employs a multimodal approach to pain management centered on the use of buprenorphine for analgesia and includes group meetings, physical therapy, and analgesic injections as well as management of psychiatric comorbidities. Every patient entering treatment received a thorough psychological evaluation in terms of pain and emotional distress. Besides psychiatric treatment for those indicated, the focus of group therapy for all patients in the clinic includes expectation and realistic goal setting, stress management, promotion of a healthy lifestyle, etc. Different techniques such as mindfulness and progressive muscle relaxation are taught and practiced. Healthy activities, hobbies, employment, and education are promoted to help patients build self-esteem, give life meaning, and fend off idle time and boredom that exacerbate pain. Furthermore, patients must agree to regular pill counting and random urine drug screens that must be positive for buprenorphine and its metabolite and negative for any other illicit substance as well as alcohol. The clinic’s highest level of care is biweekly. Treatment is phase-based depending upon treatment adherence such that patients are seen at less frequent intervals from weekly, biweekly, monthly, and every other month as they progress. Patients with SUD diagnosis and abstinence time less than 90 days were first referred to the COAT program for SUD treatment prior to entering the clinic. The High-Risk Clinic has low tolerance for active drug use. At any treatment time, patients may be transferred to the COAT clinic if the treatment team feels focus on SUD is deemed more appropriate. This is because even if the clinic is considered the highest level of ambulatory care in a pain-based setting, there are not enough therapists or supporting staff to manage an acute substance use problem. There was no rapid toxicology screening (only send-out testing) available at the center by the time of this study. The study was consistent with protection of patient rights per Health Insurance Portability and Accountability Act (HIPAA) and was approved by the West Virginia University institutional review boards.WVU hospitals use an electronic medical record system (EMR) called EPIC for inpatient and ambulatory practice management. We reviewed EPIC charts of all patients who enrolled in the WVU High-Risk Pain Clinic from March 2014 to February 2020. Those who did not remain in the clinic long enough for implementation of standardized pain assessment were excluded.Pain assessments were conducted at each visit. Level of pain was assessed using the Defense and Veterans Pain Rating Scale (DVPRS). The scale combines a 0–10 pain scale with facial expressions and colors to express pain intensity, with 0 for “No Pain” and 10 for “As bad as it could be, nothing else matters”. The scale also adds supplementary questions to determine the effects of pain on a patient’s daily functions like activity, sleep, mood, and stress. The DVPRS is a self-report pain assessment tool validated in the military population . It is aData gathered include demographics, psychiatric diagnoses, prescribed medications, the DVPRS scores , buprenorphine/naloxone dosing, time in clinic, and reason for dismissal. Psychotropic medications comprised prescriptions of Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), antipsychotics, mood stabilizers, and other antidepressants such as mirtazapine and bupropion. Pain medications comprised opioids, muscle relaxers, GABA analogues , tricyclic antidepressants (TCAs), anxiolytics/antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), and topicals such as lidocaine and capsaicin.Descriptive statistics were used for patient characteristics. Information analyzed related to treatment included medications utilized prior to admission, medications prescribed by the clinic, buprenorphine total daily dose and dosing frequency, retention rate, and reason for dismissal. Retention rate was calculated as the mean number of days a patient remained enrolled in the High-Risk Pain Clinic. Assessment of the DVPRS pain scales did not begin with the inception of the clinic. To account for this, pain scores were reported relative to number of visits, with the initial assessment of pain score considered as baseline (visit #1). For buprenorphine prescription, one patient was on buprenorphine patch (Butrans) 5 mcg/h; the rest were exclusively prescribed a sublingual bup/nal combination. As we focused on the sublingual bup/nal effect, to avoid skewing data, we did not include this Butrans patient in our calculations involving pain or buprenorphine dosing.A linear mixed-effects model was used in the longitudinal data analysis on pain score and buprenorphine dose, respectively. This approach can handle fixed and random effect model parameters, as well as nested or unbalanced designs with repeated measures from same subjects. The model included subjects as a random effect and visit number as a fixed effect adjusting for potentially confounding variables such as scores of activity, sleep, mood, and stress.For visualization, the overall pain assessment for each patient at each visit was aggregated and plotted against the number of visits. Buprenorphine dose at each visit was assessed in the same manner. For the association between pain score and buprenorphine dose, the averaged pain score was plotted at the corresponding dose.https://www.r-project.org/). Visualization was through GraphPad Prism v8 . Outliers were excluded only when identified by the robust regression and outlier removal (ROUT) analysis, which is a unique approach to identifying and removing outliers from nonlinear regression in Prism [Statistical calculations were performed using Excel 365  and R software, version 3.6.3 , leaving 78 total patients included in analysis. The mean age was 53.09 ± 14.46 years . Most paFor psychiatric history, diagnosis of Major Depressive Disorder (MDD) or depression was the most common; anxiety and Generalized Anxiety Disorder (GAD) was the second most common. There were 14 different pain diagnoses documented in this population. While chronic back pain was the most common pain diagnosis noted, many patients had more than one type of pain problem.For psychotropic medication use , many paFor pain management, 42.3% were prescribed opioid analgesics other than buprenorphine before entering the High-Risk Pain Clinic. The remaining were either obtaining illicit pain pills, buprenorphine, or heroin at least partially for pain control. We also collected information of non-opioid pain medication before and after starting the clinic . Many pap < 0.001; p < 0.001; p-values, while the negative (positive) sign implied the decreasing (increasing) trend over time. There was no significant association between overall pain score and the dose of buprenorphine prescribed , followed by twice daily (29.4%), four times daily (5.9%), and three times daily (0.47%). Overall pain scores ranged from 0–10 with a mean of 5.7 ± 2.2. Average overall pain score displayed a downward trend in relation to duration in the High-Risk Pain Clinic  were referred to a higher level of care and were therefore dismissed from the High-Risk Pain Clinic because of violation of the treatment agreement, mostly with definitive urine drug screen (UDS) results inconsistent with self-reports or evidences of diversion. Twenty-five (32%) left the clinic for reasons unrelated to substance use. For those dismissed due to relapse or inappropriate UDS, five (23.8%) tested positive for unprescribed opioids, four (19%) tested positive for ethanol, four (19%) for THC, three (14.2%) for cocaine, and two (9.5%) for methamphetamine. In addition, two (9.5%) patients had UDS results lacking the prescribed buprenorphine, one (4.8%) did not show for the random buprenorphine count, and one (4.8%) tampered with the UDS. The overall retention was 41% in the five years, 11 months, and three days studied. Mean time until dismissal for relapse or inappropriate UDS was 192.9 ± 114.6 days. Mean time in clinic for non-dismissed patients was 870.5 ± 774.2 days.Some differences between dismissed and non-dismissed patients are highlighted in We found a downward trend for overall pain score in relation to duration in the High-Risk Clinic, while the average buprenorphine dose showed the opposite trend. The relative high retention rate and long mean time in treatment confirms the feasibility of comprehensive pain and SUD management by multidisciplinary teams. Our study also showed a high percentage of underlying psychiatric illness amongst members of the High-Risk Pain Clinic, particularly depression and anxiety, and as such, a high percentage was prescribed SSRI/SNRI, sleep aids, and anxiolytics. These results are consistent with previous studies demonstrating the increased prevalence of comorbid psychiatric disorders amongst patients with chronic pain ,31,32, uWhile some evidence shows benefit to multiple daily dosing of buprenorphine for pain , the HigWhile the devastating opioid epidemic highlighted an urgent need for greater caution in opioid prescription, many studies have raised questions about the effectiveness of opioids in the management of chronic non-cancer pain. Systematic reviews revealed that in addition to various side effects that lead to poor retention, opioids in the treatment of most types of chronic pain only show modest rates of improved pain control or patient function ,35,36. MBuprenorphine has an FDA indication for pain . StudiesThe WVU High-Risk Clinic makes use of the favorable safety profile of buprenorphine to fill a clinical gap that only increases as more clinicians limit opioid prescriptions. The overall retention rate in our study was 41% and the mean time in clinic for non-dismissed patients was 870.5 days. While opioid drugs constituted 23.8% of all inappropriate UDS dismissals in the present study, ethanol, cocaine, and methamphetamine combined made up 43%, reinforcing the polysubstance nature and the importance of assessment for ethanol and illicit drug use. Furthermore, some differences were noted between patients retained in-clinic and those dismissed. We were surprised to find that 25.6% of patients with a substance use problem were dismissed from the clinic, yet none of them carried the OUD diagnosis. As OUD constituted 28.2% of all patients with substance use history, the increased retention potentially indicates an increased efficacy of the adapted COAT model for that population. Interestingly, we noticed this retention rate was higher than that of the COAT clinic, the buprenorphine MOUD program that this clinic is adapted from. In COAT, a sample analysis showed that 37.8% of patients were retained less than one year and 14.7% were retained 10 or more years ,10. The While the evidence favoring MOUD/replacement therapy to detoxification strategies in OUD is robust ,47, manyAnecdotally, we have seen patients make remarkable recoveries from pain conditions with buprenorphine that do not respond to other treatment modalities. For example, one patient with complex regional pain syndrome showed a complete recovery with only 4 mg of buprenorphine per day in twice-a-day divided doses. The properties of buprenorphine as mu-opiate receptor partial agonist, producing analgesia, and kappa-opiate receptor antagonist, possibly preventing dysphoria, may provide unique relief of pain and distress ,49.This study has four main limitations. First, as with many chart reviews, it was a retrospective study with no control group. Second, even though there were clinical assessments and documentation for most visits, there were not enough data for a good analysis of quality of life and functionality outcomes. Third, we did not have follow-up information for those patients who were dismissed or transferred to a higher level of care such as COAT. These details are very important in any healthcare outcome study especially on a medicine that is commonly used for harm reduction. Finally, the comprehensive and multi-modal nature of the High-Risk Pain Clinic presents a potential confounding factor. Non-pharmacological treatment strategies are employed often in the clinic, though documentation is less rigorous than prescribed medications and therefore difficult to analyze quantitatively. It should also be noted that all patients received continuous addiction psychotherapy and were encouraged to attend 12-step meetings. The treatment agreement included strict rules and options for referral to more comprehensive SUD treatment. All of these may limit the generalizability of the results of the current study.SUD and especially OUD complicate the already difficult management of patients with chronic pain. Treating pain and SUD separately is often unsuccessful. The current study presents an example of integrated care that involves multidisciplinary teams and utilizes a stepwise group-based COAT model. Though primarily used in the treatment of OUD, buprenorphine makes a promising substitute for traditional opioids in patients with concomitant chronic pain and SUD/high-risk opioid use behavior. With the benefit of close to six years of observation, the results of the present study support the role of buprenorphine/naloxone as a safe and effective part of comprehensive pain management in these patients.


These properties make it an effective tool in treating OUD and abuse. However, despite its advantages in treating OUD and abuse, buprenorphine can make it difficult to control acute perioperative pain. We present a case in which the Mayo Clinic Arizona protocol for patients undergoing minimally invasive ambulatory surgery while taking Suboxone® is successfully executed, resulting in adequate postoperative pain control and timely discharge from the postanesthesia recovery unit.In 2016, more than 11 million people reported misuse of opioids in the previous year. In an effort to combat opioid use disorder (OUD), the use of agonist/antagonist is becoming increasingly common, with more than 2.2 million patients reporting use of a buprenorphine containing medication such as Suboxone®. Buprenorphine is a unique opioid which acts as a partial  It binds the receptor with high affinity with only partial agonism of the receptor, which prevents other opioids with full agonist properties from activating it. Each type of opioid receptor has different effects, so selective opioid receptor agonists have the advantage of avoiding some of the untoward effects caused by full opioid agonists  with a 10-year history of chronic pelvic and abdominal pain on daily Suboxone® 2.9 mg  PO, prescribed to help treat her chronic pain, presents for a laparoscopic inguinal hernia repair under general anesthesia. Her medical history is significant for depression for which she takes Prozac. Her chronic abdominal pain began shortly after undergoing a total abdominal hysterectomy approximately 10 years previously. Since the time of the hysterectomy, she had undergone three open left inguinal hernia repairs. Additionally, she had undergone a right inguinal hernia repair, a salpingo-oophorectomy, a laparoscopic cholecystectomy, 6 laparoscopic surgeries for lysis of adhesions, and 2 cesarean sections. She was seen by multiple pain specialists who performed procedures including trigger point injections, nerve blocks, and radio frequency ablations—all of which offered some degree of transient pain relief. Pharmacologic therapies trialed to help manage her pain included ibuprofen, acetaminophen, duloxetine, gabapentin, muscle relaxants, oxycodone, and Suboxone® . While taking the Suboxone®, her pain varied from 4/10 to 6/10 on a numerical rating score. She has a remote, 2.5 pack-year smoking history. The patient's only allergy was to morphine which caused itching and fatigue. Preoperative physical exam was unremarkable aside from diffuse tenderness to palpation of her abdomen with her worst pain in the left lower quadrant. She rated her pain as 4/10 preoperatively.Preoperatively, she received acetaminophen 1 gram PO, celecoxib 200 mg PO, gabapentin 300 mg PO, and dexamethasone 4 mg IV. She was given fentanyl 100 mcg IV and midazolam 2 mg IV in addition to lidocaine 100 mg IV, propofol 200 mg IV, and rocuronium 50 mg IV for induction. Her airway was secured with an endotracheal tube after an uneventful induction. Sevoflurane and dexmedetomidine infusion at a rate of 0.4-0.5 mcg/kg/hr were utilized for maintenance of general anesthesia. Intraoperative analgesics included ketamine 40 mg IV, fentanyl 200 mcg IV, and hydromorphone 0.6 mg IV during the 2-hour case. The surgeon infiltrated the surgical site with local anesthetic  at the conclusion of the procedure. Her intraoperative course was unremarkable, and at the conclusion of the surgery she was extubated and taken to the postanesthesia care unit (PACU) with stable vital signs.The patient arrived in the PACU at approximately 9:25 am and spent 3.5 hours there. During this time, she received fentanyl 100 mcg IV given in four 25 mcg boluses 15 minutes apart, Toradol 30 mg IV, and Tylenol 1 gram PO. All of these analgesics were given during the third hour of her PACU stay. She reported a pain score of 5/10 at the time of discharge which she was comfortable with.Evaluating whether a patient is a reasonable candidate to continue their agonist/antagonist medication perioperatively should be based on both patient specific and surgical factors. Continuing perioperative buprenorphine is a strategy that should be considered for surgeries that are not associated with significant postoperative pain. While it is reasonable to expect adequate analgesia with a multimodal approach, patients should be counseled beforehand not to anticipate a pain-free perioperative experience. Many patients taking agonist/antagonist opioids can benefit from continuing these medications perioperatively but, in particular, those being treated for OUD are at a high risk for relapse if buprenorphine is discontinued , 13.Developing a strategy for perioperative pain control requires a pre-emptive, multimodal approach. Peripheral nerve blocks or neuraxial anesthetic techniques should be utilized whenever possible. Where these techniques are not possible, surgeons should infiltrate the incision with long acting local anesthetic. Higher than normal amounts of opioids will be required due to the antagonistic properties of these oral medications, and anesthesiologists should dose opioids appropriately in these patients. While pure opioid agonists are less effective in the setting of concurrent oral agonist/antagonist medications usage, they can still provide analgesia and should be used.In our experience, it is reasonable and safe for select patients taking combined agonist/antagonist opioids to undergo ambulatory surgery without bridging to short acting pure opioid agonists. Evaluation to determine whether a patient is a candidate for this strategy should include multiple factors. These factors include type of surgery, dose of buprenorphine, reason for agonist/antagonist therapy (OUD treatment vs. chronic pain treatment), and access to postoperative care from pain specialists. Perhaps the most important of these factors is the original reason for treatment: chronic pain vs OUD. Strong consideration should be given to continuing perioperative buprenorphine in patients taking the medication for treatment of OUD due to the high rate of relapse that occurs when changing to a full opioid agonist in this population. Anesthesiologists, surgeons, and addiction medicine specialists should work closely to develop a multimodal approach specific to the patient in order to control acute postsurgical pain and decrease the likelihood of OUD relapse.


Posterior spinal fusion for idiopathic scoliosis is extremely painful, with no superior single analgesic modality. We introduced a methadone-based multimodal analgesia protocol, aiming to decrease the length of hospital stay (LOS), improve pain control, and decrease the need for additional opioids.We analyzed 122 idiopathic scoliosis patients with posterior instrumented spinal fusion. They were matched by age, sex, surgeon, and the number of levels fused before and after the implementation of the new protocol. This analysis included 61 controls  and 61 patients on the new protocol . The primary outcome was LOS. Secondary outcomes included pain scores, total opioid use , time to a first bowel movement, and postdischarge phone calls.P < 0.001). Total inpatient morphine consumption was lower in the protocol group (P < 0.001). Pain scores were higher in the protocol group on the day of surgery, similar on postoperative day (POD) 1, and lower by POD 2 (P = 0.01). The new protocol also reduced the median time to first bowel movement (P < 0.001), and the number of postdischarge pain-related phone calls (P < 0.006).New protocol patients were discharged earlier  compared with control patients (3 days; Methadone-based multimodal analgesia resulted in significantly lower LOS compared with the conventional regimen. It also provided improved pain control, reduced total opioid consumption, and early bowel movement compared with the control group. It can also lead to chronic persistent postsurgical pain  and prolonged opioid use  after PSF.4Posterior spinal fusion (PSF) for adolescent idiopathic scoliosis is often excruciatingly painful procedure.8 Unfortunately, epidural analgesia has a high failure rate and can interfere with postoperative neurologic evaluation. Intrathecal morphine is associated with urinary retention, itching, and, rarely, respiratory depression.Many postoperative analgesic strategies are available for patients undergoing PSF, but no single modality has been superior. Patient-controlled analgesia (PCA) with intravenous (IV) opioids has been standard in many centers, but opioids have undesirable side effects, including respiratory depression. Epidural or intrathecal administration of local anesthetics have opioid-sparing analgesia.9 Methadone is efficacious for complex spine surgery in adults.11 Some studies suggest postoperative respiratory monitoring is prudent due to high incidence (36.8%) of respiratory depression when used with PCA hydromorphone.12 However, there is limited evidence for the effectiveness and safety of perioperative methadone in children. Methadone has been effective for postoperative pain in younger children and those undergoing Nuss procedure for surgical correction of pectus excavatum.14 There is only limited evidence of methadone for PSF is available in children. In a randomized control study of 60 adolescents undergoing PSF, intraoperative methadone decreased intraoperative opioid requirements.15 In a small study of 31 adolescents that received a single relatively larger dose of intraoperative methadone , there was no reduction in postoperative opioid consumption.16 This result could be related to the relatively shorter half-life of methadone in children compared with adults.17 Moreover, a single larger dose of intraoperative methadone in adolescents had a high incidence of respiratory depression after PSF.12 A single dose of intraoperative methadone, as part of a multimodal analgesia regimen, improved pain scores with modest shortening in LOS without significant reduction in opioid consumption on POD 1 and 2.18There is a growing body of literature to support the intraoperative use of methadone—a long-acting opioid.21 Muscle spasm contributes to a significant amount of pain after PSF. Methocarbamol, in particular, has been proven to be safe and effective for acute lower back pain.24 Nonsteroidal anti-inflammatory drugs (NSAIDs) are safe and effective in pediatric orthopedic surgery.27 Acetaminophen is a centrally acting cyclo-oxygenase inhibitor and an effective opioid-sparing analgesic in children.29Multimodal analgesia with opioids, nonopioid analgesics, and muscle relaxants reduce opioid usage, minimize opioid-related side effects, facilitate the transition from IV to oral administration, and permit earlier hospital discharge.We hypothesized that a multimodal analgesia regimen, including multiple and small doses of methadone and nonopioid analgesics and adjuncts, would promote earlier hospital discharge, improve pain scores, and lower opioid consumption in adolescents undergoing PSF.We performed this quality improvement initiative at the Riley Hospital for Children, a tertiary care hospital. Before implementing the new protocol, all PSF patients received intrathecal morphine and postoperative morphine PCA with the median LOS of 3 to 4 days. We implemented the new Acute Pain Service (APS) protocol Table  in SepteWe analyzed outcomes using a retrospective matched cohort design after approval by the institutional review board (with waived informed consent.) We compared the APS intervention cohort with the historical matched controls who received PSF before protocol implementation. All subjects were operated on by the same pediatric spine surgeon.3 A single pediatric spine surgeon performed all procedures. We excluded subjects with neuromuscular scoliosis, congenital QT prolongation, and allergy to any of the protocol drugs  during the intervention period.The baseline period (November 2012 to August 2017) included 102 patients who had PSF; we selected 61 matched patients. The intervention (APS protocol) period (September 2017 to January 2019) included 72 PSF patients; however, only 61 patients received methadone and the full interventions due to drug shortages. We matched patients on age, sex, and the number of vertebral levels fused , remifentanil (0.1–0.5 µg/kg/min), and ketamine (0.25–1 mg/kg/h) to facilitate intraoperative neuromonitoring.Before the protocol was implemented, the patients were given intrathecal morphine by the surgeon at a dose of 5 µg/kg intraoperatively. Postoperatively, they were placed on oral gabapentin (100 mg per dose) 3 times a day. They received a morphine PCA on POD0 and transitioned to oxycodone or hydrocodone on POD1 with IV morphine as needed for breakthrough pain. Patients received ketorolac, acetaminophen, and diazepam as needed. and the authors’ clinical expertise using multiple small doses of methadone and multimodal analgesia in adolescents undergoing major inpatient surgery. Preoperatively, patients received oral acetaminophen . As this multimodal protocol with scheduled ondansetron was new at our institution, we obtained an electrocardiogram (ECG) preoperatively in the orthopedic clinic to screen for baseline QT prolongation.The APS protocol Table  was deve16 We used a small dose of methadone  intraoperatively and repeated every 12 hours until discharge to minimize adverse effects and sustain analgesia.Intraoperatively, the APS group received a small dose of IV methadone . Single intraoperative doses (0.1–0.3 mg/kg) in adolescents have a higher incidence of adverse effects and lack of sustained analgesia.Postoperatively, patients received 3 more doses of methadone  every 12 hours starting on the evening of the day of surgery (POD0). An ECG was obtained on POD1 to verify that there was no significant QT prolongation (> 460 ms). Methocarbamol was given every 8 hours with the first dose given in the post-anesthesia recovery unit. Ketorolac was scheduled for the first 3 days every 6 hours, with the first dose given at 8:00 PM on POD0 (or immediately after surgery if before 2:00 PM). On POD2, we stopped ketorolac and started ibuprofen before discharge. We started oral acetaminophen every 6 hours, starting on POD1. We used IV hydromorphone as needed for breakthrough pain. Patients did not receive PCA opioids. Patients received oral oxycodone on POD 1 around noon when tolerating oral diet. Patients received scheduled ondansetron every 8 hours for the first 48 hours after surgery as well as scheduled naloxegol, a peripherally acting μ-opioid receptor antagonist, to prevent opioid-induced constipation  per day, starting 5 days preoperatively and continuing after surgery. On the morning of POD1, patients received a glycerin suppository and a dose of magnesium hydroxide. Patients who had no bowel movement by the evening of POD1 received an enema. During the intervention period, patients received additional oral Naloxegol.During the baseline and intervention periods, all patients received similar postoperative standardized physical therapy (PT) and rehabilitation measures, including getting out of bed and room with assistance.Hospital discharge criteria for both groups included: (1) able to take oral food, including oral analgesics without nausea/vomiting; (2) pain controlled by oral analgesics; (3) regular bowel movements; (4) ambulation with minimal help and without significant pain; and (5) no surgical complications .The primary outcome was time to hospital discharge (days). Secondary outcomes included opioid consumption  on each postoperative day and in total, pain scores , opioid-related side effects , and postdischarge pain-related phone calls.We used QI Macros for Excel Version 2019.06 to statistically analyze the impact of our intervention on LOS  and total MME . The LOS is displayed in a run chart, and the total MME is displayed in an X-chart. We compared categorical variables using the Chi-square test. We used the Wilcoxon rank-sum test for comparison of medians. We used a mixed model for repeated measures for comparing means of normally distributed variables and adjusted for multiple testing via Sidak correction.31 and stopped its use after the first 3 patients due to significant urinary retention observed in these patients. Other minor changes included switching from IV methadone to oral (and back to IV), and switching to granisetron from ondansetron for a short while due to drug shortages.We included a total of 122 patients—61 patients in the baseline period and 61 in the intervention period (Table P < 0.001).Patients treated with the APS protocol had significantly shorter hospital stays than patients in the baseline period Table . The medP < 0.001, Table P < 0.001). Total opioid consumption was approximately 30% lower for the APS group . In Figure The mean opioid usage (MME) (29.3 vs 9.9 mg) for patients in the intervention period was higher on POD0 compared with the control group . The overall trend showed decreasing pain scores in the APS protocol group and increasing pain scores in the control group over the first 3 days after surgery before discharge.The mean pain scores were higher in the APS group than controls on POD0 . The number of postdischarge pain-related phone calls was significantly less in the APS intervention period compared with the baseline period  od Table . The mea32 This observation is particularly significant in reducing the cost of care in a value-based model and reducing potential risks for hospital-acquired infections following major spinal instrumentation. This shorter hospitalization translates to at least $10,000 health care cost savings per patient in 2020 U.S. dollars.New methadone-based multimodal analgesic protocol significantly enhanced the recovery from PSF for patients with idiopathic scoliosis. Methadone-based multimodal analgesia significantly reduced hospital stays, postoperative pain scores, total opioid consumption, and opioid-associated side effects, including constipation. The median LOS in our study population (2 days) was significantly shorter than the national average for PSF and most of the published studies on multimodal analgesia protocols.In our protocol, we chose lower intraoperative doses of methadone to avoid adverse effects reported with higher doses in adults and children. We also dosed methadone every 12 hours to compensate for rapid clearance in children, sustain the analgesic effects, and decrease the necessity for short-acting opioids. We were able to significantly lower overall opioid use, pain scores, and opioid-related adverse effects while achieving early ambulation and the shortest reported LOS following spine fusions. In all study patients receiving the lower dose of methadone, routine ECGs revealed no significant QT prolongation or arrhythmias requiring intervention. We will discontinue routine ECGs to reduce costs further if methadone does not prolong corrected QT significantly in a larger cohort.33 there is certainly benefit in giving them a more pleasant perioperative experience.During the implementation of the protocol, we also noted other subjective improvements, including earlier mobilization from bed to chair, more productive PT sessions, and a better overall sense of patient comfort and well-being without grogginess. Given the heavy pain burden these surgeries impose on adolescents even years later,34 but it is frequently difficult to implement—even in the setting of large pediatric hospitals.35 The constant presence of the pain service has reassured patients and their families, improved inpatient acute pain management, and pain management after discharge due to the education on the discharge medication calendar.It is important to note that this was also a multidisciplinary effort between the orthopedic and the anesthesia acute pain service. A dedicated pediatric acute pain service is highly valuable,Our experience with the methadone-based standardized multimodal analgesia protocol for idiopathic scoliosis surgery led us to implement similar protocols in children undergoing other painful procedures such as pectus excavatum repair, with similar benefits. Our patients have fared so well on the methadone-based multimodal analgesia protocol that we have discussed a goal of routine POD1 discharge following major spine fusions in adolescents with idiopathic scoliosis. Several patients in the methadone-based protocol group, about 25%, were discharged home the day after spinal fusion surgery (POD1). Achieving POD1 discharge for the average patient would drastically change the landscape of adolescent scoliosis surgery, leading to substantial cost savings, about $10,000 per patient.Methadone itself is less expensive compared with the opioid PCA. Acquisition cost of PCA hydromorphone syringe (75 mcg/mL × 30 mL syringe) is $18, while methadone 5 mg is $1.58 (>10-fold cheaper). Typical pharmacy charges are about 10-fold higher than the acquisition costs. Some institutions add a charge for the use of the PCA pump ($200–500 per patient). Our research will enable institutions to provide cost-effective and safe pediatric-enhanced surgical recovery protocols for value-based care under bundled payments.36 This result is significant as we face a national opioid epidemic.The new protocol also reduced opioid use and lowered postoperative pain scores. We are following PSF patients for chronic persistent pain and long-term opioid use. Effective management of acute postoperative pain and use of ketamine and methadone perioperatively had decreased incidence of persistent surgical pain to about 5% in the last 2 years. This finding is substantially less than the 36% incidence reported in adolescents receiving nonmethadone-based multimodal acute postoperative pain management.31 pregabalin had been part of the protocol initially. However, we experienced significant postoperative urinary retention in 3 patients with pregabalin, which resolved once we stopped it.There are a few limitations to our study. It was a retrospective chart review with limited data on subjective measures such as patient satisfaction and physical mobility. However, the feedback from physical therapists and inpatient nursing staff has been consistently positive in terms of patients’ comfort, cooperation, and early ambulation without drowsiness (frequently observed with the previous pain regimen). Another limitation is that the APS analgesic protocol had minor changes during implementation due to drug shortages . The oral bioavailability of methadone is 86%, and it is considered interchangeable with IV methadone. One of the more noteworthy modifications was removing pregabalin from the protocol—almost immediately after its implementation. Due to the evidence supporting the use of neuromodulators in the setting of postoperative pain for spine surgery,Although we matched for known variables , there is potential for sampling bias secondary to our effort to match cases individually. Due to the study design, temporal changes may have occurred over time. We made efforts to generalize all other aspects of patient management . Before the protocol implementation, we examined discharge data to screen for random fluctuation and eventual regression to mean after implementation. Large prospective multicenter trials are needed to validate our findings externally.In conclusion, a new multimodal analgesic protocol following posterior spinal fusion surgery led to significantly reduced LOS, improved inpatient postoperative pain control, lower total opioid consumption, and opioid-related adverse effects following posterior spine fusion in adolescents with idiopathic scoliosis. Implementing this methadone-based multimodal analgesia protocol in other institutions may allow for enhanced recovery in children following this extremely painful surgery while lowering hospitalization costs and reducing opioid use. The protocol may lower the potential for opioid-associated adverse effects, including persistent opioid use and possibly reduce the incidence of persistent surgical pain. To replicate and externally validate this protocol in other centers, we need a large multicenter study in PSF for more complicated neuromuscular spines. We are currently evaluating the protocol for adolescents undergoing Nuss bar repairs for pectus excavatum, in addition to a continuous thoracic epidural analgesia.The authors have no financial interest to declare in relation to the content of this article.We presented this work at the 2019 annual Pediatric Orthopaedic Society of North America (POSNA) and the 2020 annual meeting of the Society for Pediatric Anesthesia (SPA).http://www.ismpp.org/gpp3). The Department of Anesthesia resources funded this study at Indiana University School of Medicine, Indianapolis. The Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Numbers, R01HD089458 (PI: S.S.), R21HD094311(PI: S.S.), and R01HD096800 (PI: S.S.) supported Dr. Sadhasivam’s effort. The content is solely the authors’ responsibility and does not necessarily represent the official views of the National Institutes of Health. The departments of Anesthesia and Clinical Pharmacology at Indiana University School of Medicine (IUSM) provided salary support for the authors.The authors acknowledge Janelle S. Renschler, DVM, PhD , for assistance with medical writing and editing, which was funded by Indiana University following Good Publication Practice (GPP3) guidelines (


Periarticular infiltration (PAI) and adductor canal block (ACB) have become popular modes of pain management after total knee arthroplasty. The purpose of our study is to evaluate the efficacy of ACB in comparison with PAI for pain control in patients undergoing primary total knee arthroplasty.This study is a prospective, 2-arm, parallel-group, open-label randomized controlled trial that is conducted at a single university hospital in China. A total of 120 patients who meet inclusion criteria are randomized in a ratio of 1:1 to either ACB or PAI group. The primary outcome is visual analog scale score at rest 24 hours after surgery, whereas the secondary outcomes include visual analog scale score at 48 hours after surgery, satisfaction, opioid consumption, and complications. All pain scores are assessed by an independent observer who is blinded to the allocation of groups.This study has limited inclusion and exclusion criteria and a well-controlled intervention. This clinical trial is expected to provide evidence of better therapy for the pain management after total knee arthroplasty.This study protocol was registered in Research Registry (researchregistry5410). The widespread use of regional anesthesia in total knee arthroplasty has played a major positive role in these improvements. Femoral nerve blocks have been shown to reduce opioid consumption and decrease postoperative pain scores. In recent years, adductor canal block (ACB), at the midpart of the thigh, has gained favor over femoral nerve block, at the groin, with the benefit of maintaining a sensory block for pain control while minimizing motor blockade to the quadriceps/extensor mechanism. Greater motor block is typically seen with proximal femoral nerve blocks, which can hamper rehabilitation and increase the risk of falls. In addition to regional blocks, which are typically performed in the preoperative setting, some surgeons favor intraoperative periarticular infiltration (PAI), typically with bupivacaine, either in conjunction with an ACB or independently.–9 In theory, PAI has the advantage of a sensory nerve block that is comparable with an ACB without the risks of quadriceps weakness, falls, and neurologic dysfunction.–7,10Over 600,000 total knee arthroplasties are performed each year in the United States. In addition, advocates of regional blocks contend that ACBs have better consistency and predictability.Utilization of these pain management tools in total knee arthroplasty is not consistent across the country. Surgeons who prefer PAI therapy over an ACB cite potential delays of surgery due to the administration of the ACB in the preoperative area, increased costs due to the ACB, and the small risks associated with a regional block. Alternatively, high-dose PAIs can convey risks of systemic and cardiovascular complications.The purpose of this randomized controlled trial is to compare the efficacy of ACB and PAI for pain management in patients undergoing a total knee arthroplasty. We hypothesized that standard PAI would be as effective as ACB for postoperative pain management following total knee arthroplasty.22.1This study is a prospective, 2-arm, parallel-group, open-label randomized controlled trial that is conducted at a single university hospital in China. The study is conducted at a single university hospital in China from March 1, 2020 till June 30, 2021. The study was approved by the institutional review board (CRD42019146454), and all patients provide written informed consent. Postoperative pain at rest after surgery is the focus of the study. This systematic review protocol has been subsequently registered in Research Registry (researchregistry5410). The flowchart of this trial is shown in Figure 2.2Eligible patients are scheduled for primary unilateral TKA, older than 18 years, and have the ability to cooperate with data acquisition. During the study period, all TKAs are performed as an in- hospital procedures. The exclusion criteria are the following: patients unwilling to participate, poorly controlled diabetes, history of inflammatory arthritis, nonambulatory/bed ridden patients, known allergy to the anesthetic drugs, history of bleeding disorder, history of arrhythmia or seizures, sepsis, and pre-existing lower extremity neurological abnormality. Participants are informed that the study is comparing the efficacy of ACB and PAI for pain control following primary unilateral TKA and that they are randomly assigned to either the ACB and PAI group.2.3An independent operator not otherwise involved in the trial generate randomized numbers from 0 to 99 using computer software . Each time a patient is included in the trial, the generated randomized number is assigned accordingly. The patients assigned an even number are allocated to the ACB group and those with an odd number are allocated to the PAI group.2.4For group A (ACB), an ultrasound transducer is used to identify the adductor canal. The transducer locate the adductor canal at mid-thigh, halfway between the inguinal crease and patella. Superficial femoral artery, sartorius muscle, adductor longus muscle, and adductor magnus muscle are identified. The hyper echoic structure located anterolateral to the artery  is identified as the target injection site. A 22-guage, 100-mm needle is introduced lateral to medial under ultrasound guidance using linear probe of a sonosite machine. Solution containing 30 mL of 0.5% ropivacaine and 100 mcg of clonidine  is injected after ensuring correct placement of the needle.For group B (PAI), the solution contained local anesthetic agent (ropivacaine), NSAID (ketorolac), epinephrine , clonidine, and normal saline according to the weight of the patient and is injected using a 20-gauge spinal needle with 20 cc syringe. The PAI is given in 8 zones around the knee as shown in Table 2.5Intravenous patient-controlled analgesia (PCA) fentanyl citrate is used for patients complaining of intolerable postoperative pain. Intravenous PCA fentanyl is started when patients request to use it and continue at 20 m g/h. For additional rescue, intravenous PCA fentanyl is used . The PCA is discontinued 24 hours after surgery, whereas the PCA pump device record the total volume of fentanyl consumed. During the study period, intravenous PCA is routinely used as rescue analgesia for inpatient surgeries. From the day after surgery, an oral COX-2-selective nonsteroidal anti-inflammatory drug (200 mg of celecoxib) is administered 2 times a day until 14 days after surgery. No oral narcotic pain medications are used during the study period. Antibiotic prophylaxis with 1.5 g of sulbactam/ampicillin is intravenously administered 30 minutes before surgery and every 8 hours after surgery for 2 days.2.6The primary outcome is pain at rest 24 hours after surgery. Pain intensity is rated using a 100-mm horizontal VAS, for which 0 mm represent no pain and 100 mm represent extreme pain and compare between groups. The postoperative pain levels at rest other than at 24 hours after surgery are compared between groups. The postoperative VAS scores for patient satisfaction with pain management are compared between the groups until 3 days after surgery. Satisfaction levels are rated using a 100 mm horizontal VAS, for which 0 mm represent completely dissatisfied and 100 mm represent completely satisfied. The total amount of fentanyl consumption in postoperative intravenous PCA is evaluated by the PCA record. Any postoperative complications that occurred during the course of the trial are recorded. All pain scores are assessed by an independent observer who is blinded to the allocation of groups.2.7We estimate that with 50 participants in each group, the study will have more than 80% power to detect a clinically important difference between the groups in regard to the change in the pain score evaluated with the VAS. This is assuming a mean intergroup difference in score of 20 mm based on previous literature and a pooled standard deviation of 35 mm on the basis of preliminary data at an alpha level of 5%. Based on this estimation, a total of 120 patients are needed with an allowance for 10% drop-out.2.8t test. For missing primary outcome data, VAS scores are replaced with the median scores for the other patients of the same treatment group at the same point in time. The comparisons between the study groups are performed with a chi-square test for categorical variables and a Student t test for continuous variables. All tests are 2-sided, and P < .05 is considered statistically significant.The primary outcome of this study is compared between groups with a Student 3–14 Various methods of pain control used in the previous years include epidural analgesia, femoral nerve block, PAI, and systemic analgesia. Perioperative pain management with PAI is a safe and effective method of controlling pain after total knee arthroplasty and it also eliminates the risk associated with FNB of quadriceps weakness. Effective use of PAI requires specific knowledge of the relevant neuroanatomy of the knee. PAI contains cocktail of local anesthetics, non steroidal anti inflammatory drugs, epinephrine , and normal salinewhich isinjected intothe periarticular tissues around the knee joint during the operation. It has gained popularity for its simplicity, safety, and selective sensory blockade unlike the motor blockade associated with femoral nerve block and epidural analgesia.,15Patients undergoing total knee arthroplasty suffer from moderate to severe pain postoperatively. Although there have been advances in technologies and instrumentations in total knee arthroplasty, pain management after the operation is still evolving.,16 The ACB is a sensory nerve block with some effect on the motor function of vastus medialis as the motor branch passes through the adductor canal. Isolated and partial effect on motor weakness of vastus medialis decreases the tendency of fall while walking. Use of ACB needs ultrasound and does not provide pain relief at the posterior aspect of the knee.,17 Whether PAI offers better pain control than ACB after total knee arthroplasty remains controversial. Therefore, this study is conducted to resolve this issue.In the recent years, ultrasound-guided ACB has gained popularity over femoral nerve block for management of pain in total knee arthroplasty patients. The adductor canal  is located within the middle third of the anterior-medial thigh and extends from the apex of the femoral triangle to the adductor hiatus. The contents of the adductor canal have traditionally been described as the femoral artery and vein, 2 fascicular branches of the femoral nerve, the saphenous nerve and the nerve to the vastus medialis, and the articular contribution of the obturator nerve, which enters the distal adductor canal just proximal to the adductor hiatus.This trial has some limitations. First, the subjects may be exclusively Chinese. Therefore, the data from this clinical trial cannot be applied to other ethnic groups. Second, owing to the small sample size, the results of this study cannot be generalized. Despite these limitations, this trial is expected to provide evidence of better therapy for the pain management after total knee arthroplasty.Jun Shi and Na Yuan planned the study design and wrote the study protocol. Chunyan Lin and Jiang Li reviewed the study protocol. Na Yuan, Jun Shi, and Chunyan Lin will recruit participants and collect data. Jun Shi and Na Yuan wrote the manuscript. All of the authors have read, commented on, and contributed to the submitted manuscript.Jun Shi orcid: 0000-0002-5768-5560.


Adenotonsillectomy is the main treatment for symptomatic tonsillar hypertrophy with postoperative pain as the most common associated complication. The present study aimed to compare the efficacy of gabapentin with that reported for acetaminophen on the postoperative pain of adenotonsillectomy in children.In this double-blind clinical trial, a total of 60 children within the age range of 7-15 years undergoing adenotonsillectomy were randomly allocated to two groups of gabapentin (n=30) and acetaminophen (n=30). The first group received a 10 mg/kg dose of gabapentin suspension preoperatively and placebo (suppository) after the intubation. The second group received a 40 mg/kg dose of acetaminophen suppository and placebo suspension simultaneous with that in the case group. Using the pain scale . A p-value less than 0.05 was considered statistically significant.There was no significant difference between the two groups considering the pain scores at 0, 2, 4, 6, 12, and 24 h after the surgery. In addition, the trend of pain intensity statistically decreased within 0 to 24 h in both acetaminophen (P<0.001) and gabapentin (P<0.001) groups. No statistically significant difference was observed between the two groups regarding the postoperative incidence of nausea and vomiting. The obtained results of the present study showed that the administration of gabapentin and acetaminophen significantly reduced the postoperative pain of tonsillectomy and need for narcotics in these patients after the surgery. However, in this study, there was no particular reported superiority for any of the two groups in terms of the effects of gabapentin suspension and rectal acetaminophen. Adenotonsillectomy is one of the most common surgeries performed among children. Tonsillectomy is reported with several complications, such as nausea, vomiting, bleeding, and postoperative pain, with the latter as the most common complication .Generally, the potential complications of tonsillectomy cause difficulty in postoperative management . Pain isIn addition, it is even reported that dehydration or uncontrolled pain is the most common cause of the referral of children to emergency departments after adenotonsillectomy, rather than postoperative bleeding . AccordiAdenotonsillectomy-related pain has been reported in 20-50% of children who underwent surgery . PostopeParticipantsThis double-blinded randomized controlled clinical trial was carried out on a total of 60 children within the age range of 7-15 years with the American Society of Anesthesiologists Physical Status I or II. The subjects were all candidates for elective adenotonsillectomy or adenoidectomy (as the inclusion criterion) admitted to Amir-Al-Momenin Hospital of Guilan University of Medical Sciences, Guilan, Iran, within February 2016 to September 2017. Furthermore, this study was approved by the Ethical Committee of Guilan University of Medical Sciences (code: IR.GUMS. REC. 1395.157). The clinical trial registration code was obtained from the center of registration of clinical trials (2016102115963N7IRCT). After explaining the study objectives and obtaining the informed consent, the patients were entered into the study. The subjects were operated under general anesthesia by a surgeon using the same procedure. The exclusion criteria were a body weight of less than 15 kg at the baseline, allergy to acetaminophen, sensitivity to gabapentin, history of seizure, previous administration of gabapentin, inability to understand the pain score of visual analog scale (VAS) (in the opinion of the study staff), renal or hepatic disease, immunosuppression, history of gastric ulceration, indigestion, dehydration through diarrhea and/or vomiting, history of severe asthma , consumption of analgesics during the last 24 h, alcohol or drug abuse, known glucose-6-phosphate dehydrogenase deficiency, diarrhea, bleeding disorders, and surgical duration of above 90 min. InterventionsThe children were divided into two groups of A (gabapentin suspension) and B (acetaminophen suppository) based on quadruple random blocks. At the initiation of the study, the sequences of the blocks were selected by simple random sampling, sealed in the envelopes, and stored at Anesthesiology Research Center. The subjects were assigned into two groups based on the gradual referral of the patients who met the inclusion criteria.The children, anesthesiologist, and ear, nose, throat surgeon were blinded to the study groups. The anesthesiologist performing the study was unaware of the constituents of the drugs and allocation of the groups. An anesthetist who was responsible for the questionnaires with different parameters was also unaware of group assignment; accordingly, blinding was satisfactorily maintained throughout the study course. In the gabapentin group, the children received a 10 mg/kg dose of gabapentin suspension 2 h before anesthesia, and the placebo (suppository) was used exactly similar in shape, size, and appearance to acetaminophen suppository after the intubation and maintenance of anesthesia. Each suppository was individually wrapped with identical foil. The standard anesthesia method was performed in the control group, similar to the gabapentin group. The children received the placebo gabapentin suspension simultaneous with that in the case group. The amount, appearance, smell, and taste of gabapentin and placebo suspension were identical. Following the intubation and maintenance of anesthesia, a 40 mg/kg dose of acetaminophen suppository was administered to the patients. Perioperative fluid therapy in both groups consisted of dextrose saline (3-5 ml/kg body weight), the anesthesia method was similarly conducted in both groups. All the patients underwent the anesthetic induction after monitoring and preoxygenation with a 2 mic/kg dose of fentanyl, 2-2.5 mg/kg dose of propofol, 0.5 mg/kg dose of atracurium, and 0.02 mg/kg dose of atropine. The tracheal intubation at an appropriate size was carried out using a dose (50-150 µg/kg) of total IV anesthesia propofol and 0.1-0.3 µg/kg dose of remifentanil based on the weight and height of the subject and maintenance of anesthesia. In the postoperative period, the patients’ vital signs and respiratory symptoms were monitored, and hypotension was treated with ephedrine. Furthermore, in case of respiratory depression, the subjects were treated with masks, oxygen therapy, and positive pressure ventilation. AssessmentsDemographic characteristics, weight, duration of surgery, and amount of bleeding in children were recorded and evaluated immediately after the surgery (while being sufficiently aware to respond) in the postanesthesia care unit. Moreover, the data were assessed after 2, 4, 6, 12, and 24 h stay in the ward for nausea, vomiting, prescribed drugs, dose of drugs, and pain severity. Pain severity was recorded based on the VAS   at 0, 2,Statistical MethodsThe demographic data were presented as the median and range. In addition, the data were presented as means and standard deviations. For the statistical analysis of the quantitative data, the independent t-test and Mann-Whitney U test were used in terms of the normal and nonnormal distribution of data, respectively. Furthermore, for the evaluation of the qualitative data  in the two groups, the Chi-square and Fisher’s exact tests were utilized in case of the normal and nonnormal data, respectively. A p-value less than 0.05 was considered statistically significant. All the statistical procedures were performed in SPSS software (version 22.0).The present study was performed on a total of 60 children undergoing adenotonsillectomy or adenoidectomy to compare the effectiveness of gabapentin suspension and acetaminophen suppository in postoperative pain. The mean values of participants’ age were reported as 8.37±2.01 and 10.40±2.84 years in the acetaminophen and gabapentin groups, respectively, with a significant difference (P=0.002). There was a significant difference in the weight of children between the two groups (P=0.006). However, no significant difference was observed in the amount of bleeding and duration of surgery between the two groups  . The trend of pain intensity statistically decreased within 0 to 24 h in both acetaminophen (P<0.001) and gabapentin (P<0.001) groups. There was no significant difference between the two groups in terms of the pain scores at the measurement times (P=0.283). In addition, no significant difference was observed in the pain scores between the two groups according to the measurement times. Moreover, the trend of pain variations was not significant during the measurement times P=0.453; . The trends of nausea and vomiting variations were not significant at the measurement times of 0 to 24 h in the acetaminophen (P=0.098) and gabapentin (P=0.675) groups. The two groups had no significant difference regarding nausea and vomiting at measurement intervals (P=0.897). According to the measurement times, no significant difference was observed in the levels of nausea and vomiting between the two groups. Furthermore, the trends of nausea and vomiting variations were not significant in both studied groups during the measurement intervals P=0.582; . th hour following the surgery (13.3% and 10%).In the current study, the highest level of morphine administration was reported in the gabapentin group at the time of 0 after the operation (66.7% and 63.3%). In addition, the highest level of ondansetron administration was also reported in the 6The general linear model was used for the comparative evaluation of the use of acetaminophen suppository and gabapentin suspension and levels of nausea and pain by controlling age, weight, duration of surgery, as well as the use of analgesic and antinausea drugs. There was no significant difference regarding the effects of the two drugs  on the severity of pain with the control of confounding variables  (P=0.731). There was only a significant difference regarding the use of analgesics (P<0.001) and interaction between the treatment group receiving analgesic (P=0.026) and antinausea drugs (P=0.04). In other words, the effect of analgesic and antinausea drugs was different in both groups. The effects of studied drugs  on nausea was not statistically significant with the control of confounding variables (P=0.115).Only the use of antinausea drugs (P<0.001), duration of surgery (P=0.005), and weight (P=0.05) had significant effects on nausea. The interaction of the type of drugs and use of analgesic (P=0.420) and antinausea drugs (P=0.113) was not significant on the level of nausea based on the generalized estimating equation. Pain and problematic swallowing following tonsillectomy are among the worst conditions for management in otolaryngology . Pain maIn another study conducted by Mogadam et al. , it was In the present study, only the effects of the two drugs were compared 24 h after the surgery; nevertheless, in a study carried out by Mikkelsen et al. , the effIn the above-mentioned study, the patients in both groups received a 50 mg dose of rofecoxib before and after the surgery (during 5 days of follow-up). This was an NSAID that can affect postoperative pain, and no difference between the two groups in terms of pain might be due to the use of this drug in two groups. Similarly, in a study performed by Mogadam et al. , the admIn the above-mentioned study, in the gabapentin group, the required mean dose of meperidine was about 15 mg, and the onset of oral intake was approximately 2 h earlier. In the above-mentioned study, blinding to treatment allocation was not been reported which could lead to bias, and it is unclear whether patients complained about receiving postoperative meperidine spontaneously or due to pain. This is important because gabapentin might reduce the demand for analgesics by increasing its postoperative sedation effect, not due to its pain reduction effect. Given that the sedation was not evaluated in the above-mentioned study, its role was not clear in the patients’ demand for analgesics. In another study conducted by Jeon et al. , the patIt has been shown in various studies that the drugs, such as gabapentin and pregabalin, not only decrease the severity of acute pain and required doses of opioids but also can play a role in the prohibition of the chronic postoperative pain. In a systematic review carried out by Hwang et al., it was demonstrated that the use of gabapentin before surgery can reduce the administered dose of opioids and associated complications . Gabapentin might also play a role in the prevention and development of chronic postoperative pains and reduction of perioperative anxiety . It seemIn the present study, the incidence of nausea and vomiting during postoperative periods (0 to 24 h) was reported with various fluctuations between the measurement times in both groups. The highest level of PONV was in the gabapentin and acetaminophen groups 12 and 4-6 h after the consumption, respectively. However, these differences were not significant in both groups at time intervals. Moreover, no significant difference was observed in the levels of nausea and vomiting between the two groups based on the time of measurement. The trend of changes in nausea and vomiting was not significant between the two study groups during the measurement times. In a study carried out by Mogadam et al.  on the aThe results of a study conducted by Mikkelsen et al. also showed that gabapentin reduced the need for opioids in the first 24 h after tonsillectomy; however, it induced more dizziness (3 times), vomiting (5 times), and walking disorders (4 times), compared to those reported for the placebo group on 0 to 5 days after the surgery. Nonetheless, the differences in this regard were statistically significant . These aIn a study conducted by Mikkelsen et al., the benefits of decreasing opioid use through gabapentin might be affected by adverse effects. In a study carried out by Jeon et al. , no compIn the present study, although the differences in the weight and age of the children were statistically significant between the two groups and the subjects in the gabapentin group were approximately 3 kg heavier and 2 years older than those in the acetaminophen group, these differences did not affect the result of the study. The reason is that the effects of acetaminophen suppository and gabapentin suspension on the pain severity with the confounding variables of age, body weight, duration of surgery, use of analgesics and anti-emetic drugs were not significant. Furthermore, the effects of two drugs on nausea were not statistically significant with controlling the studied confounding variables. In a study carried out by Mogadam et al., there was no statistically significant difference between the age, gender, and duration of surgery in the patients in three gabapentin, diclofenac, and placebo groups . In anotAcetaminophen is the most common analgesic used for children. It is an effective analgesic and antipyretic with similar power to aspirin for the treatment of mild to moderate pains. In contrast to aspirin, acetaminophen does not inhibit the function of platelets leading to less intestinal disorder and no Reye's syndrome . A studyAlthough the results of the present study showed that there was no significant difference between the acetaminophen suppository at the dose of 40 mg/kg and gabapentin syrup at the dose of 10 mg/kg in terms of pain relief and antinausea and vomiting effects, the use of NSAIDs increases the risk of postoperative bleeding. In addition, the administration of opioids increases the risks of PONV and respiratory depression. Acetaminophen alone provides a poorer pain decreasing effect than opioids, and patients require more rescue analgesia . The resBased on the literature, there has been no study carried out on the respiratory depression caused by gabapentin . The difThe obtained results of this study showed that the preoperative administration of low-dose gabapentin can reduce the severity of pain in the patients undergoing adenotonsillectomy without any adverse effects. The effects of acetaminophen suppository and gabapentin suspension on pain severity and nausea with the control of the confounding variables of age, weight, duration of surgery, and use of analgesic and antinausea drugs were not significant. However, due to the adequate evaluation of the effectiveness of the gabapentinoids and given the high heterogeneity in some parameters, it is recommended to perform further clinical trials with a robust research design. The reason is that gabapentin might reduce the demand for analgesics by increasing the effect of sedation after surgery, not due to the effect of pain reduction, and the sedation should be evaluated in future studies. As a result, the role of gabapentin in the requests for analgesics should be clarified in order to confirm the results of the present study. It is also suggested to investigate the severity of postoperative pain at the time of swallowing or resting during the first 24 h after surgery using both approaches. It is also recommended to carry out further studies with larger sample sizes, determination dynamic or resting pain, and response to treatment.