Some osteoarthritis (OA) patients experience inadequate pain relief from analgesics like acetaminophen and nonsteroidal anti-inflammatory drugs. This could be the result of experienced non-nociceptive centralized pain. Placebo-controlled randomized trials (RCT) have proven the effectiveness of duloxetine for OA and several chronic pain conditions where central sensitization (CS) is one of the key underlying pain mechanisms.Assess the efficacy of an 8-week duloxetine treatment compared to usual care in end-stage knee and hip OA patients with a level of centralized pain.Pragmatic, enriched, open-label RCT.Patients were randomized to duloxetine or to care-as-usual. Primary outcome was pain in the index joint, measured with the pain domain of the Knee injury and Osteoarthritis Outcome Score (KOOS) or the Hip disability and Osteoarthritis Outcome Score (HOOS). The intention-to-treat principle was used, with mixed-model repeated measures to analyze the effect.p < 0.001). The duloxetine group scored 11.3 points  better on the pain domain of the KOOS/HOOS (p < 0.001). Knee patients improved significantly more than hip patients .One hundred eleven patients were randomized. Nearly 44% felt much to very much better after duloxetine usage compared to 0% in the care-as-usual group . End stage Hip OA patients seem to be nonresponsive to duloxetine.2013–004313-41.Dutch Trial Registry with number NTR 4744 (15/08/2014) and in the EudraCT database with number The online version contains supplementary material available at 10.1186/s12891-022-05034-0. Osteoarthritis (OA) is characterized by disability and eventually invalidating pain that leads to seeking medical aid . The paiCS is defined as an “increased responsiveness of nociceptive neurons in the central nervous system”; “this may include increased responsiveness due to dysfunction of endogenous pain control systems” . It is tDuloxetine, a selective serotonin and norepinephrine reuptake inhibitor, seems effective in treating neuropathic pain conditions as well as chronic pain conditions where CS is one of the key underlying pain mechanisms –18. In cIn knee OA patients, placebo-controlled randomized trials have proven the effectiveness of duloxetine as a potent analgesic in the conservative treatment phase of OA , 19–22. The Duloxetine in OsteoArthritis (DOA) study was a multicenter, pragmatic, enriched, open-label randomized controlled trial aiming to assess the effects of duloxetine treatment.The study was conducted at University Medical Center Groningen (UMCG), Martini Hospital Groningen and Medical Center Leeuwarden, the Netherlands. Patients were included between December 2014 and June 2018. Adult primary hip and knee OA patients (age > 18 years) who experienced OA pain with neuropathic features  when placed on the waiting list for total joint arthroplasty by their orthopedic surgeon were considered eligible. Selection of a predefined group of potential responders (enriched design) was based on previous research showing that knee patients with OA pain and neuropathic features had six times higher odds of experiencing signs of CS than those with only nociceptive pain , 25. RadPatients were excluded if they underwent hip or knee joint procedures in the past year, received intra-articular injections in the past 3 months, had cognitive and/or neurological disorders that could interfere strongly with questionnaires, were likely to be hospitalized during the course of the study, were planned for total hip/knee arthroplasty (THA/TKA) within the study duration (current planned arthroplasty not included), or had significant peripheral nerve injury (e.g. polyneuropathy). Patients with previous exposure to duloxetine or duloxetine-specific contraindications were excluded. For a detailed list of duloxetine-related exclusion criteria used, see the published study protocol .When patients were placed on the waiting list for primary THA/TKA they were subsequently asked to fill in the modified painDETECT (mPDQ) questionnaire , 27. ThiThe intervention consisted of 10 weeks’ preoperative duloxetine treatment (7 weeks on target dosage). For purposes of safety and adherence, medication release took place at three different time points. Prior to medication release, the participant was again informed and warned about possible side effects. A chart was used to record usage and side effects. This chart was collected and discussed at every subsequent visit . Time point T1 followed after medication period 1: the initiation period (weeks 1 and 2). The first week started at the day of randomization (T0), with half of the target dose (30 mg/day) to reduce the risk of side effects . In the Patients who did not tolerate duloxetine discontinued the intervention and were advised to enter the tapering phase. However, tailored discontinuation advice was given to patients who discontinued at or before the treatment phase (before T1). The control group did not receive a specific intervention and solely received standard care-as-usual . As it was a pragmatic RCT, no restrictions were imposed on usage of escape (pain) medication or other medication. An elaborate report of what was performed at each time point, including a scheme, is described in the published study protocol of the DOA study .Collected at baseline were age (at time of inclusion), gender, body mass index (BMI), cohabitation (yes/no), educational level , smoking (yes/no), ASA (American Society of Anesthesiologists) classification    or the HFunctional status and quality of life were measured using the KOOS  or HOOS Neuropathic-like symptoms were determined using the self-reported mPDQ  which isBlunt pressure pain thresholds (PPT) were measured by an algometer . PPTs are proven to be highly reliable at painful, nonpainful and remote body sites –47. PPTsThe Visual Analogue Scale (VAS) is widely used to measure pain. Pain ratings were recorded on a 100 mm horizontal line, where 100 mm represents the worst pain imaginable and zero no pain. Patients were asked to note their mean pain status at rest over the last week  and during movement . The VAS is demonstrated as valid for measuring and comparing between chronic pain conditions .The Patient Global Impression of Improvement (PGI-I) scale measured patients’ perceived change in overall well-being (in response to therapy/treatment). It is a 7-point Likert scale that ranges from “very much worse” to “very much improved”, and is derived from the clinical global impression scale . The PGIp-value < 0.05 was considered statistically significant.Statistical analyses were conducted by using IBM SPSS (V.23). Descriptive statistics were used to describe the study sample. Sample size was determined based on 80% power (two-sided significance level of 0.05) to detect a difference of 10 points on the KOOS/HOOS pain domain in the total study population with a standard deviation of 17.2 points, as a score change of 8 to 10 points is considered to be clinically relevant  . A totalp = 0.999) and were equal with respect to hip/knee ratio (p = 0.184). However, they were on average older than participating patients . More females declined to participate . There was one screen failure due to low sodium so the definitive study population consisted of 111 patients, 57 of them randomized to the duloxetine intervention group and 54 to the care-as-usual group . Joint-specific sub-analyses revealed that 58% of the duloxetine intervention patients in the hip group were smokers, versus 25.8% in the knee OA group. In Table In total 3402 patients were screened; 725 were eligible and were asked to participate, and 112 of them indicated wanting to participate in the study , duloxetine intervention patients had statistically significantly higher scores (better) than the care-as-usual group on the domains of pain, symptoms and ADL  only the statistically significant difference in the KOOS/HOOS pain domain was preserved (6.7 points), no statistically significant differences were apparent anymore in the KOOS/HOOS domains of symptoms and ADL (see Table p = 0.002) and T3 . By contrast, among hip OA patients no difference was observed between the duloxetine intervention and the care-as-usual group at any time point . Joint-specific analyses did not find any changes between PPTs during treatment either , somnolence (30%), nausea (28%) and dry mouth (28%). Other reported AEs are shown in Table The amount of missing data in the models used (MMRM) ranged from 3.6 to 10.8% (range T1-T3). For details see Table In this pragmatic enriched randomized controlled trial among end-stage hip and knee OA patients, an 8-week duloxetine intervention showed having more analgesic effects than usual care. Nearly 44% of patients felt much to very much better after 8 weeks of duloxetine usage compared to 0% in the usual care group. The duloxetine intervention seems to have a clinically relevant effect in improving joint related pain and function  , 57. AddThe two-week tapering phase which included 2 weeks on half the treatment phase dosage showed decreased analgesic effects of duloxetine. None of the differences within the pain- and function-related outcome measures on the KOOS/HOOS reached clinically relevant threshold levels , 57. JoiThe present results can be compared to previous literature only to a limited extent. Firstly, studies among hip OA patients are lacking. Secondly, other knee OA studies as well as studies on other chronic musculoskeletal pain conditions compared duloxetine intervention to placebo in a highly controlled fashion, as opposed to our pragmatic design . Lastly, none of the studies used an enriched design that only included patients with end-stage OA pain with neuropathic features . Despite these issues of heterogeneity, results found in previous studies were comparable to ours. Those studies found the duloxetine intervention group to be superior in relieving OA-related pain when compared to the care-as-usual group , 52, 58.The discrepancy between knee and hip OA regarding the effect of the duloxetine intervention is clearly noticeable, yet one must bear in mind that the study was not powered on detecting statistically significant differences within the two OA entities separately. On the other hand, nearly all differences in the knee OA group were statistically significant and clinically relevant. One could only ponder about the reasons why these differences are so prominent between the two OA entities. One factor could be that knee OA patients are more centrally sensitized and thus more prone to respond to a centrally acting agent like duloxetine. This could be the result of enhanced pain perception and proprioception in knee OA, which provokes early symptomatic presentation . As a coNearly all patients who used duloxetine experienced treatment-emergent AEs (94.7%). These were generally modest and mainly present at the start of the duloxetine intervention. The found percentage is higher than reported percentages in literature though: a recent study by Wang et al. found that 60.8% of duloxetine patients experienced at least one treatment-emergent AE when using 60 mg/d duloxetine for 13 weeks . CompareDue to its uniqueness, by using a pragmatic and enriched trial design this study offers new insights. The foremost insight is that end-stage knee OA patients still possess the ability to respond well to conservative duloxetine treatment. Significant pain relief was already noticeable after 2 weeks of treatment. As a result it could be hypothesized that joint-replacement surgery can be postponed in a subset of patients, or could even no longer be needed. This would have a major impact not only at the individual level but also at the societal level, as joint replacement surgery is a costly and frequently performed intervention worldwide. Another new insight is that it appears possible to desensitize knee OA patients preoperatively. Clinically relevant pain relief up to 10 weeks was seen in knee OA patients. It is known that a preoperative level of central sensitization (CS) is linked with less pain relief after arthroplasty, thus even when articular nerve fibers that induced CS are removed . This coDespite the advantages, the design used also has several limitations. Due to its enriched nature effects could only be seen in end-stage OA patients. However, results will probably not be worse in non-end-stage OA patients with neuropathic-like symptoms, as we believe that these patients should be easier to desensitize because of their less prolonged exposure to pain. Another limitation could be the relatively high proportion of patients who declined to participate (85%). The study patients and the patients who declined differed in age and gender distribution, so a level of selection bias could be present. It seems to be of little importance though, as the patients who declined did not differ on mean mPDQ-score from those patients who participated. As duloxetine therapy is contraindicated for subjects with certain comorbidities, our results cannot be extrapolated to every patient with end-stage OA and neuropathic-like symptoms. Nearly 20% of our screened target population was deemed as not suitable due to duloxetine-related contraindications. On the other hand, other analgesics often used in OA, such as NSAIDs, are also frequently contraindicated.Adding duloxetine treatment to usual care seems to be especially beneficial for end-stage knee OA patients with neuropathic-like symptoms/central sensitization. End-stage hip OA patients seem to be non-responsive to duloxetine, so there seems to be room for additional conservative treatment in a subset of these patients. It could therefore be advised to screen every knee arthroplasty candidate for the possibility of adding duloxetine to usual care. Treatment should be done in a controlled fashion, as AEs are commonly experienced. In knee OA patients treatment seems to have the potential to delay the process toward arthroplasty. In the long term this could even mean fewer joint replacement surgeries and hence revisions. Future postoperative results of our study should be awaited to have further information on the ability to reduce residual postsurgical pain.Additional file 1.


To validate and evaluate the intra- and inter-rater reliability of the 2-min step test (2MST) in measuring the functional performance of patients with knee pain associated with osteoarthritis (OA).Forty-one patients with knee OA was included. Two examiners assessed the patients at two times with interval between the test and retest from 7 to 14 days. All executions of 2MST were recorded in real time by the examiners and were also recorded by video. The intraclass correlation coefficient (ICC) and 95% confidence interval (CI), standard error of measurement (SEM) and minimum detectable difference (MDD) were used to determine reliability. In the construct validity, we correlate the score of the 2MST with the other instruments used in the study: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Numerical Pain Scale (NPS), Pain-Related Catastrophizing Thoughts Scale (PCTS) and Chronic Pain Self-Efficacy Scale (PSEQ). The agreement between the face-to-face assessment and the evaluation based on the video record was assessed using the Bland-Altman methodology in the 4 moments of the 2MST.2MST presented excellent intra-  and inter-rater reliability . The agreement was acceptable between face-to-face assessments and the analyzes performed on video. All instruments showed a statistically significant correlation with 2MST, except the PCTS. A correlation magnitude above 0.50 was found between the 2MST and pain and function domains of the WOMAC, and a correlation magnitude between 0.30 and 0.50 with the joint stiffness domain of the WOMAC, NRPS and PSEQ.2MST proved to be valid for assessing functional capacity in patients with knee OA, with excellent reliability. Osteoarthritis (OA) is a chronic-degenerative joint disease that is evidenced by the wear of the joint cartilage , 2. In tAssociated with subjective methods, objective tests are used to assess functional capacity, commonly in assessment routines in rehabilitation centers and in research. Six-minute walk tests (6MWT), Timed Up and Go (TUG), gait speed tests, Chair-Stand Test (CST), and Stair-Climb Test are recommended for patients with knee OA , 8, althIn addition to these, another test that measures functional capacity and is applicable in some populations, such as elderly people of both sexes , 10, hypWhen compared to the TUG and 6MWT tests, the 2MST presents the positive aspects of being of low cost, quick execution and not requiring large spaces or specific furniture for its realization. 2MST only needs a wall for its execution, which within the routine of a rehabilitation service facilitates the evaluative dynamics, since its execution can be performed inside the outpatient clinic, inpatient room or in the corridor. However, there is still a lack in the literature on construct validity and reliability of the use of 2MST in patients with knee OA, despite being a promising tool to investigate functional capacity.The clinical plausibility for the application of 2MST in patients with knee OA is related to the importance of the climbing up and down movements, as explained below: the movement during the 2MST performance involves the knee and hip joints; stair climbing is one of the first task affected in patients with knee OA ; and lowGiven this scenario, the present study aimed to assess the construct validity and intra- and inter-examiner reliability of the 2MST in measuring the functional performance of patients with knee pain associated with OA. The hypothesis of this study is that 2MST is a reliable and valid measure for the population tested.This is a study of the construct validity and reliability of the 2MST. The research was carried out in the Adult Orthopedic Rehabilitation sector of Hospital Sarah  from July 1, 2020 to January 30, 2021, approved by the institution’s research ethics committee (protocol number 3.962.645). All research participants validated their participation by signing an informed consent form.The sample calculation considered the confidence coefficient of 0.95 and the amplitude of the confidence interval for the intraclass correlation coefficient (ICC) of 0.30. In addition, the calculation was performed to detect adequate reliability (ICC = 0.75) according to the classification of Fleiss . Thus, aWe included in this study: patients of both genders; with a minimum age of 40 years and a maximum of 80 years; complaint of knee pain lasting more than 3 months, diagnosis of knee OA issued after evaluation by an experienced orthopedist, based on criteria established by the American College of Rheumatology with clinical evaluation and imaging. The criteria were presence of pain, presence of osteophytes and at least one of the 3 characteristics . Patients with grade 2 or 3 in the classification of Kellgren and Lawrence were included in the study .The non-inclusion criteria adopted in the study were: individuals with a history of lower limb surgery; use of mobility aids; neurological disorder (sensory and/or motor); hip OA; use of prosthesis or orthosis in the lower limbs; cardiopulmonary diseases or any other acute adverse health condition that may make it impossible to carry out the proposed tests. Exclusion criteria were patients who did not show up within the stipulated period of 7 to 14 days for the retest.The present study was integrated by two physical therapist examiners who performed the measurements with the 2MST independently in two moments (test and retest), resulting in a total of 4 test applications for each participant, two evaluations on the first day and two more on the second day. The assessments were carried out by two physiotherapists with more than 10 years of experience. In addition, a 1-month prior training was carried out to standardize the execution of the tests.When measuring functional capacity using 2MST, the examiner measured the maximum number of knee lifts that the individual performs in 2 min. Before starting the test, a marking was made on the wall, at the midpoint between the patella and the anterosuperior iliac spine. The examiner counted the number of right knee elevations that reached this mark for patients who had pain associated with right knee OA and for patients with bilateral symptomatic knee OA. The counting of left knee elevations was performed only in patients with exclusive symptoms of left OA.Two previous runs of the test were performed for familiarization, for a period of 30 s . After 1 min of rest, the first examiner  applied the test for 2 min, giving verbal information to start the test, another when 1 min had passed and when there were 30 s to the end of the test. After a 10-min rest break, the second examiner performed the same procedure. The order of examiners was defined by drawing lots before each application of 2MST.After a minimum interval of 7 days and a maximum of 14 days, the patients were evaluated with the 2MST again by the two examiners. The same pattern performed in the test was maintained, with the maintenance of the time, in the same environment, without the patient having performed any type of physical exercise on the day of the assessment, in order to avoid fatigue before the assessment.All 2MST runs were recorded for review by the examiners. In addition, the planes were filmed for further analysis using an iPhone 8 cell phone  and a universal telescope tripod set at the height of the marking made on the wall. A third independent examiner counted the number of steps using video recordings. This measure was taken to allow for the analysis of agreement, considering video-based counting as the reference measure.To determine the construct validity through correlations, patients answered validated instruments, translated and adapted to Brazilian Portuguese, commonly used in patients diagnosed with knee OA. Therefore, we used several questionnaires and scales to better assess the pain of patients with knee AO, within a biopsychosocial model, considering pain intensity, physical function, joint stiffness, catastrophizing and self-efficacy.The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a self-administered questionnaire designed specifically for individuals with knee or hip OA. It was culturally validated and adapted to Brazilian Portuguese . The queThe Numerical Pain Scale (NPS) is a scale consisting of a sequence from 0 to 10, where the value 0 represents “no pain” and the number 10 represents “the worst pain imaginable”. Thus, individuals graded their pain based on this parameter. This scale is validated for Portuguese . Each paThe Pain-Related Catastrophizing Thoughts Scale (PCTS) was used to assess catastrophizing in relation to pain. It is composed of 9 items scaled on a Likert scale, ranging from 0 to 5 associated with the words “almost never” and “almost always”. The total score is the sum of the scores of the completed items, divided by the number of these items answered, with the minimum score being 0 and the maximum 5. Higher scores indicate a greater presence of catastrophic thoughts. The scale was adapted and validated for Brazilian Portuguese [The Pain Self-Efficacy Questionnaire (PSEQ) was developed to investigate the degree of confidence that patients with chronic pain have about themselves to perform daily activities or functions. It consists of 10 items, with response options ranging from 0 to 6, 0 being “not at all confident” and 6 “completely confident”, totaling a score from 0 to 60. The higher the score, the greater is your self-efficacy. This instrument is validated for Brazilian Portuguese [2,3) was used to determine intra- and inter-examiner reliability, with its respective 95% confidence interval (CI), standard error of measurement (SEM) and minimal detectable difference (MDD) [To characterize the sample, quantitative data were described as mean and standard deviation (SD), and qualitative data as number and percentage. The intraclass correlation coefficient (ICCce (MDD) . To intece (MDD)  was usedTo determine the construct validity, the Shapiro-Wilk normality test was initially applied. Upon identification of non-normal distribution of data, Spearman’s correlation coefficient (rho) was used to verify the magnitude of correlation between 2MST and NPRS, WOMAC, PCTS and PSEQ. As a hypothesis for the magnitudes of correlation, we expect a correlation ≥0.50 between 2MST and the physical function domain of the WOMAC (similar constructs) and a correlation ranging from 0.30 to 0.50 with the pain and joint stiffness domains of the WOMAC, NPRS, PCTS and PSEQ (related but different constructs). It is expected that at least 75% of the hypotheses defined a priori are confirmed .The agreement between the face-to-face evaluations of the 2MST and the evaluation performed based on the video recording was analyzed using the Bland-Altman methodology, considering 4 moments of the completion of the 2MST .The software used for the analyzes was SPSS  and a significance level of 5% was considered.Forty-three patients diagnosed with knee OA were included in the study, with a sample loss of two individuals who did not attend within the recommended period for the retest. Thus, the final sample consisted of 41 volunteers.Thus, according to Table Table Regarding reliability, we observed excellent ICC values ≥ 0.94) when considering different times and different examiners, as shown in Table  when conUsing the Bland-Altman methodology, Figs. The 2MST showed excellent intra- and inter-examiner reliability in patients with knee OA and was adequately correlated with the NPRS, WOMAC and PSEQ instruments. Other studies have investigated the reliability of 2MST in other populations. The error values inherent to the test were less than 7%. The mean values of the execution in the 2MST were slightly higher in the retest, possibly due to the learning factor; however, the ICC values were adequate.The scientific literature has only two studies investigating the reliability of the 2MST. Excellent intra-examiner reliability was found in the elderly, with an ICC value of 0.90 . Our resOur study was the first to assess clinimetric properties of 2MST in a population of knee OA. A systematic review conducted by Bohannon and Crouch  evaluatiIn analyzing the construct validity, we correlated the 2MST score with the NPRS, WOMAC, PCTS and PSEQ scores. With the exception of PCTS, all instruments showed a statistically significant correlation with 2MST, with a magnitude of correlation above 0.30. In addition, a correlation magnitude above 0.50 was found between 2MST and the WOMAC pain and function domains. More than 75% of our hypotheses were confirmed, demonstrating sufficient results for construct validation, according to international guidelines . Therefor = 0.35), kinesiophobia (r = − 0.43) and catastrophizing (r = − 0.28). Investigating catastrophizing in patients with knee OA, Gomes et al. [The relationship between physical function and pain measures has already been investigated in previous studies with patients with knee OA. In a similar way to the present study, Odole et al.  identifis et al.  found nos et al. .We used self-report instruments  already validated in the population with knee OA to assess the magnitude of correlation with 2MST, and this aspect is an important limitation of our study. Other 2MST validation studies used performance assessment instruments in different populations, showing an adequate correlation with the 1-mile walk time in healthy elderly , and weaOur study observed adequate agreement between the evaluations carried out in person and the evaluations carried out through video recording. We consider measurement through video as a reference value. The results showed that the mean difference between the two methods is close to 0, which reflects excellent agreement. Therefore, both forms of application of the 2MST can be used, and professionals involved in the rehabilitation of these patients should choose which form of assessment best suits their clinical context.This study had some limitations that should be mentioned. Our study performed the test and retest keeping the same conditions regarding location, time, fatigue, but we did not control the stability of the clinical symptoms, related to possible pain variation in the 7 to 14-day interval. Reliability analysis by sex was not performed, although we did not observe this analysis in other reliability studies , 31, 32.2MST proved to be valid for assessing functional capacity in patients with knee OA, with excellent reliability. The study supports the use of the 2MST in the clinical context and in research with patients with pain, associated with knee OA.


To assess the feasibility and outcome of ultrasound-guided cryoablation in patients with a sensitized stump neuroma after limb amputation.p-value less than 0.05 was deemed statistically significant.Seven patients  were included in this retrospective study. Ultrasound-guided cryoablation of a previously identified painful stump neuroma was performed. Pain was assessed on the visual analogue scale (VAS) and compared before and after cryoablation (Wilcoxon Test). The degree of pain alleviation was correlated with patient age, duration of pain before ablation and time interval between amputation and ablation (Spearman correlation). A p < 0.05). Patient satisfaction with cryoablation treatment was very high (median score 70 / 100).Nine cryoablations were performed for 8 neuromas. Technical success was 100%, there were no major complications. Mean follow-up was 27 months. There was a statistically significant decrease of pain from mean 8.3 / 10 (baseline) to 4 /10 (on day one), 2.1 / 10 (at one week) and 3 / 10 (at last follow-up) (In our small population observational study, ultrasound-guided cryoablation of a sensitized stump neuroma was effective and safe for pain alleviation with very good long-term results.Level 2, Observational study with dramatic effect Approximately 50.000–70.000 amputations are performed each year in Germany . In 2005Experience with cryoablation for treatment of neuroma is very limited and mostly derived from treatment of Morton Neuroma , 6. BaseThis retrospective observational study of prospectively collected data was IRB-approved. Informed consent was obtained from all patients. Patients were referred for cryoablation of a symptomatic stump neuroma between March 2018 and December 2020. Inclusion criteria were as follows: patient age ≥ 18 years, adequate coagulation status, on imaging recognizable painful stump neuroma and decrease of pain after probatory perineural infiltration. The final study population comprised seven patients . A single cryoprobe (IceSphere™ or IceSeed™) was advanced to the previously identified neuroma and ablation started (2 cycles of 6 min freezing separated by a 4-min thaw cycle). The ablation zone and surrounding structures were continuously monitored with ultrasound. Care was taken that the resulting ice ball covered the whole neuroma without extending less than 0,5 cm to the skin surface. In addition, skin protection using warm gel cushions was performed. Patients were discharged the next morning, after follow-up ultrasound. Technical success of the procedure   and compPain intensity before and after cryoablation was evaluated using the visual analogue scale . Outpatient clinical follow-up was scheduled 6 weeks after the ablation. At final follow-up, patients were asked how satisfied they were with the cryoablation treatment  and whether they would be willing to undergo this treatment again, if needed.p-value < 0.05 deemed statistically significant).Statistical analysis was performed using GraphPad Prim . Pain scores before and after cryoablation were compared (Wilcoxon-Test). The degree of pain alleviation after cryoablation was correlated with patient age, duration of pain before ablation and time interval between amputation and ablation . Patient satisfaction with cryoablation treatment was very high (median score 70/100).Mean follow-up after cryoablation was 27 months (range 6.8–40 months). Mean pain score on the VAS before cryoablation was 8.3/10 (range 5–10). All patients reported marked and statistically significant pain alleviation after cryoablation  , and betTo the best of our knowledge, there are only two studies so far in which cryoablation for a painful neuroma was performed specifically in the setting of post-amputation pain. The results of our present study are comparable to those two published case series, but of note, follow-up in our study was distinctly longer. Neumann et al. performed cryoablation as an alternative to phenol injections in 10 patients with a neuroma and therapy refractory stump pain . At one This study has some limitations. First, the number of patients included is small. Secondly, even though this was a prospective study, patients’ quality of life before and after treatment was not assessed in detail, e.g., with a standardized questionnaire or tools dedicated for assessment of neuropathic pain.In conclusion, the results our prospective small cohort observational study show that ultrasound-guided cryoablation of a sensitized stump neuroma in patients with pain may be a safe and effective treatment with very encouraging short- and long-term results.


Pain strongly coexists with depression. Ketamine has great analgesic and antidepressant effects, acting as a promising role in treating depression with pain. Few studies have evaluated impact of pain symptoms on antidepressant effect of ketamine infusions. Thus, present study investigated whether pain symptoms in individuals with depression moderate response to ketamine.One hundred and four individuals with major depressive disorder and bipolar depression received six intravenous infusions of ketamine. The Montgomery–Åsberg Depression Rating Scale (MADRS) was administered at baseline, the next morning after each infusion and 2 weeks (Day 26) after the last infusion. Pain symptoms were collected at baseline using the short-form McGill Pain Questionnaire (SF-MPQ).p < 0.05). Then follow-up simple slopes analyses suggested that all patients across groups showed a significant symptomatic improvement after ketamine infusions , and patients with severe pain  had greater improvement in depressive symptoms than those with mild pain or non-pain .The prevalence of pain in patients with depression was 48.8%. Mix model analyses showed that pre-treatment pain symptoms assessed by each domain of SF-MPQ significantly moderated antidepressant response to six infusions of ketamine from baseline to day 26 (all A significant and rapid improvement in depressive symptoms was observed in patients with depression and pain after ketamine treatment. Ketamine may be a novel and promising antidepressant preferentially for the therapy of depression with severe pain. Both depression and pain are widespread and debilitating conditions, contributing to substantial disability as well as large socioeconomic burden worldwide , 2. The In recent decades, intensified efforts are underway to develop new antidepressants. Ketamine is a non-selective N-methyl-D-aspartic acid receptor (NMDAR) antagonist with anesthetic and analgesic effects, which can effectively relieve acute and chronic pain –15. KetaKetamine has also been reported to be effective in individuals with the comorbidity of depression pain , 25. A rTaken together, ketamine may be a promising treatment for individuals experiencing comorbid depression and pain. However, there is limited clinical research that has evaluated the role of pre-treatment pain symptoms in response to repeated ketamine infusions in individuals with depression. Thus, the study herein aimed to determine whether pre-treatment pain symptoms moderate the antidepressant efficacy of repeated intravenous ketamine infusions in individuals with MDD or BD. Considering the powerful effect of ketamine on alleviating pain, we hypothesize that pre-treatment pain severity may differently moderate the response to ketamine infusions in patients with depression when compared to conventional antidepressant treatment.Present study was a single-arm open-label clinical trial of six ketamine infusions conducted in The Affiliated Brain Hospital of Guangzhou Medical University from November 2016 to July 2018 which aimed to explore the antidepressant efficacy of adjunctive ketamine in patients with MDD or BD. The protocol was approved by the Clinical Research Ethics Committee of The Affiliated Brain Hospital of Guangzhou Medical University with a clinical trial number, ChiCTROOC-17012239. All participants provided informed consent before entering our study. Patient selection and study design are introduced briefly in our current study, as they have been described in detail in our previous study (Participants who satisfied the following inclusion criteria were permitted to participate in our study: (1) aged 18∼65 years old; (2) were suffering from MDD or BD without psychotic symptoms according to the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5); (3) were experiencing moderate to severe depressive symptoms defined as a score of ≥17 on the 17-item Hamilton Depression Rating scale (HAMD-17) , and werParticipants received six intravenous infusions of ketamine for 2 weeks . After an overnight fast, enrolled patients received an intravenous (IV) infusion of ketamine dosed at 0.5 mg/kg diluted in 0.9% saline, which was delivered at least 40 min. IV ketamine infusions were performed on days 1, 3, 5, 8, 10, and 12 during the trial.Depressive symptoms were measured by the Montgomery–Åsberg Depression Rating Scale (MADRS) , which wp < 0.05. Student’s t-test for continuous variables and the chi-square test categorical variables were used to compare demographic variables and clinical data between the groups (pain vs. non-pain). Analysis of variance was performed to compare differences in pre-treatment depressive severity between severe pain, mild pain, and non-pain groups. Bonferroni test was used in post hoc comparisons. With respect to missing data, a mixed model was performed to assess change in MADRS scores from baseline to day 26. The interaction effect between ketamine treatment and pre-treatment pain severity was calculated to evaluate whether overall changes in depressive symptoms measured by MADRS score from baseline to day 26, were moderated by pre-treatment pain symptoms, as measured by VAS, sensory index, affective index, PPI and their total score. Follow-up simple slopes comparisons were performed for significant interactions, comparing difference of slopes between mild, severe pain and non-pain groups. Patients exhibiting no pain symptoms at pre-treatment were characterized as “non-pain,” patients exhibiting the mean or below the average score  were characterized as “mild pain” and patients exhibiting above the average score were characterized as “severe pain.” Therefore, five separate models were conducted in our statistical analyses. Age, gender, body mass index (BMI), education, duration of illness, diagnosis, and pre-treatment depression severity were included as covariates in each model. In addition, pre-treatment MADRS score was evaluated for multicollinearity with pre-treatment pain symptoms before entering the model.The retrospective exploratory analysis was conducted in SPSS 22.0 statistical software. All tests were two-sided with significance at N = 50) were suffering pain before ketamine treatment. Baseline sociodemographic and clinical characteristics are presented in A total of 104 depressive patients with pre-treatment pain data received six infusions of ketamine. 16 patients dropped out at day 26. Thus, depressive symptoms assessed by MADRS were available for 104 patients at pre-treatment and for 88 patients at day 26. 48.8% of patients (Post hoc comparisons using the Bonferroni test indicated that the mean pre-treatment MADRS score of patients with severe sensory index (mean = 37.6 ± 5.1) was significantly higher than patients with mild sensory index  or patients without pain . However, the mean pre-treatment MADRS score did not significantly differ between patients with mild sensory index and patients without pain (p = 1.000). Similar findings were observed when comparation were performed among patients with mild/severe affective index and non-pain, with mild/severe PPI and non-pain, as well as mild/severe total pain and non-pain, consistently suggesting that pre-treatment MADRS score in patients with severe pain was higher than patients with mild pain or non-pain . Mean pre-treatment MADRS scores in patients with severe VAS (mean = 35.3 ± 6.9) was also higher than patients with mild VAS (mean = 30.4 ± 6.3), but this difference didn’t reach a statistical significance (p = 0.093). Similarly, mean pre-treatment MADRS scores in patients with severe VAS was higher than patients without pain (mean = 31.5 ± 8.2), but this difference did not reach a statistical significance either (p = 0.068).According to mean scores of VAS, sensory index, affective index, PPI, and total pain, there were 23, 32, 24, 26, and 24 patients with mild pain, respectively, as well as 27, 18, 26, 24, and 26 patients with severe pain, respectively. As shown in P-value for each model. In summary, total pain significantly moderated changes in depressive symptoms from baseline to day 26 . Follow-up simple slopes analyses showed that patients with mild total pain , severe total pain , and non-pain  all reported significant reductions in depressive symptoms from baseline to day 26. B = −0.332, t = −5.089, P < 0.001), sensory index , affective index , and PPI  were, respectively, included as moderators, such that all significantly moderated antidepressant effect of IV ketamine treatment. Participants with mild VAS  and severe VAS  both reported significant reductions in depressive symptoms from baseline to day 26. A similar pattern was observed when VAS /severe  sensory index, with mild /severe  affective index, or with mild /severe  PPI all reported significant reductions in depressive symptoms from baseline to day 26. Similarly, participants with mild  the rate of pain in depressive patients was high (48.8%); (2) patients with greater pain severity also had higher pre-treatment depressive scores assessed by MADRS; (3) the benefits of repeated infusions of ketamine were observed in patients affected by MDD/BD, both with and without pain; and (4) patients affected by MDD/BD with higher pre-treatment pain exhibited more robust symptomatic improvement, suggesting pre-treatment pain severity moderated ketamine’s antidepressant effect, which is inconsistent with outcomes observed with conventional antidepressants.Nearly a half of patients with depressive symptoms in our study reported pain symptoms, which was consistent with previous reports , 27. ThiOur study revealed that significant and rapid reductions in depressive symptoms were observed across groups after receiving six infusions of IV ketamine, suggesting that ketamine has a robust antidepressant effect which has been supported by a wealth of studies –38. HoweIt has been reported that pain adversely affects the treatment response to conventional antidepressants in persons with depression. For example, results from the STAR*D study indicated that MDD patients with physical pain symptoms were less likely to remit and took longer to achieve remission when they were treated by selective serotonin reuptake inhibitor (SSRI) antidepressants . A previKetamine, a novel, rapid-acting antidepressant, has been reported to have therapeutic effects in both pain and depressive symptoms, and may be an ideal treatment option for individuals with depression and comorbid pain symptoms , 27. ForThere may be neurobiological mechanisms underlying the enhanced ketamine’s antidepressant effect in patients with depression and severe pain. Excessive activation of inflammation has been implicated in the pathogenic mechanism of the comorbidity of depression and pain. In animal models of depression with concomitant neuropathic pain, the increased expression of pro-inflammatory cytokines is observed in brain regions that are responsible for processing emotion and pain , 40. SimKetamine has anti-inflammatory effects, which may be implicated in its therapeutic effect on pain and depressive symptoms . MoreoveRegarding to the adverse effects, ketamine IV three times a week in our study showed well-tolerated and safe during the infusions as the psychotomimetic and dissociative symptoms, and blood pressure and pulse elevations were very mild and transient, which have been described in detail in our previous publication . In receSeveral limitations should be noted. First, this was a retrospective analysis of data from an open-label clinical study without placebo controls. And the potential subjective bias of patients and researchers may affect the interpretation of the results because of the lack of blind method. Second, the sample size of this study is relatively small, which may lead to sampling bias. Moreover, due to the limited sample size, patients with either MDD or BD analyzed as a whole in this study may increase heterogeneity. Third, we only recruited depressive patients with treatment-resistant and with suicidality, which may limit the generalizability of these results for depression patients. Fourth, baseline demographic characteristics of patients with mild, severe and non-pain were not shown because they were divided into multiple groups according to different domains of SF-MPQ. Fifth, we did not measure biological indicators such as plasma cytokines which may enhance persuasive evidence. Thus, it is necessary for further study to measure biological indicators in these depressive patients.In summary, our study showed that depressive patients with varying degrees of pain exhibited a significant and rapid improvement in depressive symptoms after six infusions of ketamine treatment, and pre-treatment pain symptoms moderated ketamine’s antidepressant effect. Overall, our findings suggest that ketamine may be a novel and promising antidepressant preferentially for the therapy of depression with severe pain.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Clinical Research Ethics Committee of The Affiliated Brain Hospital of Guangzhou Medical University. The patients/participants provided their written informed consent to participate in this study.YN and YZ designed the study and wrote the protocol. YN provided research supervision. XL and YZ wrote the manuscript. RM helped to revise the manuscript. All authors participated in the data collection and contributed and approved the final manuscript.RM has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and AbbVie. RM is a CEO of Braxia Scientific Corp. The remaining 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.


Medical cannabis may be a useful tool for managing treatment-resistant epilepsy and chronic pain, which affect many patients in pediatric palliative care (PPC); however, little evidence is available in this setting.cannabis sativa for 1 year. Only mild and transient adverse events occurred: drowsiness, euphoria, restlessness and tachycardia; the resolution was either spontaneous or obtained by modifying the administration schedule. Treatment was never discontinued. No overdoses occurred. All patients experienced seizures during the pre-treatment observation period, and obtained a reduction in seizure frequency, although with variable extent while receiving cannabis. In addition, a benefit on pain was observed, based on the caregiver’s evaluation, and a reduction of analgesic use.We aimed to describe a clinical experience in a setting where high-level evidence may not be obtained. We report our clinical experience in a pediatric palliative care department in Italy. Caregivers reported changes in intensity and frequency of pain and epilepsy events. Six patients received a titrated plant extract of Our experience suggests that a titrated plant extract preparation of medical cannabis may be useful to control treatment-resistant pain and epilepsy in PPC patients. Pediatric palliative care (PPC) aims to improve the quality of life of children with complex needs who are affected by a wide range of serious medical conditions for which no curative treatments are available. In this setting, a special focus on the care of families is pivotal. The role of the endocannabinoid system in epileptogenesis and pain inhibition has recently attracted attention in adult palliative care, based on the pharmacological basis to the use of exogenous cannabinoids to treat some of the more frequent and troublesome conditions of patients in palliative care, such as pain, poor appetite, weight loss, anxiety and treatment-resistant epilepsy , 2. In ap ≤ 0.0001) [A systematic review of clinical trials assessing pharmaceutical-grade cannabidiol (CBD) in children with epilepsy, including data from 17 observational studies, showed that 20 mg/kg/day CBD was more effective than placebo in terms of seizure number reduction . A meta- 0.0001) .Although conflicting data have been published on neuropathic pain, a systematic review in palliative medicine found limited evidence for the benefit of THC/CBD spray in the treatment of neuropathic pain, and a meta-analysis of 18 clinical studies on chronic pain and 776 patients found a moderate efficacy of treatment with cannabis –16.cannabis sativa for 1 year.Medical cannabis could be a useful tool for managing treatment-resistant epilepsy and chronic pain, which affect many patients in the PPC , 18; howIn accordance with regional recommendations for the prescription of cannabinoids, medical cannabis treatment was proposed to six patients followed-up in the Centro Regionale Veneto di Cure Palliative Pediatriche e Terapia del Dolore of Padova Hospital, Italy – a referral center for PPC in northern Italy – who were suffering from treatment-resistant epilepsy and/or chronic pain and/or spasticity resistant to standard treatment lines, without contraindication to the use of medical cannabis due to psychiatric or cardiovascular disease. Data presented here cover an observation period of 1 month before initiation of cannabis and 12 months during treatment (except for patient 3). The previously prescribed antiepileptic and analgesic therapy were continued in concomitance with cannabis.Treatment with FM2, with clinical outcomes, are reported in Table Patients were treated with cannabis FM2 (Farmaceutico Militare 2 cannabinoids), produced by Stabilimento Farmaceutico Militare, Florence, Italy . FM2 is The following data were recorded: daily frequency of seizures (treatment success was defined as reduction ≥50% of seizures frequency) and use of rescue therapy –23; painCaregivers provided written consent. Cannabinoids were prescribed following regional recommendations for the prescription of cannabinoids. The procedures followed and described here were in accordance with the Declaration of Helsinki as revised in 2013.A 4-year-old boy with epileptic encephalopathy and mixed chronic pain had mild spasticity, sleep disorder, and severe neurological impairment. He was nourished by percutaneous endoscopic gastrostomy (PEG) and had a bodyweight of 13 kg. Uncontrolled epilepsy was the main complaint, and irritability episodes were frequent and interpreted as poor pain control. Data collection started 27 days before FM2 treatment, in a period without interventions on therapies and/or care. Before initiation of cannabis, the patient was free from pain on 23/27 (85%) days. In total, 15 tonic–clonic seizures occurred in 27 days (0.6/day), and 22/27 days (81.5%) were free from seizures. All seizures presented in a cluster, and 14/15 seizures led to oxygen desaturation. Seizures rescue therapy was used four-times.FM2 treatment started with the dose of 0.11 mg/kg/day, which was increased weekly up to 0.59 mg/kg/day, without adverse events Table .Overall, fairly good control of pain was obtained, with a 15% increase of days free from pain. The proportion of days without seizures was 81.5% before the use of cannabis and was slightly reduced during the first month of treatment; it was then progressively increased, up to 90%. The intensity of seizure clusters was reported by the caregiver to be reduced. An overall reduction of irritability and an improvement of relationships were observed.The PEDsQL questionnaire showed that the disease impact on the family was reduced after 1 year of cannabis use . Improvement was obtained in the subscales emotional condition, care, daily life activities and family relationships.An 18-year-old boy, affected with lissencephaly, severe neurological impairment, nourished by PEG, with a bodyweight of 33 kg, and spasticity, had drug-resistant epilepsy on treatment with benzodiazepines, phenobarbital, valproate and topiramate. He also received gastroprotective drugs and food supplementation. He suffered from chronic mixed pain, resistant to treatment with non-steroid anti-inflammatory drugs (NSAIDs) + opioids + corticosteroids. He was observed for 13 days before starting cannabis treatment while continuing the previously prescribed therapy. The pain was reported each day, in this period, with a mean NRS scale intensity = 3.5. Overall, 113 seizures occurred, with a daily frequency = 8.7, and no days were free from episodes. Seizures presented as spasms in 41 cases and tonic–clonic episodes in 72 cases. Seizures never led to oxygen desaturation, and rescue therapy was not used.), which was moderate before treatment, together with a relevant reduction of seizure frequency, from 8.7/day to 2.3/day. At the end of the observation, the impact of disease on the family quality of life was not changed, as the PEDsQL total score was 34 at baseline and 37 at 12 months after initiation of cannabis. A little improvement was observed in the subscales emotional condition, social life and cognition, while the impact on care and daily life activities was increased.FM2 dose was initially 0.11 mg/kg/day and increased weekly up to 0.52 mg/kg/day Table . The patA 19-year-old boy who had a kidney transplant was affected with coenzyme Q10 deficiency, nurtured by PEG, and had a bodyweight of 34 kg. Chronic mixed pain, severe neurological impairment, mild spasticity and agitation were present. He was treated with benzodiazepines, phenobarbital, oxcarbazepine, proton pump inhibitors, corticosteroids and immunosuppressors. On-demand analgesic treatment was based on NSAIDs + opioids + corticosteroids. During the pre-cannabis 30-day period of observation, he received analgesics 12-fold, and the mean pain intensity, as caregiver-evaluated NRS was 4; 12/30 (40%) days were free from pain. Seizures occurred every day with a frequency of 6 episodes/day ; all seizures were tonic–clonic, and 120 episodes lasted > 5 min; rescue therapy was administered three-times.FM2 was started with 0.1 mg/kg/day and the dose increased weekly up to 0.48 mg/kg/day. At the highest dose, the patient had mild euphoria, which spontaneously remitted Table .He obtained a relevant reduction of seizure frequency (2 seizures/day) and pain control  with the use of medical cannabis; in addition, a positive effect was observed on spasticity, agitation, sleep disorder and relationship. Clinical data are available for 6 months of observation because the caregiver compliance was poor.The disease impact on the family quality of life was reduced after 1 year of treatment with medical cannabis. The total PEDsQL score was 18 at baseline and 38 at the observation end. Improvements were observed in the areas of health and physical activity, emotional condition, social life, cognition, communication, care and family relationships. Only the impact on daily life activities was unchanged.A 14-year-old girl was affected with Rett’s syndrome, had moderate cognitive dysfunction, and had no particular pain. She had a bodyweight of 35 kg, was nurtured by PEG, presented with mild spasticity and restlessness. Antiepileptic treatment was based on valproate and benzodiazepine when needed; she also received a proton pump inhibitor and food supplementation. During the 30 days of observation before cannabis initiation, she had 58 tonic–clonic seizures (1.9/day), 33 of which lasted > 5 min; 9 (30%) days were free from seizures. No pain was reported from caregivers, but daily episodes of restlessness were observed. FM2 treatment was initiated with the daily dosage of 0.1 mg/kg/day, and the dose increased up to 0.22 mg/kg/day  days were free from pain. He had 300 (10/day) absence and tonic–clonic type seizures, all lasting < 5 min and without oxygen desaturation. No days free from seizures were observed.FM2 treatment was started with 0.12 mg/kg/day, and increased weekly to 0.62 mg/kg/day. At the maximal dose, drowsiness occurred and remitted after the administration schedule was changed from 33% of total dose three-times/day to 25% + 25% + 50% of total dose in the morning, afternoon and evening, respectively. After dose reduction to 0.42 mg/kg/day, euphoria occurred and remitted after the dose was reduced to 0.2 mg/kg/day, of which 15% + 20% + 65% was administered in the morning, afternoon and evening, respectively  and seizures (3 seizures/day), this patient obtained a reduction of restlessness and improvement of relationship ability.The total PEDsQL score was 41 at baseline and was increased up to 56 at the observation end. The areas that improved after 1 year of treatment with cannabis were health and physical activity, emotional condition, care, daily life activities and family relationships. On the contrary, the impact on social life, cognition and communication was not improved.A 5-year-old female child, affected with epileptic encephalopathy, severe psychomotor impairment, moderate pain associated spasticity, with NRS as high as 10 (caregiver report). She also had restlessness and sleep disorder. Therapy was based on benzodiazepines, phenobarbital and oxcarbazepine. She received a proton pump inhibitor and food supplementation. The pain was treated with NSAIDs, opioids and baclofen.Before FM2 treatment, she had 300 (10/day) absence and tonic–clonic type seizures, without oxygen desaturation. Pain occurrence and intensity were not recorded.At the beginning of the observation period, she was treated with FM20.71 mg/kg/day, prescribed by another center. Involuntarily, the dosage was increased to 1.2 mg/kg/day due to high titration , for 1 month Table . As irriDuring treatment with FM2, she had some adverse events: irritability requiring dose reduction, euphoria, loss of appetite, restlessness and tachycardia, which remitted spontaneously.Through the observation period, this patient obtained an improvement of sleep disorder and relationship ability; the caregiver reported a reduction of pain intensity  and seizure frequency (0.33/day). The impact of disease on family quality of life could not be evaluated. The PEDsQL questionnaire could not be completed because this patient had already received cannabis before our observation, and a baseline was unavailable.We report the clinical course of six patients in the PPC setting, all presenting with resistant symptoms and “global suffering”, who had received cannabis therapy for treatment-resistant epilepsy and chronic pain for 1 year. The treatment with medical cannabis in our setting appears to be feasible and safe. A titrated plant extract was used, which was administered in an oily vehicle either orally or enterally. The extract was titrated every month and the dosage was calculated and tailored according to the relative THC content of the preparation. The effective dosage was reached by progressively increasing the daily dose . This meIn our experience, only mild and transient adverse events occurred: drowsiness, euphoria, restlessness and tachycardia; the resolution was either spontaneous or obtained by modifying the administration schedule. Treatment was never discontinued. No overdoses occurred, suggesting that the drug was safe and easily managed by caregivers. A safety concern in using medical cannabis in children is the risk of drug tolerance, which may be checked in palliative care patients by the caregivers and was not observed in our cases. In addition, sedation induced by cannabis may be an advantage for patients in PPC who have moderate/severe neurological impairment; so that higher doses may be tolerated in comparison with patients with better cognitive abilities, who view sedation as an adverse event. Similarly, the impact of medical cannabis on long-term neurological development, which is debated in the literature, is not an issue in patients with a life-limiting/threatening disease.This report cannot be considered an observational study, and no statistical analysis of data can be proposed. Patients are heterogeneous in terms of main diagnosis, age, and pain and epilepsy severity at baseline. Nevertheless, we believe that some considerations may be drawn from this case series description and may be useful to clinicians dealing with PPC patients.All patients experienced seizures during the observation period, and obtained a reduction in seizure frequency, although with variable extent; specifically, four out of six patients had a > 50% decrease in seizure frequency, which can be considered a threshold for efficacy . The effSpasticity was improved only in two subjects. Kuhlen et al.  administIn conclusion, our experience showed that a titrated plant extract preparation of medical cannabis affected treatment-resistant pain and epilepsy in PPC patients in some cases; this therapy was effective in some patients and was not associated with adverse events which could discourage the use. Careful dosage control is necessary to meet the therapeutic interval; this can be obtained by a strict titration of herbal extract and relative dosage adjustments. Based on our experience, the efficacy and safety of cannabis in PPC patients should be further investigated by clinical studies: further studies statistically driven should demonstrate a significant effect, which at the moment is only descriptively observed.


Enhanced recovery protocols optimize pain control via multimodal approaches that include transversus abdominis plane (TAP) block. The aim of this study was to evaluate the effect of preoperative vs. postoperative plain 0.25 % bupivacaine TAP block on postoperative opioid use after colorectal surgery.n = 240) vs. postoperative (n = 22) plain 0.25 % bupivacaine TAP blocks. The study was conducted in a single tertiary care institution and included patients who underwent colorectal resections between August 2018 and January 2020. The primary outcome of the study was postoperative opioid use. Secondary outcomes included operative details, length of stay, reoperation, and readmission rates.A retrospective cohort study comparing postoperative opioid use in patients who received preoperative (p = 0.012) and opioid medications on discharge  relative to patients who received preoperative TAP. When needed, a significantly smaller amount of opioid was prescribed to the postoperative group . No significant differences were noted in the duration of postoperative PCA use, amount of oral opioid use, and length of stay.Patients who received postoperative plain 0.25 % bupivacaine TAP blocks were less likely to require postoperative patient-controlled analgesia (PCA) (59.1 % vs. 83.3 %; Plain 0.25 % bupivacaine TAP block administered postoperatively was associated with significantly lower need for postoperative PCA and discharge opioid medications. The overall hospital length of stay was not affected by the timing of TAP block. Because of the limited sample size in this study, conclusions cannot be generalized, and more research will be required. Enhanced recovery protocols (ERP) after surgery have the aim of reducing morbidity and the surgical stress response while advancing early return of patients to their baseline functioning . ComponeOptimal pain management is an integral part of an ERP, particularly after colon surgery. Poor pain control may lead to longer length of stay, cost, and patient dissatisfaction . Many ERA TAP block may be administered at any time during the immediate perioperative period. However, whether plain bupivacaine TAP block is effective in colorectal surgery remains to be elucidated. There have been no studies assessing the timing of TAP block administration for optimal postoperative pain control. In the present study, we assessed the effect of preoperative vs. postoperative administration of TAP block using plain 0.25 % bupivacaine on postoperative opioid use in patients undergoing colorectal surgery. Furthermore, we assessed for any effects on length of stay, rates of reoperation, and readmission.All patients who received TAP blocks during a transabdominal colorectal resection between August 2018 and January 2020 were identified through hospital chart review. The TAP procedure was performed by the regional anesthesiologist on duty that day. The majority of TAP blocks are performed preoperatively in our institution. At times, the TAP block was done at the conclusion of the operation often due to timing issues. All included patients underwent colorectal resection done by colon and rectal surgeons at our tertiary care hospital. We abstracted patient demographics, medical comorbidities, preoperative diagnosis, past medical and surgical history, procedure-related details, and postoperative opioid use after the index operation until discharge. The study was approved by the Henry Ford Health System Institutional Review Board. This manuscript was conducted in accordance with the ethical standards laid down in the amended 1964 Declaration of Helsinki.Patients were divided in 2 groups based on timing of TAP block procedure: before (preoperative) or immediately after (postoperative) their surgical procedure.Under ultrasound guidance, TAP blocks were performed by, or under supervision of, the attending anesthesiologist who specializes in acute pain management and regional anesthesia. The blocks were performed either 1 h preoperatively or at the conclusion of the surgery procedure within 30 min of reaching the post-anesthesia care unit. The TAP block consisted of bilateral injection of 20 mL of 0.25 % plain bupivacaine in the fascial plane between the internal oblique and transversus abdominis muscles in the midaxillary line. None of the patients in the 2 groups received additional regional anesthesia, including epidural or spinal anesthesia.Our postoperative pain management protocol consisted of scheduled acetaminophen, muscle relaxant (methocarbamol or cyclobenzaprine), gabapentin, and ketorolac in the absence of any contraindication. Patient-controlled analgesia (PCAs) were initiated for patients who had inadequate pain control, had pain-related hypertension or tachycardia, or were unable to ambulate or participate in pulmonary toilet. All patients were routinely assessed for their pain levels. However, the use of numerical pain scoring was not consistent amongst the patients and hence, was not included in the study. While there may be minor differences in pain management based on specific surgeon-preference, most of the patients were treated using this protocol. Finally, the decision to prescribe discharge opioid was based on several factors such as surgeon’s discretion, the level patient’s pain control, and history of chronic opioid use.The primary outcome of the study was postoperative opioid use. The incidence, type, and total amount of opioid in milligram morphine equivalent (MME) and non-opioid analgesic medications administered after the index procedure were recorded. Secondary outcomes included procedure-related operative details, length of hospital stay, rates of readmission, and reoperation.P < 0.05 was considered statistically significant. All analyses were done in SAS 9.4 .Statistical analyses were conducted to compare the baseline characteristics of the patients who received preoperative TAP blocks with those who received postoperative TAP blocks. Continuous variables were described using the mean and standard deviation (SD), and categorical variables were described with the frequency and percentage. Analysis of variance or Kruskal–Wallis tests were used for continuous variables and chi-square tests or Fisher’s exact tests were used for categorical variables as appropriate. 2 (7.32 kg/m2). There were no significant differences in the 2 groups with regard to age, sex, body mass index, American Society of Anesthesiology classification, history of cancer or inflammatory bowel disease, and opioid use at the time of the index procedure  patient age was 57.8 years 16 years), 45 % were men, and the mean (SD) body mass index was 28.4 kg/m6 years, p = 0.012). However, when given a PCA, the postoperative TAP group used a significantly higher amount of morphine compared to their counterparts . The postoperative TAP group was less likely to be prescribed opioid medication at the time of discharge . For patients who received prescription opioid at the time of discharge, the patients who had postoperative TAP received a significantly smaller amount of opioid . There were no differences between the groups with regard to duration of PCA or intravenous and oral opioid use.Table Table Postoperative pain management is an integral part of achieving the goals of ERPs after colorectal surgery. TAP blocks are an attractive approach for minimizing the use of opioids, especially given their low risk of adverse effects. Although usually done preoperatively, our study showed that postoperative TAP block with plain bupivacaine appeared to be at least as efficacious as preoperative TAP block in reducing postoperative intravenous opioid use, both PCA and administered intravenous injections. Furthermore, postoperative plain TAP block was associated with a reduced total amount of prescription opioids needed to the time of discharge from the hospital. Other variables such as length of stay, estimated operative blood loss, procedure length, reoperation and readmission rates did not differ between preoperative or postoperative administration of the TAP.The effectiveness and feasibility of TAP blocks in colorectal surgery has been shown in multiple studies , 13–17. Considering the short duration of action of plain bupivacaine, the timing of its administration for TAP blocks can be planned to provide optimal analgesia. Preoperative administration is easily performed in the preoperative area and does not affect surgical planning such as ostomy procedures. It is also in line with preemptive analgesia. Oliveira et al., through a meta-analysis that included a variety of abdominopelvic surgeries, reported a greater postoperative pain control, reduced pain at rest, and decreased opioid used with preoperative TAP compared to placebo or no treatment . The majThe study was limited by its retrospective design, the small number of patients who received postoperative plain bupivacaine TAP block procedures, and by having been performed in a single center. Although the TAP blocks were performed by, or under supervision of, the attending anesthesiologists who specialize in acute pain management and regional anesthesia, we acknowledge the possibility that performer-related differences could lead to differences in pain relief. However, the regional block was administered by well-trained and experienced anesthesiologists who routinely perform the procedure, hence minimizing the effect of performer-related differences. Finally, our study did not directly measure the patient pain scores. Instead, we used the amount of postoperative opioid used as a surrogate for the adequacy of pain control. Per our ERP, additional analgesia is prescribed on an as-needed basis and coincides with the patient’s assessment of pain on a numeric scale.TAP blocks provide an effective and feasible means of optimizing pain control in the era of enhanced recovery after surgery. When administered postoperatively, plain bupivacaine TAP may be as effective as preoperative TAP blocks, offering the same analgesic effect and minimizing intravenous opioid use.


This study compared the effects of adductor canal blocks with those of a low concentration of popliteal-sciatic nerve block (SNB) and dexamethasone as an adjunctive technique for total knee arthroplasties (TKA) in patients susceptible to the adverse effects of NSAIDs.A prospective, double-blinded, randomized controlled trial was performed in 50 patients susceptible to the adverse effects of NSAIDs undergoing unilateral TKAs. All patients received spinal anesthesia, adductor canal blocks, and periarticular infiltration. The 25 patients in the intervention group received SNB (0.125% bupivacaine [20 ml] and dexamethasone [5 mg]).p-values, 0.012, 0.021, and 0.010, respectively. Movement-evoked pain scores at 6, 12, and 18 h were also lower: control group, 3 (0–5.5), 5 (2.5–6.5), and 7 (4–9); intervention group, 0 (0–1.5), 2 (0–4), and 3 (2–5); p-values, 0.019, 0.005, and 0.001, respectively. There were no differences in motor function. Moreover, the mean morphine consumption 24 h was also reduced in the SNB group: control group, 3.80 ± 2.48 mg; intervention group, 1.96 ± 2 mg; p-value, 0.005.The SNB group significantly had lower median resting pain scores at 6, 12, and 18 h: the control group, 1 (0–4.5), 3 (0–5), and 3 (2–5); the intervention group, 0 (0–0), 0 (0–3), and 1 (0–3); For patients susceptible to the adverse effects of NSAIDs, a low concentration of SNB and dexamethasone is an effective adjunctive technique for early postoperative pain control  following TKAs, without an increase in motor weakness.ClinicalTrials.gov, NCT03486548, Registered 3 April 2018. Total knee arthroplasty (TKA), one of the most common surgeries, causes moderate to severe postoperative pain. Multimodal analgesia is currently the standard treatment for acute postoperative pain control, and it aims to reduce the usage of opioids. The absence of opioid side effects promotes early ambulation, hastens postoperative recovery, decreases the incidence of postoperative complications, and improves patient satisfaction .A peripheral nerve block is a popular technique for acute postoperative pain control after TKA. The sensory nerves that supply the anterior side of the knee originate from branches of the femoral nerve, the lateral femoral cutaneous nerve, and the common peroneal nerve. In comparison, the posterior side of the knee is supplied by the popliteal nerve plexus, which derives from the tibial nerve, and branches of the obturator nerve , 3. WhilAt our institute, multimodal analgesia is currently utilized for postoperative pain control after TKA. Depending on the judgement of the attending anesthesiologist, the multimodal analgesia comprises a varying combination of spinal anesthesia, adductor canal block, periarticular infiltration, postoperative multimodal medication, and systemic nonsteroidal anti-inflammatory drugs (NSAIDs). The study by Gwam et al. reported an average pain score of 4.94 (range 0–9) for TKA patients whose postoperative pain was being managed with a combination of an adductor canal block and periarticular infiltration . MoreovePatients susceptible to the adverse effects of NSAIDs—such as patients with chronic kidney disease, coronary artery disease, gastric ulcer, a history of stroke, or advanced age—have a limited ability to use systemic NSAIDs postoperatively but can be safe for a local infiltration with NSAIDs has the local rather than systemic effect , 10. WitA sciatic nerve block (SNB) is considered to reduce posterior knee pain , 15. It The primary purpose of this study was to evaluate the benefit of overall postoperative pain control by adding a combination of a low concentration of popliteal-SNB and dexamethasone as an adjunctive technique for TKA in patients susceptible to the adverse effects of NSAIDs. In addition, it compared their effects with those of an adductor canal block (ACB) and periarticular infiltration analgesia (PIA) for such patients.ClinicalTrials.gov, NCT03486548, Registered 3 April 2018, https://clinicaltrials.gov/ct2/show/NCT03486548. The investigation was conducted on patients aged 50–85 years; had American Society of Anesthesiologists physical statuses of I–III; and were scheduled to undergo elective, unilateral, primary TKA at Siriraj Hospital May 2018–December 2019. The inclusion criteria were patients susceptible to the adverse effects of NSAIDs: history of chronic kidney disease (estimated glomerular filtration rate < 50 ml/min/1.73 m2), coronary artery disease, cerebrovascular disease, gastric ulcer, or an allergy to NSAIDs other than ketorolac. The exclusion criteria were a bodyweight of < 45 kg; allergy to bupivacaine, ketorolac, or dexamethasone; uncontrolled diabetes; contraindication to regional anesthesia; cognitive impairment; preexisting neuropathy; a neurological deficit in the lower extremities; and preexisting pain requiring the chronic use of oral morphine . Patients who declined to participate were also excluded.Prior to commencement, this single-center, prospective, double-blinded, randomized controlled trial was approved by the Siriraj Institutional Review Board (COA no. Si123/2018) and registered at n = 50) were randomized into an intervention group and a control group in blocks of four. This was achieved by using the sealed-envelope technique and computer-generated randomization lists sourced from an internet-based application (www.randomization.com). In the intervention group (n = 25), the patients received an SNB with an infusion of 0.125% bupivacaine (20 ml) and dexamethasone (5 mg). As to the control group (n = 25), the patients received only a subcutaneous injection of 1% xylocaine (1 ml) in the popliteal area without an SNB. The patients and assessors were blinded to the treatment allocations.The patients . Following standard anesthetic monitoring , the patients were sedated using intravenous fentanyl (25–50 mcg) and midazolam (0.5–1 mg) before being administered oxygen through a nasal cannula (3 L/min).For both groups, an anesthesiologist specializing in regional anesthesia performed an ultrasound-guided ACB in the popliteal area, using 15 ml of 0.33% bupivacaine. All patients were then placed in the lateral decubitus position. Both the control- and intervention-group patients were administered a subcutaneous local infiltration of 1% xylocaine (1 ml). However, the intervention-group patients subsequently also received an ultrasound-guided SNB ; for that procedure, a mix of 0.125% bupivacaine (20 ml) and dexamethasone (5 mg) was used.In the operating room, the patients received 2.0 ml of spinal anesthesia with isobaric bupivacaine and an intravenous propofol infusion (25 to 50 mcg/kg/min) to achieve a mild to moderate sedation. At the end of the operation, all patients received PIA with 0.25% bupivacaine (40 ml) and ketorolac (30 mg). During the first three postoperative days, the standard oral postoperative regimen was followed for all patients: paracetamol (1000 mg every 6 h), gabapentin (300 mg before bedtime), and intravenous morphine for pain, as needed (1 mg/hour).The primary outcome was the effects of using a combination of a low concentration of popliteal-SNB and dexamethasone as an adjunctive technique for TKA in patients susceptible to the adverse effects of NSAIDs on their pain scores during the first 24 postoperative hours. Postoperatively, the pain scores and motor function were determined by only one assessor, who was blinded to the group allocations. At 6, 12, 18, and 24 h after surgery, we assessed the postoperative pain scores at the anterior and posterior aspects of the knee while at rest and with motion (45 degrees of knee flexion). At the same times, the function of the tibialis anterior muscle was assessed and graded into 3 categories: 0 ; 1 ; and 2 = no strength to flex the ankle. Pain scores during physiotherapy were also recorded.Drawing upon data relating to adductor canal blocks and multimodal periarticular analgesia from work by Gwam et al. , a prospAll data were analyzed using IBM SPSS Statistics for Windows . The data were tested for normal distribution using histograms. Continuous data were presented as means and standard deviations (SD) or as medians and interquartile ranges (IQR), whereas categorical data were reported as numbers and percentages. A comparative analysis of the data of the 2 groups used the chi-squared test for group data, the unpaired t-test for continuous data with normal distribution, and the Mann–Whitney U test for continuous data with an abnormal distribution.In all, 63 patients who met the inclusion criteria were recruited. However, ten declined the invitation to join the study, while another three were not enrolled because of the unavailability of the researcher . No significant differences were found in the age and sex distributions, body mass indexes, estimated glomerular filtration rates, underlying diseases, preoperative pain scores, and surgical and tourniquet times of the 2 groups Table .Table 1Dp-values = 0.012, 0.021, and 0.010). The median (IQR) pain scores on movement at 6, 12, and 18 h were 3 (0–5.5), 5 (2.5–6.5), and 7 (4–9) for the control group, and 0 (0–1.5), 2 (0–4) and 3 (2–5) for the intervention group . The median (IQR) anterior-knee pain scores at 6, 12, and 18 h were 2 (0–4.5), 2 (0–4), and 3 (0.5–5) for the control group, and 0 (0–0), 0 (0–3), and 1 (0–3) for the intervention group .As to the postoperative pain scores of the groups Table , there wp-value = 0.038). There were also no significant differences in the motor function of the tibialis anterior muscle, the pain scores recorded during physiotherapy within 24 h and 48 h, nor the levels of patient satisfaction of the 2 groups.In contrast, a significant difference in the posterior pain scores was found only at the 12-h timepoint: the median (IQR) were 0 (0–2.5) and 0 (0–0) for the control and intervention groups, respectively . Nevertheless, there was no statistical difference in their hospital lengths of stay, with mean ± SD values of 132 ± 25 h and 128 ± 25 h for the control and intervention groups, respectively .The total morphine consumption of the 2 groups differed significantly during the first 24 h after the TKAs , as well as 24-h morphine consumption, were significantly lower in the SNB group compared to the control group. In the previous studies, SNB was an effective rescue block in patients with severe posterior knee pain , 19. HowAlthough we primarily hypothesized that pain would be alleviated in the SNB group due to the analgesia in the sciatic nerve distribution, mainly to reduce posterior knee pain. However, the median posterior knee pain score was reduced only at 12 h. One of the reasons would be our intention to use a low concentration of bupivacaine (0.125%) for SNBs to limit local anesthetic doses. With this concentration, the patients might not be able to characterize the specific area of pain, particularly if the pain was mild. Secondly, only 5 (20%) patients (1 in the SNB and 4 in the control group) reported moderate-severe posterior knee pain. Due to the small sample size, it might be challenging to demonstrate the statistical difference in posterior knee pain. The incidence of moderate-severe posterior knee pain in our study also correlates to the previous studies by Gi et al. and Kampitak et al. The authors reported that 10–30% of the patients underwent TKA with a femoral nerve block and PIA had posterior knee pain , 21. TheWe also added dexamethasone 5 mg to the SNB, while the control group patients did not receive dexamethasone. It has been well-demonstrated that dexamethasone is an effective adjunct to other multimodal analgesia techniques for postoperative pain control in TKA, regardless of the routes of administration , 22–24. Although the mean 24-h morphine consumption was statistically lower in the SNB group (1.96 ± 2 mg Vs. 3.80 ± 2.48 mg), the slight difference may have modest clinical effects. The overall morphine consumption in our study was relatively lower than that reported from the earlier studies in patients with TKA. The reason might be that the patient-controlled analgesia was not cooperated in our protocol for morphine administration. Additionally, in older studies, 24-h morphine consumption and pain score were relatively high because multimodal analgesia combined with ultrasound-guided peripheral nerve block technique had not yet been a standard of care , 25. AmoThe risks of bupivacaine toxicity when combining several blocks must be taken into account. We limited the total dose of bupivacaine for the peripheral nerve blocks not to exceed 1.7 mg/kg (75 mg for 45 kg patient). Also, 100 mg of PIA was a low range commonly used in other studies, 100–400 mg, due to minimal absorption at this injection site and was considered safe by several studies , 27, 28.There are some limitations to this study. First, this was a single-center study using a small sample size, which had led to limitations for the analysis of the difference in posterior knee pain. Secondly, we did not use patient-controlled analgesia for administering morphine postoperatively, therefore, it might underrepresent the 24-h morphine dose. Third, NSAIDs was still used in this study as a single dose of ketorolac in PIA. Only systemic NSAIDs was omitted. Finally, dexamethasone added into the SNB for an extended duration of analgesia may be a potential confounder for better pain control in the SNB group.For patients susceptible to the adverse effects of NSAIDs, adding a low concentration of SNB combined with dexamethasone is an effective adjunctive technique to ACB and PIA for acute postoperative pain control in TKA. It offers benefits in early postoperative pain control  without a significant motor blockade.


IntroductionThe prescription opioid epidemic and widespread use of narcotic medications have introduced new challenges when treating patients undergoing spine surgery. Given the ubiquity of preoperative opioid consumption amongst patients undergoing spine surgery, further research is needed to characterize perioperative risks. Our goal is to compare outcomes following primary lumbar decompression, instrumentation, and fusion based on preoperative opioid prescriptions.MethodsPatients older than 18 years of age who underwent a primary one- to two-level lumbar decompression, instrumentation, and fusion were included in the study. Patients with known malignancy, surgery involving three or more lumbar levels, current or previous use of neuromodulation, revision surgery, anterior or far lateral interbody fusions, acute fractures, or other concurrent procedures were excluded. Patients were divided into chronic opioid therapy , acute opioid therapy , and opiate-naïve groups. Opioid prescriptions, demographics, smoking status, readmission rates within one year, and reoperation rates within two years were recorded based on electronic medical record documentation.ResultsOut of 416 patients identified, 114 patients met the inclusion criteria. Thirty-eight patients (33.3%) were on COT, 38 patients (33.3%) were on AOT, and 38 patients (33.3%) were opioid naïve preoperatively. Readmission rates within one year for COT, AOT, and opioid naïve patients were 34.2%, 26.3%, and 10.5%, respectively (p=0.047). Reoperation rates within two years for COT, AOT, and opioid naïve patients were 34.2%, 15.8%, and 13.2%, respectively (p=0.049). We also found current or former smokers were more likely to be on AOT or COT than never smokers . ConclusionLong-term opiate use is associated with an increased risk for readmission within one year and revision within two years. Physicians should discuss the increased risks of readmission and revision surgery associated with lumbar decompression and fusion seen in patients on preoperative opioid therapy. In the United States, the widespread use of opioid medications has created significant challenges for clinicians and patients. According to the 2019 National Survey on Drug Use and Health, two million people were diagnosed with an opioid use disorder in 2018 [Over the past five years, multiple database studies have highlighted important associations between preoperative opioid use and surgical outcomes. Preoperative opioid use is associated with increased length of stay, increased 90-day readmission rates, implant-related complications, infection rates, pulmonary insufficiency, and increased healthcare-related costs -5. TheseNearly all previous studies rely on large databases to collect clinical and patient-reported outcomes. While this provides well-powered studies, limitations of a database study include reliance on administrative claims, coding methodology, and the inability to exclude patients who were prescribed opioids for unrelated problems ,6. The pAfter the Human Investigation Committee  of Loma Linda University approved this study (IRB#5190139), the authors performed a retrospective review of the medical records of all patients who underwent lumbar decompression and fusion at a tertiary referral center from 2013-2017. Inclusion criteria included patients older than 18 years of age who underwent a primary one- or two-level posterior decompression (laminectomy or laminotomy) with either posterolateral intertransverse arthrodesis (PLF), transforaminal lumbar interbody fusion (TLIF), or posterior lumbar interbody fusion (PLIF). Exclusion criteria included patients without at least two years of follow up, patients undergoing revision surgery, patients with known malignancy (neoplasm of the spine or other body sites), surgery involving three or more levels, patients with current or previous use of neuromodulation , patients who required iliac crest bone graft harvest during surgery, anterior (ALIF) or far lateral interbody fusions (DLIF), patients with acute fractures or patients undergoing other concurrent procedures.The definition of chronic opioid therapy (COT) varies significantly in the literature ,8. A 201VAS is a common, single-unit outcome measure for leg and back pain. The original description involves a 10 cm line with the numbers 0-10 associated with increasing pain scores from "no pain" to "unbearable pain". VAS scores were recorded for back and leg pain prior to surgery as well as between 6-12 months postoperatively. Data is presented as a "delta" VAS  with negative numbers associated with improvement in pain. Nicotine use was recorded as "current", "former", or "never" users based on smoking history documented in the electronic medical record (EMR). Any readmission or subsequent surgery was recorded along with the underlying reason as documented in the EMR.Categorical data was compared using chi-squared tests, and continuous variables were compared using analysis of variance (ANOVA) tests. Statistical analysis was conducted using SPSS 21.0 .Initial review of patient data yielded 416 patients who met inclusion criteria by undergoing a one to two-level posterior decompression, instrumentation, and fusion via PLF, TLIF, or PLIF between 2013 and 2017. Of the 416 patients, 297 were excluded because they were associated with revision surgery, fractures, malignancy, three or more levels, anterior or far lateral interbody fusions, and/or other concurrent procedures. Two patients in each group were lost to follow-up . The delta VAS scores for back pain for COT, AOT, and opioid naïve patients were -1.29, -2.18, and -1.68, respectively (p=0.171). Patients who were opioid naïve received significantly more leg pain relief following surgery, but there was no significant absolute difference in back pain.Given the known association between nicotine use and nociception, VAS scores were compared to nicotine use Table . The delAmongst never-smokers, the delta VAS scores for leg pain for COT, AOT, and opioid naïve patients were -4.56, -4.90, and -5.26, respectively (p=0.53). Amongst former smokers, delta VAS scores for leg pain for COT, AOT, and opioid naïve patients were -3.95, -4.73, and -6.57, respectively (p=0.032). Amongst current smokers, delta VAS scores for leg pain for COT, AOT, and opioid naïve patients were -3.67, -3.57, and -4.25, respectively (p=0.897). Only former smokers had a statistically significant decrease in delta VAS scores for leg pain.The readmission rate between opioid non-users, acute users, and chronic users was 10.5%, 26.3%, and 34.2%, respectively (p=0.047). Table The reasons for readmission directly related to spine surgery included infection  and/or need for further surgery . Other reasons for admission that were indirectly related to spine surgery included stroke  gastrointestinal bleed , symptomatic anemia , deep vein thrombosis , perianal abscess  and pneumonia .Causes for reoperation included infection , pseudarthrosis  adjacent segment disease  recurrent stenosis at another level  and/or implant migration .In the current study, the rate of readmission of opioid naïve, acute users, and chronic users was 10.5%, 26.3%, and 34.2%, respectively (p=0.047). The rate of reoperation between opioid naïve, acute users, and chronic users was 13.2%, 15.8%, and 34.2%, respectively (p=0.049). These findings are similar to those in recent studies, which also found a correlation between readmission or reoperation rate and history of opioid use [Increased readmission and reoperation rates ultimately lead to increased healthcare costs. In a prospective longitudinal registry study, Sivaganesan et al.  found thPreoperative opioid use was associated with less improvement in postoperative leg pain but no difference in postoperative back pain relief  9 and 10 coding definitions lack, such as individual levels of surgery, approach, radiographic parameters, changes in patient-reported outcome measures such as VAS scores, and surgical/anesthesia notes. Loss to follow-up bias could have potentially affected the internal validity of our results. However, we found a loss of follow-up of only two patients in each group after applying the inclusion and exclusion criteria. This led to a loss of follow-up of 5.3% in each group. Previous studies have demonstrated that <5% loss leads to little bias, while >20% poses a serious threat to validity .Chronic opioid use is associated with worse patient-reported outcome measures, increased risk for readmission within one year, and increased revision rate within two years following a primary posterior lumbar decompression, instrumentation, and fusion. Smokers are more likely to be chronic opioid users. Given the prevalence of opioid usage in the U.S. population, physicians should continue to educate acute and chronic opioid users about their increased risk of readmission and revision associated with lumbar decompression and fusion surgery.