Background: Paresthesia-based spinal cord stimulation (PB-SCS) is used for the treatment of complex regional pain syndrome (CRPS), but many patients are refractory to PB-SCS or experience attenuation of analgesic effect over time due to tolerance. Novel SCS modes including high-frequency, BurstTM, and high-density (HDTM) stimulation were introduced recently and this systematic review was conducted to summarize the evidence on their role for CRPS.Materials and Methods: We searched MEDLINE and other databases  for studies including adults with refractory CRPS treated by paresthesia-free SCS (PF-SCS) modes compared to placebo, conventional medical treatment, or PB-SCS. We determined the posttreatment intensity of pain (up to 24 months after intervention), changes in CRPS-associated symptoms, and associated domains. Sustainability and adverse effects were also assessed.Results: We identified 13 studies  including 62 patients with upper or lower limb CRPS. Eleven papers reported on outcomes of high-frequency stimulation at 10 kHz (HF-10) and other high frequencies, two papers were on Burst, and one paper was on HD. In 59 patients, pain intensity with novel SCS modes was reduced by 30% to 100% with a corresponding reduction in analgesic medications. Novel SCS modes also attenuated CRPS-associated symptoms and six papers reported significant improvement of quality of life.Conclusions: Novel SCS modes have the potential to provide analgesia in patients with CRPS. However, the low quality of available evidence necessitates definitive and prospective comparative effectiveness studies to establish the role of these modes in CRPS. The incidence of this syndrome is 5.46–26.2 per 100 000 person-years with a prevalence of 20.57 cases per 100 000 person-years.2 More women than men seem to be affected and the upper extremity is the most commonly involved body part.3 Though identifying this syndrome accurately can be a challenge, the criteria to diagnose CRPS were refined in 2007 to improve the specificity and reduce sensitivity.4 Several mechanisms seem to play a role in the development of CRPS, including inflammation, vasomotor dysfunction, central sensitization, neuroplasticity, and autoimmune involvement.5Complex regional pain syndrome (CRPS) is characterized by spontaneous and or evoked regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional but may not (CRPS type I) or may be (CRPS type II) in the distribution of a specific nerve territory or dermatome. CRPS usually has a predominance of abnormal sensory, motor, sudomotor, vasomotor, and trophic findings and it shows variable progression over time.7 Physical therapies should be the mainstay of treatment and these include desensitization, restoration of range of motion, and strength of muscles in the affected extremity. Interventional approaches include neural plexus and sympathetic chain blocks. However, failure to relieve pain and resolve associated symptoms of CRPS is common with these pharmacological and physical therapies.Though a variety of treatment modalities have been proposed for treatment of CRPS, a significant number of patients experience unsatisfactory pain relief and/or have adverse effects from existing pharmacological or neuromodulatory interventions. Pharmacological therapies include nonsteroidal anti-inflammatory drugs, corticosteroids, anticonvulsants, antidepressants, dimethylsulfoxide, N-acetylcysteine, transdermal patches , intravenous infusions of ketamine, and vasodilators.9 Paresthesia-based spinal cord stimulation (PB-SCS), with stimulating frequencies between 30 and 60 Hz that confer a tingling sensation, has been extensively used to treat CRPS over the last 2 decades but it suffers from limitations including attenuation of benefit with time and painful or unwanted paresthesias. The recent increase in availability and use of novel SCS modes promises to address these shortcomings.Neuromodulation approaches including spinal cord, dorsal root ganglia, and peripheral nerve stimulation have been used for chronic pain syndromes with traditionally neuropathic but more recently nociceptive pathologies, including failed back surgery syndrome, CRPS, and other neuropathic pain syndromes.TM), and BurstTM stimulation. It has been proposed these modes share the property of delivering higher amounts of electric charge to the spinal cord, or perhaps the same amount of charge with a higher efficacy, with frequencies in the range of 500 Hz to 10 kHz and stimulation amplitudes that are below the perception threshold.10 These “higher” stimulation frequencies potentially modulate  action potentials that contribute to painful sensations or sympathetic dysregulation but come with the advantage of being paresthesia free.11 It has been suggested that in patients with failure of conventional low-frequency PB-SCS to achieve analgesia, at the time of either SCS trial or loss of benefit with passage of time despite initial success, increasing the stimulation frequency or changing the stimulation pattern to deliver one of the novel SCS modes could confer analgesic benefit despite the absence of paresthesias.12There are three new stimulation modes currently in use: high-frequency stimulation at 10 kHz (HF-10), high-density .13Though the three novel SCS modes share the feature of not having paresthesias, there are some differences among these three modes due to unique combinations of frequency, subperception threshold amplitude, and pulse width. Clinically used high-frequency SCS is usually at a stimulation frequency of 10 kHz applied via bipolar stimulation but any stimulating frequency above 1 kHz has been considered as high.It is not surprising that there has been an increasing interest in the use of PF-SCS in patients with CRPS, a cohort that lacks access to effective analgesic options. There are now a number of recent publications and conference presentations on this topic. The objectives of this scoping review were to evaluate the analgesic impact and adverse effects of PF-SCS on patients with CRPS who had received these modes either as a primary neuromodulation treatment or when it was introduced following failure of PB-SCS.15 This review was registered with PROSPERO .This scoping review was conducted according to the recommendations of the Cochrane Collaboration and it is reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Appendix 1).www.clinicaltrials.gov). Papers in all languages were included when it was possible to translate them into English. Examples of specific search terms used include “spinal cord stimulation,” “neuromodulation,” “burst stimulation or neuromodulation,” “paresthesia-free stimulation,” “high frequency stimulation or neuromodulation,” “high density stimulation or neuromodulation,” “stimulation frequency above 500 kHz,” “complex regional pain syndrome (CRPS),” “algodystrophy,” “Südeck’s atrophy,” and “reflex sympathetic dystrophy.” Boolean operators  were used to combine search terms. The scope of studies included randomized controlled trials, systematic reviews, observational or cohort studies, case–control studies, case series/reports, and conference abstracts.We conducted comprehensive, serial searches of the literature from inception to September 21, 2017, with the assistance of a medical information specialist. The following databases were searched: EMBASE, 1947 onward; MEDLINE, 1946 onward; MEDLINE In-Process and Other Non-Indexed Citations ; and Cochrane Database of Systematic Reviews. PROSPERO and Cochrane Central Register of Controlled Trials were included to identify reviews or trials that may have been published but missed during the initial search on MEDLINE and EMBASE. We also searched Google Scholar (first 200 search results were reviewed) to complement search results from the aforementioned databases with the objective of accessing all content relevant to the topic. Proceedings of the major annual meetings of anesthesiology and pain societies  in the last 2 years were also searched. We also searched for trials in the metaregister of controlled trials , refractive to conventional medical management and or conventional PB-SCS.Intervention: The interventions of interest were the novel SCS modes, including Burst, high-frequency (HF-10), and HD stimulation.Comparator: Comparators included placebo treatment or conventional medical management or conventional PB-SCS.Outcome: Our primary outcome was change in intensity of pain assessed on a numeric rating scale (NRS) or visual analogue scale (VAS) at 1 to 12 months after initiation of the intervention. Secondary outcomes of interest included change in CRPS-associated vasomotor, sudomotor, and trophic symptoms and impact of SCS on pain-associated domains . Sustainability of analgesic benefit and adverse effects were also noted.We prespecified eligibility criteria using the population, intervention, comparator, and outcomes model as follows:Titles, abstracts, and, when required, full text of the papers identified from the initial search were examined for relevance as per the inclusion criteria for this review. Only studies that met the abovementioned criteria were included for data extraction. We completed the search by reviewing the bibliographies of every selected article to look for possible additional articles that were not identified by the initial search.The reference data, populations, and outcomes were extracted from the articles into prespecified tables using a standardized data extraction form. The data collection form was pilot-tested before its use. We extracted information on studies’ source (study ID and reviewer ID), number of patients, type of study, patient characteristics, details of intervention, comparator group where reported, previous treatments, follow-up time points, outcomes, and adverse effects of the intervention. Dichotomous outcomes were extracted where indicated. For continuous data, extraction of means (or medians) and standard deviations (or interquartile ranges or ranges) was performed. We also contacted authors of studies included in our scoping review when we needed more information about their analysis or reported results.Data were independently extracted by two reviewers (Y.H. and M.C.) and any conflicts were resolved by consensus and inputs from the senior author (A.B.).High: Any trial with a high risk of bias listed on three or more domains.Unclear: Any trial with a high risk of bias listed on more than one domain but less than three domains.Low: Any trial with a high risk of bias on no domain or one domain and with no significant methodologic concerns that may have affected the study results.Two review authors (Y.H. and A.B.) independently assessed the risk of bias for randomized controlled trials using the Cochrane Collaboration’s instrument for assessing the risk of bias. Any disagreement was resolved through discussion or, if necessary, arbitration by the senior author (A.B.). The risk of bias instrument assesses the following domains: generation of the allocation sequence, allocation concealment, blinding of investigators and participants, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias that have less empirical evidence of bias but together may be considered important . Each item was classified as low, unclear, or high risk of bias. A decision to classify “overall bias” as low, unclear, or high was made by the reviewers using the following method:16 This tool has 18 items with three response choices to each question: Yes, unclear/partially reported, or no.The quality of the case series was assessed using the quality appraisal tool developed by Moga et al.Our synthesis of clinical studies was anticipated to focus on results from randomized controlled trials followed by prospective trials or case series or reports. Limited scope for meta-analysis was anticipated due to the limited number, clinical heterogeneity, methodological diversity, and paucity of clinical trials.Our initial search revealed a total of 2099 records. We found another three articles while perusing references from articles that were short-listed and 15 records were found in the clinical trial registries. Details of the search strategy for high-frequency SCS for treatment of CRPS are provided in Appendix 2. Similar methodology was followed for searches for role of Burst and HD SCS in CRPS.21 five conference abstracts,26 and one randomized controlled trial (RCT27)   and 2.1027The results for assessment of the quality of case series included in this review are listed in Appendix 3. Overall, the quality of the case series was moderate with the number of “yes” responses suggesting adherence to quality metrics (maximum possible score is 18) varying from 10 to 13 in the three studies. The overall risk of bias was deemed to be low for the single RCT in this review.13 Use of the IASP Budapest criteria to diagnose CRPS4 was stated only in two papers.23 Twenty-three patients had CRPS in the upper limbs and 39 patients had CRPS in the lower limbs. One publication did not provide details about the location of CRPS but positioning of the SCS leads suggested that patients had CRPS in the lower limbs.13 The duration of CRPS prior to interventions ranged from 5 months to 16 years but this information was not provided in four papers.26The selected papers included a total of 62 patients with CRPS, of whom the majority were females. The age range of patients was between 30 to 75 years and pain intensity in all patients was severe with NRS of 6/10 (or VAS of 60/100) or higher. A diagnosis of CRPS with details of the affected anatomy was provided in all papers except one.27 two described use of Burst SCS mode,27 one described use of HD SCS mode,13 and three studies described use of high-frequency stimulation in the 500 to 10 000 Hz range.27 The pulse width of HF-10 SCS waves was provided in only one study22 (30 ms) and another study on SCS at 1.15 kHz reported the pulse width as 120 ms.20 Of the only two studies on high-frequency SCS up to 10 kHz that reported on the stimulation amplitude, the amplitude range was 0.5–3.5 mA12 and 0.5–10 V19 and the study with SCS at 1.15 kHz reported the amplitude as 5.0 V.20 The two studies on Burst SCS described use of similar parameters: pulse frequency of 500 Hz with a burst frequency of 40 Hz, amplitude of 0.225 mA, and pulse width of 1000 ms.27 The solitary paper on use of HD SCS in patients with CRPS reported use of a frequency range between 130 and 1000 Hz (median 409 Hz), amplitude of 2.4 V, and pulse width ranging from 150 to 1000 ms.13A majority (ten) of these studies involved use of HF-10 SCS therapy,26CRPS is a challenging condition to treat and it is not unusual for a variety of therapeutic modalities to be trialed before an effective option is found. Out of the 62 patients in this review, 15 patients had failed treatment with a multitude of approaches prior to use of PF-SCS. These previous therapies included conventional medical management , peripheral nerve and lumbar sympathetic blocks or radiofrequency lesioning, topical treatments, physiotherapy, transcutaneous electrical nerve stimulation (TENS), cognitive behavioral therapy (CBT), and PB-SCS.26 Though details were not provided, gradual development of tolerance to PB-SCS with increase in intensity of pain after several years of pain relief and/or patients’ dislike of paresthesias (or paresthesias in nonpainful body regions) associated with PB-SCS were the common themes that instigated trials of PF-SCS. Two studies reported failure of PB-SCS during the trial phase.24 Only one RCT conducted a direct comparison of multiple SCS modes: 500 Hz, 1200 Hz, Burst, conventional, and placebo.27 All five modes were programmed in random order during the 10-week crossover period with 2 weeks per setting in this study.A total of eight patients in four reports were previously treated with conventional PB-SCS with analgesic benefit for up to 4 years.26 Burst,27 and other high-frequency SCS modes.27 In the 39 patients with CRPS of the lower limb, stimulating contacts were placed at the eighth to twelfth thoracic vertebral (T8–T12) levels for HF-10,27 HD,13 other high frequencies,27 and Burst SCS modes.27 Only two papers described checking for paresthesias in the region of pain by stimulation to aid radiological guidance for positioning the lead for HF-1012 or Burst and other high-frequency SCS therapies.27 In one study, the authors did not specify the level of SCS lead contacts but stated that “optimal positioning with overlapping paresthesia in painful area” were achieved for Burst SCS (p. 3).18In the 23 patients with documented CRPS of the upper limb, the stimulating contacts of SCS leads were at the second to seventh cervical vertebral (C2–C7) levels for HF-10,25 and another study that used 1.15 kHz for SCS mentioned that the patient had a pre-existing implanted paddle lead.20Details of the type of SCS trial (percutaneous versus tunneled) were not provided in majority of the studies included in this review. Only two papers mentioned that a trial with HF-10 mode was done percutaneously26 or Burst and other high frequencies.27 However, three of the papers in this review did not provide any details about the type or number of leads.19The majority of studies included in this review described the type and number of leads used for delivering PF-SCS. Octopolar cylindrical leads (one or two) were used in 55 patients for HF-1021 high-frequency SCS at 1.15 kHz,20 and Burst and other high-frequency SCS27 and the duration of follow-up was up to 12 months in four publications involving HD13 or HF-10.26 In one study on two patients, HF-10 SCS was delivered for only half a day as part of a trial process.19 Eight patients in three papers included in this review were followed beyond 12 months with Burst18 and HF-10 SCS.25The extent of follow-up had a wide variation in papers included in this review, with a range of less than a day to 24 months. Six of the 13 papers including 41 patients published results of follow-up up to 6 months after initiation of HF-10 SCS,17 used the NRS or VAS to measure intensity of pain and the reduction in intensity of pain ranged from 30% to 100%. Of the 62 patients treated with the novel SCS modes, three failed to get analgesic benefit from the 10-kHz HF-SCS. Of note, these three patients had CRPS involving the feet and they also failed an additional week of conventional PB-SCS despite adequate paresthesia coverage of the affected area.12 None of the 13 papers reported worsening of intensity or symptoms of CRPS with the novel SCS modes.All of the papers included in this review except one27 Al-Kaisy and colleagues used the painDETECT12 as a screening tool to establish whether pain was neuropathic in nature. All six patients with CRPS in this study had high painDETECT scores but the authors did not attempt to correlate these scores with success or failure of HF-SCS. A study by Kriek and colleagues described use of the McGill Pain Questionnaire (MPQ).27 The authors described significant reduction in scores on the sensory scale of the MPQ following therapy with all stimulation modes in the trial  but not with placebo.Characteristics of pain prior to initiation of SCS was assessed in only two studies with the aid of validated tools.26 or Burst SCS18 with reversal to normal or a halt in progression of these features. None of the studies included in this review mentioned the effect of the novel SCS modes on trophic symptoms and signs of CRPS. The impact of these modes on range of motion ranged from “no worsening” in one report18 to an overall improvement26 and one case report in which the patient was able to resume pre-injury activities.25The impact of PF-SCS on vasomotor and sudomotor symptoms was described in five papers involving use of HF-1025 Santarelli and colleagues used the Short Form 36 (SF-36) for this domain with use of HF-10 SCS and they reported significant improvement.23 Two other publications commented on improvement in quality of life with high frequency (1.15 kHz) and HF-10 SCS without specifying which tool was used.21 The severity of pain and the impact on patient’s daily functioning was also investigated with the use of the Brief Pain Inventory (BPI) in one paper with an improvement (reduction) of 45% in the BPI score in all three patients who responded to HF-10 SCS.12The impact of the novel SCS modes on quality of life, measured with the EuroQol–five dimensions (EQ-5D) score in two reports that had four patients in total, ranged from an improvement of 101% at 6 months to 341% improvement at 18 months with HF-10 mode.26 Burst,18 or high-frequency (1.15 kHz) SCS.20Nine of the 13 studies included in this review commented on impact of PF-SCS on analgesic medications. All patients with analgesic benefit from HF-10 SCS were able to lower their daily use of anticonvulsants and opioids, with some patients reporting complete discontinuation of all analgesics with HF-10,23 and one study assessed anxiety subjectively.21 All three papers involved use of HF-10 SCS and reported significant reduction in PCS and CES-D scores and anxiety. Furthermore, only one study commented on improvement of sleep quality with high-frequency (1.15 kHz) SCS but the authors did not use a validated tool to evaluate this domain.20Only two studies reported use of validated tools to measure pain-related catastrophization and depression 27We found only one RCT that compared patients’ preferences about the type of stimulation for CRPS. Four types of stimulation  were compared with placebo in this trial. Fifty-two percent of the study patients preferred nonparesthesia SCS . Though VAS pain scores were lower with preferred stimulation type in responders, all nonparesthesia SCS settings had higher global perceived effect (GPE) scores than placebo.27 Inability to feel paresthesias was identified as a limitation of the novel SCS modes by some patients in this trial. High-frequency SCS (but not Burst) consumes large amounts of energy and it often requires a rechargeable battery with frequent charging and longer duration of charging times compared to conventional PB-SCS. This lack of “recharge burden” with conventional PB-SCS was another reason for some patients preferring this mode in this trial.27The adverse effects profile of the novel SCS modes appeared to be similar to conventional PB-SCS and no adverse effects on the central or peripheral nervous system were reported in the publications included in this review. However, Kriek and colleagues identified factors that played a role in patients choosing the type of SCS when they were given an option to trial SCS at 40 Hz, 500 Hz, or 1200 Hz or using Burst stimulation.13 Burst,18 high frequency at 1.15 kHz,20 and HF-1026 settings, with the authors reporting some degree of restoration of analgesic benefit to the patients. We also found one publication in which it was reported that a patient was reprogrammed to HF-10 SCS after a negative conventional SCS-based trial. This patient responded with complete relief of pain, improved range of motion, and resolution of vasomotor and sudomotor changes with a reduction in analgesic requirement after initiation of HF-10 SCS.21Loss of analgesic effect in patients who previously responded to conventional PB-SCS can have several reasons, including dislocation or malfunction of hardware or development of tolerance. In this review, we came across reports of six patients in four publications who stopped having analgesic benefit with conventional SCS after initial success and despite no lead migration. These patients were reprogrammed with novel SCS modes including HD,This scoping review of the literature on the role of the novel modes of SCS for patients with CRPS is the first of its kind to evaluate evidence for high-frequency, HF-10, Burst, and HD stimulation for this syndrome. Twelve case series or reports and one RCT reported on the use of the novel SCS modes, with failure of conventional PB-SCS being the most common indication for use of these modes. Outcomes were monitored for variable periods of time following initiation of the novel modes.8 Conventional SCS is tonic or paresthesia based and its frequency of stimulation ranges between 30 and 80 Hz with patients perceiving nonpainful paresthesias in lieu of otherwise painful sensations. PB-SCS has been shown to deliver good outcomes for some patients with CRPS but many patients have no or unsatisfactory pain relief with this type of SCS or they cannot tolerate the paresthesias. Another therapeutic challenge with conventional SCS is the development of tolerance, leading to diminishing analgesic effect.28 These limitations have spurred the search for innovations in neuromodulation for treating CRPS. Though not a novel stimulation mode, an excellent example of these efforts is the recently published RCT on stimulation of the dorsal root ganglia  to treat CRPS.29 However, this modality relies on a specific anatomic target while using conventional frequencies and subthreshold amplitudes for stimulation.Though a variety of therapeutic modalities are used to treat CRPS, SCS is one of the few modalities with a high rate of analgesic success for this syndrome.11 Evidence for this SCS mode suggests suppression of mechanical hypersensitivity similar to PB-SCS, while requiring significantly lower intensity of stimulation intensity.32 The mechanism of action of Burst is also unclear, but proposed explanations include modulation of the medial pain pathway directly by actions on C-fibers synapsing onto lamina I neurons and disruption of synchronous burst firing of the high-threshold fibers that results in inhibition of activation directly related to pain perception.10 This is an interesting theory because conventional SCS exerts its effect at the level of the spinal cord and it predominantly modulates the lateral pain pathways.33 HD SCS is delivered by increasing the frequency while retaining pulse width of 300–500 ms and keeping the amplitude below the perception threshold. This mode is postulated to transmit higher amounts of electric charge from the SCS electrodes to the neural tissue, thereby increasing analgesic efficacy, without discomfort or damage to the nervous system.13None of the novel SCS modes are associated with paresthesias, but the postulated mechanisms of action vary for each mode. A majority of papers (11 out of 13) included in our review described the use of high-frequency SCS, an entity that lacks a consensus definition, but any mode with a frequency above 1 kHz is generally accepted in this classification.34 Thus, eliminating reliance on paresthesias can save time and reduce patient discomfort while avoiding the need to adjust stimulation intensity with change in position of the patient.35 Use of novel SCS modes also avoids problems due to paresthesias in the painful region or unwanted paresthesias in the nonpainful body locations. These advantages can shorten SCS trial and implantation procedure times. However, this approach requires definitive knowledge of epidural levels of SCS lead placement for pain in specific body regions that provide relief in CRPS. Though the space between the ninth and tenth thoracic vertebra is accepted as the appropriate level for HF-SCS to relieve low back pain, there is a lack of information regarding appropriate levels to relieve pain in the limbs (as is often the presentation in CRPS), especially in the lower limbs.36 This may explain the finding that all three patients with CRPS of the feet failed to get any benefit from HF-10 SCS in one of the studies included in our review.12 Pending availability of more information regarding “sweet spots” for placing SCS leads to treat CRPS in the limbs, it may be reasonable to check for paresthesias in the region of pain when placing SCS leads with the goal of delivering SCS with one of the novel modes , an approach that was utilized in the RCT by Kriek and colleagues included in this review.27 The recently published Effects of Pulse Rate on Clinical Outcomes (PROCO) study has contributed to knowledge regarding optimal lead placement and stimulation frequency for high-frequency modes. This study recruited patients with low back pain (with or without lower limb pain) who were implanted with SCS systems and underwent an 8-week search to identify the best location (sweet spot) of stimulation at 10 kHz within the searched region (T8–T11). Patients who responded to 10-kHz SCS proceeded to double-blind rate randomization to 1-, 4-, 7-, and 10-kHz SCS at the same sweet spot found for 10 kHz in randomized order (4 weeks at each frequency). The authors found that all four frequencies provided equivalent pain and the mean charge per second differed across frequencies, with 1-kHz SCS requiring 60%–70% less charge than higher frequencies.37 However, the authors did not specify whether patients with CRPS were enrolled in this study. In another study by Al-Kaisy and colleagues, 24 subjects with predominantly axial low back pain undergoing SCS therapy for failed back surgery syndrome were randomized to sham, 1200 Hz, 3030 Hz, and 5882 Hz with a four-phase crossover design over 12 weeks.38 The authors found that SCS at 5882 Hz stimulation produced significant pain relief for axial low back pain compared with lower frequencies and sham stimulation.38 Results from these studies suggest the need for more research into optimal “high” frequency for analgesia, especially in patients with CRPS.Relying on paresthesias to decide on optimal lead positioning in the epidural space and maintaining paresthesias at the location of pain can be challenging and frustrating for patients and health care providers. It requires time and cooperation from a patient who may be quasisedated during the SCS lead placement procedure.24 However, in the RCT included in this review,27 patients were sequentially transitioned from one stimulation mode to another. Though a short washout period (2 days) was provided between application of different SCS modes in this study, a therapeutic bias is possible because the analgesic effects of novel SCS modes could be influenced by previous effects of conventional SCS due to a carryover effect. The same bias could have affected results of two case reports in this review in which HF-10 SCS modes were introduced after failure of conventional SCS, although the follow-up periods exceeded 4 months with preservation of the good results, thereby minimizing the influence of carryover effects.24 Finally, lack of blinding of patients in these papers to the introduction of novel SCS modes after failure of conventional SCS may have influenced reporting of outcomes by patients.This review shows that patients who are unresponsive to conventional PB-SCS, or those who develop tolerance to it over time, can attain therapeutic benefit by switching to the novel SCS modes.23 Further, though CRPS type II is a neuropathic pain syndrome, CRPS type I does not meet the most recent IASP definition of neuropathic pain due to the absence of an identifiable nerve injury.39 However, both types of CRPS have a phenotype that is similar to the presentation of neuropathic pain syndromes. Using validated tools to establish that the pain is neuropathic  and then serial follow-ups with appropriate tools  to establish whether there is resolution of neuropathic character of the pain with use of novel SCS modes can help build confidence in the ability of these modes to relieve pain in patients with CRPS. Finally, though CRPS has abnormal sensory, sudomotor, vasomotor, trophic, and motor features, the majority of papers in our systematic review only focused on the effect of stimulation on pain and sensory changes. Because all components of CRPS contribute to morbidity, effects of therapies on all domains should be evaluated. Only five papers in this review mentioned the effect of novel SCS modes on nonsensory domains of CRPS.26Though the Budapest diagnostic criteria for CRPS were accepted by the IASP over 5 years ago, these criteria were used in only two of the papers in this review.40 SCS is a resource-intensive intervention and comprehensive evaluation of outcomes to establish its impact in CRPS is essential. Recently published studies have also cast doubts on the assumption that benefit from high-frequency SCS is enhanced proportional to the frequency of stimulation.37 Thus, multidomain monitoring of features of CRPS and estimation of cost–benefit ratios are essential for establishing efficacy and effectiveness of novel SCS modes.A majority of the papers included in this review did not describe use of validated tools to evaluate psychological  and physical function. This is surprising because the importance of evaluating pain-related domains in clinical and research settings is established and validated tools to evaluate these domains are also widely available.11 However, HF-10 and HD potentially deliver electrical charge of a higher magnitude or with a higher efficacy to the spinal cord10 and require frequent recharging of the implanted pulse generator. These modes are also fairly new to clinical practice and their long-term adverse effects, if any, are unknown.None of the papers included in this review reported any serious adverse effects or safety issues when novel SCS modes were used in patients with CRPS. Animal and clinical studies have been published on the possible adverse effects of HF-10 on the spinal cord and these studies report a safety profile similar to that of conventional SCS.We have provided recommendations for data elements to be included in studies on novel SCS modes for patients with CRPS in 21 and five conference abstracts.26 Case series or reports occupies a low rung in the hierarchy for evidence-based medicine because observational data are prone to various types of biases, including expectation, measurement, and reporting biases.41 Further, abstracts are often not considered to be peer reviewed. A case in point is the absence of papers in the literature that report failure of novel SCS modes in CRPS. The wide range of follow-up periods in papers included in this review also makes it difficult to gauge the longevity of benefit from these modes. One of the case series included in this review had an observation period of only half a day following initiation of the novel SCS modes but the authors acknowledged that their study was not designed to test the long-term effect of such therapy. We agree with the authors reasoning about the observation that patients experienced benefit with high-frequency stimulation suggests a strong effect of high-frequency SCS therapy. Only 30% of patients included in this review were followed beyond 6 months following initiation of novel SCS modes and a few papers reported outcomes at 12 months or beyond following initiation of these modes.25 Follow-up for a year and beyond is usually required to assess longevity of analgesic effects, as well as the effect of novel SCS modes on other CRPS symptoms and the possible long-term adverse effects and failure resulting in explantation of the system.There are some limitations of our review. Although we conducted a comprehensive search of literature, only 13 papers on novel SCS modes for CRPS with a total of 62 patients were identified. The quality of evidence supporting use of these modes was modest and the papers included in this review were seven case reports or seriesIn our scoping review, we found papers that reported benefit from HF-10, Burst, and HD SCS modes in patients with CRPS. However, the low quality of this evidence precludes any definitive conclusions as to whether these novel SCS modes provide better therapeutic efficacy over the long term compared to conventional paresthesia-based modes in patients with CRPS. Rigorous head-to-head comparisons of the novel SCS modes against each other and against conventional paresthesia-based modes in patients with a diagnosis of CRPS established as per IASP criteria are required. Evaluation of all pain-related domains over a period of time (at least one year) in these trials is essential to build a high-quality pool of evidence for the role of novel SCS modes in SCS.Click here for additional data file.


Background: Propofol injection pain, despite various interventions, still occurs during the anesthesia induction and causes intense discomfort and anxiety in patients. This study aimed to explore the effect of intravenous dexmedetomidine on propofol injection pain prior to anesthesia induction with propofol at 4°C.Methods: A total of 251 patients (American Society of Anesthesiologists I–II) who underwent oral and maxillofacial surgery were randomly assigned to a combination group (n = 63), lidocaine group (n = 62), dexmedetomidine group (n = 63), and placebo-control group (n = 63); they received 0.5 ug/kg dexmedetomidine prior to anesthesia induction with propofol at 4°C, 40 mg lidocaine, 0.5 ug/kg dexmedetomidine prior to anesthesia induction, and normal saline, respectively. Incidence of pain, pain intensity, and reaction to the pain stimulus were evaluated by using verbal categorial scoring (VCS), a numerical rating scale (NRS), and the Surgical Pleth Index (SPI), respectively. In addition, hemodynamic parameters such as heart rate (HR) and mean arterial pressure (MAP) were also measured. The VCS and NRS were evaluated at 5 s after propofol injection. In addition, SPI, HR, and MAP were evaluated at three time points (before anesthesia induction and 5 and 30 s after propofol injection).Results: The incidence of pain in the combination group (51%) was significantly lower than that in the lidocaine group (71%), dexmedetomidine group (67%), or placebo-control group (94%) (p < 0.001). VCS and NRS scores in the combination group were also lower compared with the other three groups (p < 0.001), with no statistically significant differences between the lidocaine group and dexmedetomidine group (p > 0.05). The SPI of the combination group decreased significantly in comparison with the other three groups at 5 s after propofol injection  and 30 s after propofol injection . Further comparisons between HR and MAP revealed no significant differences across the groups (p > 0.05).Conclusion: Because of the sedative nature of dexmedetomidine and analgesic effect of low temperature, this study showed that intravenous dexmedetomidine prior to anesthesia induction with propofol at 4°C is highly effective in attenuating the incidence and severity of pain during injection compared with lidocaine (40 mg), dexmedetomidine 0.5 ug/kg) and placebo. This approach was not associated with any anesthesia complications.Clinical Trial Registration:ClinicalTrials.gov, identifier: ChiCTR-2000034663 Propofol, a common intravenous anesthetic, is extensively used in induction, sedation, and maintenance of general anesthesia because of its rapid onset and quick patient recovery , 2. HoweSeveral factors account for propofol injection pain. For instance, increasing evidence has demonstrated that the lipid solvent irritates the vein intima and activates a local kallikrein-kinin cascade by releasing bradykinin and inflammatory factors , 9, and Multiple strategies such as pharmacological and non-pharmacological therapy have proved to be efficacious in attenuating injection pain. In addition, drugs including lidocaine, ketamine, magnesium sulfate, and triglycerides are commonly used as pain relievers during propofol injection , 11, 12.Compared to lidocaine used alone, combination therapy is recommended in clinical situations . Therefohttp://www.chictr.org.cn. Number ChiCTR-2000034663).This study was designed as a double-blinded, randomized, and placebo-controlled clinical trial and all patients underwent oral and maxillofacial surgery at the Affiliated Stomatological Hospital of Sun Yat-sen University. The objectives and procedures of this study and adverse effects were explained completely, and all patients signed the written informed consent after a preoperative interview with an anesthetist. This clinical trial was conducted in accordance with the Declaration of Helsinki and obtained approval by the Ethics and Research Committee of the Affiliated Stomatological Hospital of Sun Yat-sen University, Guangzhou, China [Number (2018)3-105]. This trial was registered at the Chinese clinical trial registry  were eventually enrolled in the four groups through random allocation .Using a computer-generated randomization table, patients were randomly assigned into “Dex- (0.5 ug/kg) plus propofol at 4°C group (combination group),” “lidocaine group (40 mg),” “Dex- (0.5 ug/kg),” and “placebo-control group” according to a 1:1:1 ratio. A random allocation sequence of 251 consecutive and numbered envelopes, representing different group assignments, were directly delivered to an anesthetic nurse. Throughout the period of study and data collection, the principal investigator and participants remained unaware of each group assignment, while two anesthetic nurses and anesthetists were also blinded to participants' group assignment. the group assignments were announced only after finishing data analysis.Demographic data including age, gender, American Society of Anesthesiologists (ASA) physical status, weight, and height were recorded for all patients in the 30 min before they entered the operating room. After entering the operating room, patients received standard monitoring of the electrocardiograph, non-invasive blood pressure, and pulse oximetry. Hemodynamic indexes, including mean arterial pressure (MAP) and heart rate (HR), were recorded when patients remained silent. After that, an 18G cannula was inserted into a large vein on the dorsum of the non-dominant hand 20 min before anesthesia induction, and an infusion of lactated Ringer′s solution (5 ml/kg/h) was applied to maintain its patency.Prior to anesthesia induction, Dex-  was dissolved in a 50-ml syringe and the combination group was injected of 0.5 ug/kg DEX- for about 5 min, 40 mg lidocaine was dissolved in a 10-ml syringe and gently injected in 3 min in the lidocaine group, and patients in the placebo-control group were informed of being injected with an analgesic and received an equivalent volume of normal saline. Injections of Dex-, lidocaine, and normal saline were all undertaken via a three-way connector. Then, 6 L/min of pre-oxygenation was administered to patients with a mask, after which the principal anesthetist informed the anesthetic nurse to start anesthesia induction. During anesthesia induction, the combination group received propofol refrigerated at 4°C, and another three groups received propofol at room temperature. Because propofol injection (0.5 mg/kg) is a targeted dose, it should be injected within 30 s. However, it is worth noting that injection of 4°C propofol must be close to the puncture point of the intravenous infusion to avoid increasing its temperature. Therefore, another three-way connector close to the intravenous site was used to inject 4°C propofol.In this experiment, primary outcomes included data collection on the pain scale of VCS, NRS, and SPI, and MAP and HR were recorded as secondary outcomes. Two anesthetic nurses assessed the intensity of propofol injection pain in about 5–10 s by using VCS and NRS. VCS is a 4-point pain scale: 0–no pain, 1–mild pain with no behavioral sign, 2–moderate pain accompanied by a behavioral sign, and 3–severe pain with a strong vocal response accompanied by facial grimacing, arm withdrawal, or crying . PatientBased on findings from a previous study in which 64% of patients experienced propofol injection pain , it was 2-test and one-way ANOVA test across the groups. Because the VCS scores were not normally distributed, we used the Kruskal-Wallis test to compare VCS, whereas the Mann-Whitney U-test was used for multiple comparisons between different groups. Comparisons of the incidence of pain between groups were determined by the χ2-test or Fisher's exact test. Repeated measures ANOVA was used to compare hemodynamic parameters  between different groups and the three time points. A comparison of the two groups was made by Bonferroni correction where necessary. A p < 0.05 was considered statistically significant.All data were analyzed using SPSS 20.0 for Windows . Demographic and clinical characteristics were expressed as means ± standard deviation (continuous variables) or frequency  and analyzed by the χp > 0.05).Demographic characteristics and clinical baseline data are summarized in p < 0.001) (p < 0.001). Additionally, no significant differences in mild pain were found among the groups. However, the incidence of moderate pain in the placebo-control group (40%) was significantly higher compared to the other three groups (p < 0.001). Further, severe injection pain occurred in only three patients in the placebo-control group.The total incidence of propofol injection pain in the combination group (51%) was significantly lower than in the lidocaine group (71%), Dex- group (67%), or control group (94%) (< 0.001) . AccordiH = 44.90, p < 0.001), Also, the NRS scores had statistically significant differences among the four groups . Meanwhile, it was obvious that scores of VCS and NRS in the combination group were also lower compared with the other three groups (p < 0.05). In other words, the combination group was superior to the other three groups with respect to pain reduction. Through ANOVA, SPI showed a significant difference among groups in 5 s after propofol injection  and 30 s after propofol injection . Primary outcomes in the combination group were significantly different from those in the other three groups, whereas the lidocaine group and Dex- group showed a significant difference compared with the placebo-control group.By comparing the pain scores of VCS, NRS, and SPI between groups , we founF = 186.28, p < 0.001), . Further, comparisons between HR and MAP showed no significant difference among the four groups , , and interaction by times and groups was also showed no significant difference , .Comparisons of the hemodynamic parameters  among the four groups are presented in We designed a randomized, double-blind study to explore the efficacy of 0.5 ug/kg Dex- given prior to anesthesia induction with propofol at 4°C to attenuate injection pain in patients under general anesthesia. According to the findings, it was evident that 0.5 ug/kg Dex- pre-administration plus 4°C propofol had a favorable effect in alleviating propofol injection pain compared to lidocaine (40 mg) and Dex-(0.5 ug/kg). In addition, the difference between HR and MAP was not statistically significant among the four groups, and no anesthesia-induced complications such as anaphylaxis, hypotension, and bradycardia occurred during surgery.Prevention of propofol injection pain deserves more attention, especially because of the discomfort experienced during anesthesia induction, and the mechanism of propofol injection pain should be elucidated. It is well-recognized that propofol is an excellent anesthetic that has a phenol group, and resultant pain can occur immediately or be delayed after propofol injection. However, propofol can directly irritate the afferent nerve endings within the mucous membranes and venous intima and cause immediate pain. Additionally, delayed pain arises when the kallikrein-kinin systems are activated by propofol molecules, generating bradykinin and inducing local vasodilation and hyperpermeability . ConsequBecause of its local anesthetic effects on the venous intima by inhibiting sodium-specific ion channels and stabilizing the kinin cascade , lidocaiDex- may have a great impact on pain relief because of its significant sedative action. Dex-, as a highly potent alpha-2 adrenoreceptor agonist, has been proved to exert significant analgesic effects by raising the pain threshold and is also widely used in the sedation of critical patients on the basis of its sedative and anti-anxiety properties. The analgesic effect of Dex- could be achieved with a high dose of 1 ug/kg over 10 min ; howeverRR = 0.82, 95% CI:0.64–1.04)  . TherefoThere are some limitations to our study. First, we did not use a high dose of Dex-, such as 0.75 or 1 ug/kg, so it is not clear whether the effects of a high dose of dexmedetomidine could significantly reduce pain. Second, patients were not followed up for potential adverse effects after discharge of operation room. Finally, because patients in the lidocaine group did not use a tourniquet for venous occlusion, the contact between lidocaine and venous intima was not efficient. This explains why pain alleviation in the lidocaine group was inferior to that of the combination group.In summary, considering the sedative nature of Dex- and the analgesic effect of low temperature, this double-blind, randomized, placebo-controlled trial demonstrated that intravenous Dex- prior to anesthesia induction with propofol at 4°C can effectively attenuate propofol injection pain compared with lidocaine (40 mg), Dex- (0.5 ug/kg), and placebo. It is worth noting that no significant adverse events arose during the intervention process.https://pan.baidu.com/s/1_tLnhB22hZVe4XbDPlHQSA~Code:7jrm&lt.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: The studies involving human participants were reviewed and approved by Ethics and Research Committee of the Affiliated Stomatological Hospital of Sun Yat-sen University, Guangzhou, China. The patients/participants provided their written informed consent to participate in this study.YL, YG, and ZX conceived of the study and improved the design. YL and LL were responsible for collecting clinical data. XT and QX provided statistical analysis and interpretation. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This study suggests that a multidisciplinary strategy including rehabilitation is essential, especially in patients with poor predictive markers at an early phase, and we should consider suitable rehabilitation programs to prevent a decline in exercise tolerance and improve social reintegration and overall QOL in patients after allo-HSCT.As the proportion of long-term survivors after allogeneic hematopoietic stem cell transplantation  is on the rise, it is essential to consider the significance of quality of life (QOL), including reintegration with society (returning to school or work). This retrospective cohort study aims to illustrate the precise epidemiology of social reintegration later after allo-HSCT and determine its predictive indicators. We enrolled 56 patients, and 40 patients (71%) attained social reintegration at 2 years post-HSCT. Reintegration failure markedly correlated with an inferior performance status and concurrent chronic graft-versus-host disease. In non-reintegrated patients, the physical function at discharge measured by the 6-min walking distance (6MWD) was markedly decreased. On the multivariate risk analyses, sex  0.07; 95% confidence interval (CI) 0.01–0.54;  With the increasing proportion of long-term survivors after allo-HSCT, quality of life (QOL) could be equally significant. In particular, reintegration with society (returning to school or work) after allo-HSCT is a major factor to enhance the QOL in socially active younger patients5.Allogeneic hematopoietic stem cell transplantation  is a curative treatment for hematological malignancies. Recently, there have been a remarkable increase in the 5-year survival rate post-HSCT because of the sophisticated conditioning regimens and the development of supportive care for post-transplant complications6, and unemployment remains exorbitant in this population. As the precise data on social reintegration remain limited, the crucial parameters for patients at the timing of their reintegration also remain unclear. In addition, correlation analyses focusing on social reintegration and patients’ factors at pre- and early post-HSCT have been performed only in one pediatric study; later unemployment rates were persistently high in adult patients who survived the previous childhood allo-HSCT, especially in those with a younger age at HSCT, lower performance status (PS) before HSCT, related bone marrow grafts, and myeloablative conditioning regimens with total body irradiation7. However, no studies dealing with adult reintegration, have been published, and there are no ways to predict a patient’s future probability of reintegration at the early phase after allo-HSCT. Thus, such data and analyses help to establish effective follow-up systems for long-term survivors with multidisciplinary care teams comprising physicians, nurses, therapists, and other professional healthcare providers8.However, reintegration in society is not easily attained after allo-HSCT. Reportedly, a median of 2 years is necessary for patients to return to work9. In addition, our study and others have reported that the physical function, including muscle strength and exercise tolerance, often decrease in the early phase post-transplantation because of post-transplant complications such as acute graft-versus-host disease (aGVHD) and declined physical activity14. Besides, it takes as long as 1 year to restore such declined physical function6. Overall, the studies mentioned above suggest that the physical function (muscle strength and exercise tolerance) in early post-HSCT could be a risk factor predicting the later prolonged decline in the physical function and the following lower probability of social reintegration.A previous study indicated that unemployment and following social non-reintegration could be related to the concurrent declined physical function at 1-year post-HSCTHence, this study aims to (1) illustrate the precise epidemiology of social reintegration 2 years after allo-HSCT and related patients’ factors, and (2) explore the correlation of the social reintegration of long-term survivors with early post-HSCT physical function, and other transplant-related factors. This study could be beneficial to plan more effective and patient-oriented multidisciplinary strategies, including rehabilitation, which could lead more patients to social reintegration and a superior QOL during the lengthy clinical courses after allo-HSCT.17. We excluded patients if early death or relapse  was recorded, were unemployed before HSCT (had no full-time or part-time job), or had not attended school before HSCT. In this study, “before HSCT” indicates the time of diagnosis for hematological disease. This study adhered to the tenets of the Declaration of Helsinki by the World Medical Association and the ethical guidelines for medical research involving humans and was approved by the Institutional Review Board of Kyoto University . We observed an informed consent from all the participants involved in the study.From the database, we obtained data on adult patients (age: 18–60 years) who underwent allo-HSCT at Kyoto University Hospital  between April 2011 and April 201818, while BMI, total protein, and albumin as indicators for nutrition, and C-reactive protein as inflammatory marker. Nutrition and inflammation were closely related to exercise tolerance19.We obtained descriptive data from the database and included the following variables: sex, age, body mass index (BMI), ECOG (Eastern Cooperative Oncology Group) PS (Performance Status) as a commonly used performance status score, hematopoietic cell transplantation comorbidity index (HCT-CI), diagnosis, stem cell source, disease status, conditioning, aGVHD, time to neutrophil engraftment, hospitalized period after HSCT, and evaluation results at discharge . Hemoglobin was used as the marker related to exercise toleranceIn this study, social reintegration was defined as returning to paid work or school and evaluated at 2 years after allo-HSCT. Of note, patients working in non-paid style, such as volunteer and housework, were categorized as being socially non-reintegrated. Work pattern was defined by working hours, and full-time work was defined as 40 h or more per week, while part-time work as < 40 h per week. Furthermore, the social reintegration status was established by specialized nurses in an outpatient clinic during long-term follow-up sessions.11. For the patients before engraftment, the rehabilitation program was performed in clean rooms, where the interventions mainly focused on maintaining personal activities and physical functions. The exercise therapies were performed every weekday (five times a week) for 20–40 min, and involved stretching, strength training, walking, and bicycle ergometer. The exercise load was set at “somewhat strong” according to the revised Borg scale, and the target heart rate was set using Karvonen method with exercise loads of 40%–60%20. Notably, rehabilitation was continued inside the ward even during the aseptic management periods (neutrophil counts < 500/μL)11. Even when bed-ridden, the patients were provided with range of motion exercises (ROM practice) and muscle training to prevent contractures and muscle weakness on the bed.All enrolled patients used the rehabilitation protocol. The study cohort was under rehabilitation interventions during hospitalized periods between pre-HSCT (before starting conditioning regimens) and dischargeIn the patients after engraftment, the rehabilitation program was performed in the rehabilitation center, where the interventions mainly focused on improving the physical function and re-acquiring activities of daily living (ADL) movement for discharge. Activities included ADL training (stair climbing practice and floor movement practice) and the training in clean rooms. The intervention time could attain 1 h, and the exercises load was set at “somewhat strong” or rather higher “strong” levels.21 and the 6-min walking distance (6MWD) for exercise tolerance11. In this study, the KES was measured during a 3-s isometric contraction using IsoForce GT-330 . Precisely, patients were seated on a chair keeping the angles of their hip and knee joints at 90° and instructed to extend the knee joints (to kick forward); then, the force was measured with a sensor placed 5 cm above the lateral malleolus. We used the higher score (N) obtained from two trials in future analyses. In addition, the torque was calculated by multiplying strength by the lever arm length and was expressed as the ratio to body weight (Nm/kg)21. Besides, the 6MWD test was conducted as recommended by the American Thoracic Society22, where patients were requested to walk back and forth along a straight 30-m course on the corridor at the maximum efforts for 6 min, and the walking distance was recorded. The reported 6MWD in the healthy control ranged from 494 to 631 m according to the sex, age, height, and weight 24. The physical function tests (KES and 6MWD) were assessed pre-transplantation (before conditioning regimens) and just before discharge (1 week before discharge).Besides rehabilitation interventions, the physical function was routinely assessed using standardized tests of the knee extensor strength (KES) for muscle strengthp < 0.05 was considered statistically significant. Using the Mann–Whitney U-test and unpaired t-test, we compared the patients’ characteristics, including the physical function between socially reintegrated and non-reintegrated groups. In addition, we evaluated the magnitude of change in the physical function (Δ) at discharge compared with at pre-HSCT. Furthermore, we used the paired t-test to compare changes in the physical function within each group over time.The statistical analyses were performed using SPSS software ver. 18.0 . A two-sided p value to determine the correlation between pre- or post-HSCT characteristics and later social reintegration. Moreover, we performed multivariate logistic regression analyses with dependent variables using variables with a p < 0.2 in univariate analyses. We used the forced entry method to build the model. In the power analyses where the two subgroups are compared, and the social reintegration incidence differed in three times, total 42 patients were necessary to detect the significant difference with an alpha error of 0.05.In addition, we used the univariate simple logistic regression test to calculate the unadjusted odds ratio (OR), 95% confidence intervals (CI), and N = 16) and non-working/studying status pre-HSCT (N = 11). We finally enrolled 56 patients  had respiratory dysfunction with arrythmia or diabetes, or rheumatoid disease with inflammatory colitis. Regarding the disease status, 75% of the cohort was transplanted at complete remission (because we excluded patients with relapse or early death within 2 years post-HSCT).During the study period, 83 patients underwent allo-HSCT. Of these, we excluded 27 patients because of early death or relapse N = 6 and nonN = 16), one patient was categorized as a house worker, while the other patients were not employed either in the paid or non-paid style. Regarding social reintegration, in both groups, the patient distributions were almost similar in age, BMI, disease type or status, stem cell sources, and other post-HSCT variables, whereas the distribution of sex and HCT-CI was skewed (Table From 23 patients 41%) at 1-year post-HSCT, social reintegration increased to 40 patients (71%) at 2 years post-HSCT. In the socially reintegrated group, 35 patients returned to full-time work or school, while five patients acquired a part-time job . The physical function was assessed by the KES (as markers for muscle strength) and the 6MWD (as markers for exercise tolerance) at two time-points of pre-HSCT and at discharge. The KES was equivalent in pre- and post-HSCT periods ; this tendency was similar in each group of future social reintegration . Besides, we observed no significant difference between both groups at each time-point . Furthermore, ΔKES (difference between pre- and post-HSCT) did not significantly differ between both groups ; adherence was not related to the future social reintegration ; this was not observed in the future social reintegration group . In the non-reintegration group, however, the difference between these two time-points was apparent and statistically significant . The 6MWD decline in the future non-social reintegration group was more apparent in the analyses for Δ6MWD .The 6MWD exhibited more significant and specific changes. Overall, the 6MWD significantly declined in post-HSCT , hemoglobin, total protein, serum albumin, and C-reactive protein, the proportion of patients with inferior PS and cGVHD was significantly skewed in the non-reintegrated group (p = 0.55). Owing to the multivariate analyses using variables extracted in the univariate analyses, sex , higher HCT-CI , and Δ6MWD  were identified as significant risk factors that predict the incidence of social reintegration (Table vs. part-time) had no significant impact on the probability of post-HSCT reintegration.In order to identify the factors that can predict social reintegration in the later phase post-HSCT, we sought to establish the logistic regression model using pre-HSCT patient characteristics and those with early post-HSCT. The univariate analyses revealed that the patients’ sex, HCT-CI, PS, hemoglobin, albumin at discharge, and 6MWD were relevant to the incidence of social reintegration Table . The medvs. > 45 years) indicated that our main results  can be reproducible in each age group (data not shown).Subgroup analyses on the age  revealed these two major findings: (1) social reintegration was achieved in 71% of patients with long-term survival, and the concurrent poor PS (≥ 2) and cGVHD exerted a significant impact on the inferior reintegration; and (2) the 6MWD changed early after allo-HSCT (at discharge), including the patient sex and HCT-CI, could predict the probability of the social reintegration status at 2 years post-HSCT. To the best of our knowledge, this is the first study to reveal the correlation between social reintegration and early physical function, and suggest the significance of rehabilitation intervention to attain a higher incidence of social reintegration and a better QOL after allo-HSCT26. Specifically, employment after HSCT is an indicator of post-transplantation recovery and function with economic and social implications9. In accordance with our study (71% at 2 years), other studies reported an 81%–89% of social reintegration at 5 year post-transplant28. In this study, we focused on reintegration not at 5 but 2 years post-HSCT, primarily because this is the earliest timing when the risk of infection and cGVHD is saturated29, and also because previous studies have indicated that 1–2 years is the median time needed for patients to return to their work30.First, this study illustrated the accurate status of social reintegration 2 years after allo-HSCT through the face-to-face survey at the outpatient unit. Among various parameters, employment and returning to school are the most important markers of functional recovery in cancer survivors31. In this study, poor PS concurrent cGVHD, at 2 years markedly correlated with the lower incidence of social reintegration. Notably, cGVHD encompasses various symptoms, including the eyes, mouth, skin, nail, hair, gastrointestinal tract, lungs, liver, muscles and joints, and genitalia29, together with additional immunosuppressive therapies could deteriorate the patients’ PS and warrant frequent hospital visits or admissions; these situations could hinder patients from reemployment or returning to school32.Even at 2 years after allo-HSCT, as many as 29% of our cohort were socially not-reintegrated; thus, we focused on the factors associated with social reintegration. A previous study reported that HSCT complication-associated deterioration of PS correlated with health-related failure to return to work or school28. It is reported that gender wage gap in Japan is the third largest in the OECD (Organization for Economic Co-operation and Development) area33, and female HSCT recipients may be less liable to return to work, which can explain the skewed distribution of the included patients’ sex and the post-HSCT lower incidence of reintegrated females. On the other hand, this is the first study to report the correlation between higher HCT-CI and lower reintegration. Patients with high HCT-CI scores are complicated with dysfunctions in single or multiple organs per se or because of chemo/radiotherapies pre-HSCT34. Perhaps, such pre-transplant complications could be frequently carried over or deteriorate during the clinical courses after allo-HSCT16, resulting in lower PS and poorer social reintegration, as discussed above.Second, we performed the analyses to identify the variables (pre- or early post-HSCT) that could predict later social reintegration. The multivariate analyses suggested that female sex, higher HCT-CI, and changes in the 6MWD at discharge were significant factors. Regarding sex, our findings corroborated previous studies36, this study is the first to compare patients with and without social reintegration. In addition, the superiority of the 6MWD at discharge was established in the socially integrated group, although their hospital stay was shorter (the 6MWD measurement at an earlier time-point post-HSCT in this group working as a bias), supporting the earlier recovery or improvement of 6MWD in the future reintegrated group. We found that changes can be a predictive factor for the future social reintegration; this suggests that recovery or improvement is the key for better reintegration. On the other hand, the KES test, which indicates instantaneous muscle strength21, exhibited a nonsignificant difference between both groups.Besides the female sex and higher HCT-CI, correlation with the declined 6MWD and a lower incidence of social reintegration is a novel non-elucidated finding. The 6MWD test is a standardized assessment of exercise tolerance and is often used in allo-HSCT patients. Although some studies have reported a decreased distance early post-HSCT37. In Japan especially, rehabilitation programs in the outpatient clinics are not covered by the insurance, and no rehabilitation is provided after discharge. Therefore, insufficient exercise tolerance (shorter 6MWD) cannot be fully restored without appropriate rehabilitation interventions even long after the discharge; this may be the reason why Δ6MWD at discharge is strongly related to the lower social reintegration two years later. Revision of the rehabilitation program to increase the total exercise load using short, higher intensity interval-based protocols can also be helpful to improve cardiorespiratory fitness and following refinement of exercise tolerance38, and continuous rehabilitation programs in the outpatient clinics39.These findings suggested that among various physical functions, insufficient exercise tolerance (6MWD) at an early time-point post-HSCT, not the loss of instantaneous muscle strength (KES), could interfere with subsequent social reintegration over time. To be socially reintegrated after allo-HSCT, it is speculated that patients need to attain sufficient exercise tolerance, which could overcome the continuous demands of exercise, including long-distance commutation and long-time work without intervals, and this study indicates that tolerance at this time (2 years post-HSCT) could be closely related to early post-HSCT (at discharge). Thus, a multidisciplinary approach to patients with lower exercise tolerance at the early time-point post-HSCT could be crucial for future reintegration, and rehabilitation interventions to maintain  or restore (after discharge) the exercise tolerance could increase the future social reintegration probability40. Third, the number of the patients and observational periods are also limited, and we excluded patients in the non-working/studying status pre-HSCT. Moreover, we did not record the magnitude of physical activity during the rehabilitation programs. We did not include various confounding factors after the discharge until 2 years later. Thus, the findings of this study should be validated in future multicentered prospective trials including other countries.Hence, this study revealed the epidemiology of post-HSCT social reintegration and its predictive factors; however, there exist some limitations. First, we did not evaluate physical function (including 6MWD) and QOL while judging social reintegration (2 years post-HSCT). Thus, changes in these parameters long after HSCT should be analyzed in future research to determine the impacts of physical function on the social reintegration. Second, this study was conducted at a single institute within a limited period, and the wide differences were not considered regarding social support services and attitudes for social reintegration based on each region and country where HSCTs were performed as well as decades, patient sex, and age. Of notes, the hospitalization periods in Japan are usually longer (60–170 days) than those in the other countries, because the treatments of GVHD, infection, CMV reactivation, and so on are often performed during the hospital stayIn conclusion, this study demonstrated that social reintegration was attained in 71% of patients 2 years after allo-HSCT, and poorer PS and concurrent cGVHD correlated with a lower chance of social reintegration (reemployment and return to school). In addition, female sex, higher HCT-CI, and declined exercise tolerance (6MWD) early after allo-HSCT were predictive factors of the later lower social reintegration among long-term survivors; all these are crucial indicators for subsequent reintegration and the need of supportive care. Thus, this study suggests that a multidisciplinary strategy, including rehabilitation, is imperative, especially for patients with poor predictive markers at an early phase, and an appropriate rehabilitation program to prevent a decline in exercise tolerance should be considered to improve social reintegration and overall QOL in patients after allo-HSCT.Supplementary Information


Most patients with atrial fibrillation (AF) report symptoms, while one-third are asymptomatic. We hypothesised that sensory processing, in particular pain, differs in patients with symptomatic and asymptomatic AF.Thirty individuals with permanent AF (15 symptomatic and 15 asymptomatic) completed the Atrial Fibrillation 6 (AF6) and short form 36 Health Survey questionnaires and underwent quantitative pain sensitisation testing using pressure algometry at the sternum (referred pain area) and the tibialis anterior muscle . The primary objective was to assess differences in pressure pain thresholds (PPT), temporal summation of pain (TSP) and conditioned pain modulation (CPM) in the two groups. The secondary objective was to determine association of demographic and clinical parameters to measures of pain sensitisation.The symptomatic group had lower PPTs at both tibialis (p=0.004) and sternum (p=0.01), and impaired CPM (p=0.025) and facilitated TSP (p=0.008) at the tibialis but not sternum, compared with the asymptomatic group. The AF6 sum score was negatively correlated to PPT on both tibialis  and sternum  and positively correlated to TSP on both tibialis  and sternum , but not to CPM. The physical component summary score was positively correlated to the PPT on both tibialis  and sternum  and negatively to TSP on the tibialis  but not sternum.Patients with symptomatic AF exhibit lower pain tolerance than patients with asymptomatic AF, as well as impaired pain inhibitory control and facilitated summation of pain, indicating that pain sensitisation may be of importance in symptomatic AF.Trial registration numberNCT04649437. It is unclear why some individuals with atrial fibrillation (AF) experience symptoms whereas others are asymptomatic, and little is known of the physiological mechanisms underlying AF symptomology. Previous studies have found that symptomatic AF is more frequent in women, at younger ages, and in patients with non-permanent AF. It is possible that patients with symptomatic AF differ in pain processing from those not perceiving symptoms.Patients with symptomatic AF show significant signs of pain sensitisation compared with patients with no perceived symptoms of AF.Our findings suggest there is potential for investigation of therapies to target pain sensitisation in patients with symptomatic AF.Approximately one-third of individuals with atrial fibrillation (AF) report no symptoms, but up to 25% report severe symptoms such as palpitations, dyspnoea, chest pain and syncope.Study participants were recruited from a database consisting of all individuals aged 20 years or older with an initial or recurrent AF diagnosis between 1 January 2015 and 31 December 2018 in Örebro County, Sweden. The database comprised patients derived from the Medrave 4 Registry for primary care, the Auricula Registry  and the National Patient Registry for inpatient and specialised outpatient care. Eligibility criteria for the current study were ≤75 years old, permanent AF  to 10 (severe symptoms) is reported for each of the six items and scores are added to obtain a cumulative sum score ranging from 0 to 60, with higher values reflecting more severe symptoms.11 16The physician-assessed modified EHRA scale was used to assess symptom severity relating specifically to the time when patients feel symptoms of AF. Patients reporting no AF symptoms are categorised as class I. Class IIa experienced mild, class IIb moderate, class III severe and class IV, disabling symptoms.13The patient-reported SF-36 has a recall period of 4 weeks and consists of 36 items assessing eight domains on a scale ranging from 0 to 100, with higher values indicating better health-related quality of life. The eight domains generate a physical component summary score and a mental component summary score, which were used to assess health-related quality of life.12Quantitative sensory tests were conducted by a blinded investigator (AJ) in the following order: pressure pain threshold (PPT), temporal summation of pain (TSP) and conditioned pain modulation (CPM). PPTs and TSP were performed at the tibialis anterior muscle 5 cm distal to the tibial tuberosity, and at the sternum between the third and fifth intercostal spaces, with 1 min intervals between repeats and sites.2 probe of the handheld pressure algometer  was placed perpendicular to the skin, and pressure was increased at a rate of approximately 30 kPa/s. Participants were instructed to press the stop button on the algometer when they first experienced the sensation of pain. The mean of three measurements at each site was used for analysis.The PPT was defined as the minimum pressure required for the sensation of pressure to change to pain. The 1 cm2 tip) with a weighted load  was used to induce TSP.A pin-prick device (0.25 mmThe right hand was immersed up to the wrist in circulating water at 2°C–4 °C for up to 2 min (cold pressor test). The PPT from both sites were assessed before (unconditioned) and after (conditioned) the 2 min immersion and reassessed 10 minutes after the hand was withdrawn from the water. The CPM was calculated as the absolute difference in PPT during the immersion compared with the pre-immersion PPT. A negative value indicates inefficient CPM and a positive value indicates efficient CPM.Data were tested for normality using the Shapiro-Wilk’s test. Independent sample t-tests were performed to analyse differences between groups in age, BMI, AF duration and physical/mental component summary scores, and dependent sample t-tests to quantify difference in initial and repeat AF6 sum scores.2 test was employed to test for differences in sex, comorbidities, rate control agents , and completion of the full 2 min immersion cold pressor test between the two groups. A mixed model analysis of variance (ANOVA) was used to assess the primary objective of the study, with within-factor time , and between groups. One-way ANOVA was used to characterise differences in CPM and TSP. To adjust for age, sex and BMI, these variables were included as covariates for CPM and TSP. Sidak-corrected post hoc tests were employed where appropriate, if main or interaction factors were significant. Secondary objectives were tested using correlational analyses, Pearson’s product-moment or Spearman’s rank correlation where appropriate for demographic and clinical parameters, and pain sensitisation as reflected by PPT, CPM and TSP. A p<0.05 was considered significant. Data were reported as mean±SEM unless otherwise stated. Statistical analyses were performed using IBM SPSS Statistics V.27.The χPatients and public were not invited to comment on the study design and were not consulted to develop outcomes relevant to patients or to interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy. Before publication, the results of this study were not disseminated to patients or the public.Thirty patients were enrolled in the study between November 2020 and January 2021  .The groups were well matched, except for a significantly higher BMI in the symptomatic group (t (17.8)=−3.73, p=0.002). The resting heart rate was adequately rate controlled in all patients with no significant differences between the groups and no significant differences in treatment with rate control agents.Patients in the symptomatic group had significantly lower AF6 sum scores at inclusion in the study (30±11) than recorded in spring of 2020 , while all asymptomatic patients had an AF6 sum score of 0 both times. The item consistently scoring as most severe was breathing difficulties on exertion .Patients with symptomatic AF were considered to be in EHRA class IIa–III, whereas all asymptomatic patients were considered to be in EHRA class I. Symptomatic patients reported significantly lower physical and mental component summary scores compared with asymptomatic patients (t(19.19)=8, p<0.001 and t(21.696)=5.27, respectively, p<0.001).Four patients (13%) reported chest pain at some point during the prior 7 days, all of whom were in the symptomatic group . A body chart with superimposed chest pain distribution is shown in An overview of quantitative sensory testing values is available as 10.1136/openhrt-2021-001699.supp1Supplementary dataF1.34,37.53 =0.52, p=0.53, η2=0.02) but a significant main effect of time  on sternum PPTs was found. Post hoc between-group analysis showed significantly lower PPTs on the sternum for symptomatic patients , and PPTs were significantly increased 2 min (p=0.02) and 10 min (p=0.04) after hand immersion overall  or main effect of time . Patients with symptomatic AF reported lower PPTs over the tibialis anterior muscle than did the asymptomatic group (p=0.004).The mixed model ANOVA did not reveal significant interaction between time and group . There was no significant difference between asymptomatic and symptomatic AF patients in sternum TSP (p=0.13).2=6, p=0.01). Sternum CPM, assessed by one-way ANOVA adjusted for age, sex and BMI, was not significantly different between groups (p=0.16). Conversely, CPM over the tibialis anterior muscle, adjusted for age, sex and BMI, was significantly higher in the asymptomatic group compared with the symptomatic group (p=0.025). No patient showed angina pectoris, bradycardia, or syncope during the cold pressor test.All asymptomatic patients kept their hand immersed in the cold water for the full 2 min, while those in the symptomatic group withdrew their hand significantly sooner  and the sternum . There was a significant positive correlation of the AF6 sum score with TSP of both the tibialis anterior muscle  and the sternum . There were significant correlations between the physical component summary scores and the PPTs of both the tibialis anterior muscle  and the sternum  and significant negative correlation with TSP of the tibialis anterior muscle  but not the sternum. We observed significant positive correlation between the mental summary scores and the CPM of the tibialis anterior muscle  but not of the sternum or other measures of pain sensitisation. Male sex was significantly positively correlated to PPT of the tibialis anterior muscle  and CPM of the sternum .The study showed significant quantitative signs of local and general pain sensitisation in patients with permanent symptomatic AF as compared with patients with asymptomatic AF, and significant correlation between quantitative pain sensitisation parameters and AF symptom severity scores.Little is known about the pathophysiological mechanisms underlying AF symptomatology.This study included patients with permanent AF to avoid taking into account if patients had sinus rhythm or AF during quantitative sensory testing in this first proof-of-concept study, even though patients with permanent AF are the least symptomatic compared with patients with paroxysmal and persistent AF. It is possible that even greater differences in pain sensitisation would have been observed in a study including patients with non-permanent AF. An AF duration of 7 years is long, and patients tend to adapt to symptoms.The groups were well matched, although the symptomatic group had a higher BMI. Obesity is a known risk factor for AF and obese patients have more diastolic dysfunction, sympathicotonia and increased fatty and inflammatory infiltration of the atria compared with normal-weight patients with AF.26The present study showed lower pressure pain thresholds over the referred pain area to the heart (sternum) and a distant area  indicating both local and widespread pain sensitisation in patients with symptomatic AF.The facilitated TSP in humans most likely reflects increased gain of the dorsal horn neurons, as shown in other animals.9 30The AF6 sum score demonstrated strong correlations with both TSP (positive) and PPT (negative), but no significant correlations to CPM. This could indicate an association between AF symptom severity and pain amplification but warrants further study.The study raises important questions: (1) does AF affect pain mechanisms and increase pain sensitivity per se, or is pain sensitivity an individual trait; (2) are some patients with AF a priori more pain susceptible than others; and (3) does pain sensitisation persist during periods without AF in patients with non-permanent AF?In addition to existing treatment options for symptom relief such as rate control and lifestyle modifications, this study suggests evaluation therapies targeting pain and pain sensitisation in patients with symptomatic AF. Our methods should be replicated in larger cohorts and in patients with non-permanent AF.This study has several limitations. It included a small sample size, but differences were identified between symptomatic and asymptomatic groups. Second, and possibly more important, we lacked a control group without AF and the study should be considered hypothesis generating. Finally, we excluded patients with neurological and musculoskeletal disorders and diabetes to minimise the risk that some patients could be sensitised due to other conditions, but we cannot exclude the possibility that patients had unstated previous or intermittent pain conditions.Patients with symptomatic AF show substantial signs of quantitative pain sensitisation compared with patients with asymptomatic AF, and pain sensitisation increases with an AF symptom severity score. This suggests the need for new management strategies to modulate symptoms of AF.


The opioid crisis amplified the concern for the appropriate use of opioids. Our study aims to investigate the pain levels and amount of opiates needed during the first three days following total knee arthroplasty (TKA), whereby Drug Enforcement Administration (DEA) Schedule II oral opiates are not available.  A year-long retrospective review of adult patients who underwent TKA was conducted. The postoperative pain scores and mean morphine equivalents (MME) were measured. These outcomes were assessed according to demographics, anesthesia, and analgesia used.  For our 78 patients, there was no statistical difference for stratification by baseline characteristics except in spinal anesthesia, which decreased pain on the first day. Conversely, MME increased to its significantly highest of 14.22 ± 29.58 mg on day 3. The effect was noted for patient-controlled analgesia where patients with intravenous analgesia received less opioid than those on epidural analgesia on postoperative day one.  Using a similar regimen of analgesia, postoperative pain following TKA would be controlled by a relatively low amount of opioids by the third postoperative day. Spinal anesthesia and patient-controlled epidural analgesia were linked to better pain control and less opioid needed. Total knee arthroplasty (TKA) is a common procedure, usually used to treat knee osteoarthritis. Around 700000 and more than 100000 procedures are performed annually in the US and UK, respectively .TKA is a cost-effective procedure with a good patient satisfaction rate. Most studies reported a satisfaction rate of approximately 80%. Patients stated decreased pain levels, improved function, and better quality of life postoperatively. Patient satisfaction level was associated, among other factors, with less pain and improved functional status, while dissatisfaction was associated with a longer hospital stay . An impoProper management of postoperative pain speeds patient's mobilization, decreases thromboembolic complications, improves main physiological functions, shortens the length of hospital stay, and improves patient's participation in physical therapy. Thus, optimal pain management helps in patient's wellbeing while reducing healthcare costs .TKA usually has moderate to severe postoperative pain levels. The anesthetic-controlled pain score following TKA ranged from 2.7 to 7.64 on the visual analogue scale . Unlike Our study evaluates the pain level and the amount of opioid consumed during the first three postoperative days following TKA and describes any differences in these outcomes by the various patient characteristics, in a setting where DEA Schedule II oral pain medication is not available.We followed the retrospective observational study design. The institutional review board at our local institution approved the study.The latest consecutive 100 adult patients who had undergone primary TKA during a year were identified from our institutional inpatient database using the appropriate Current Procedural Terminology (CPT) code of 27447. These surgeries were performed by multiple orthopedic surgeons; however, all followed institutionalized protocols. Tourniquets were used in all of the surgeries and anesthesia dosage followed per kg of weight guidelines.The inclusion criteria consisted of any patient over 18 years old who had undergone primary TKA. The exclusion criteria included any patient who had undergone previous knee surgery, had diabetic neuropathy, had a history of chronic pain (diagnosed or recorded for more than 3 months unrelated to the knee), had any psychiatric or neurologic disease, or had a history of drug dependence. The excluded patients also included those who were taking any psychoactive drug, analgesics, or medication having an analgesic effect (steroid and anticonvulsants) for a period longer than 3 months, those who did not receive patient-controlled analgesia (PCA)/patient-controlled epidural analgesia (PCEA), and any patient who had more than 30% of the pain or pain medication data missing.The collected data included patient characteristics , surgery-related variables , pain levels, and details of the anesthetic and analgesics or any similar effect medication used during their admission for TKA both preoperatively and postoperatively.The two main outcomes were pain score and amount of administered opioids.The pain scores were reported using the numerical rating scale (NRS), where 0 indicates no pain and 10 indicates extreme pain. We derived the NRS scores for each day of the patients' hospital stay and calculated the mean NRS score for the first three days following TKA.Similarly, we collected the amount of pain medication and opioids received by each patient for the first three days following TKA and calculated its correspondent morphine milligram equivalent (MME) in mg . We measU-test or Kruskal–Wallis test as appropriate. A confidence interval of 95% and a p value of <0.05 (with Bonferroni correction as needed) were used to indicate the statistically significant difference for all analyses.The data were recorded, cleaned, and analyzed using IBM SPSS Statistics for Windows, version 25 . The mean and standard deviation (SD) was used for continuous variables; while frequency and percent were used for categorical data. The pain scores and MME distribution were not normally distributed; hence, nonparametric tests were performed. The daily values were compared using Friedman's two-way analysis of variance (ANOVA) among the three days and the Wilcoxon signed rank test between the two days. Furthermore, we stratified the pain scores and the MME levels by the patients' baseline variables and the means were compared using the Mann–Whitney Seventy-eight TKA patients met the inclusion/exclusion criteria and were included . The majKnee osteoarthritis was the indication for surgery in almost all patients. Most of the TKAs were unilateral (73%), did not receive preoperative analgesia (79.5%), and underwent either spinal, epidural, and/or general anesthesia. No local anesthetics were applied during any of the cases. During surgery, the mean duration of anesthesia was 253.77 ± 117.46 minutes. Postoperatively, 38.5% received PCA and 61.5% received PCEA for pain control . All patp < 0.01). Moreover, while the differences between preoperative versus postoperative days 1 or 2 pain scores were statistically significant with p < 0.01, the difference between preoperative and postoperative day 3 scores was nonsignificant with a Bonferroni-corrected p value of 0.10.The mean daily pain score was the highest on the first postoperative day with a value of 2.10 ± 1.67 and decreased gradually in the following days . A signiAlternatively, the maximum amount of MME was 81 mg on the postoperative day 1, 135 mg on day 2, and 148 mg on day 3. The daily MME was lowest on day 1 and reached its highest by postoperative day 3 (6.35 ± 14.79 mg vs. 14.22 ± 29.58 mg). However, the difference reached the border of statistical significance only for postoperative day 3 compared to postoperative day 1.p < 0.01).The stratification of pain score did not show any significant difference between genders, smoking status, education level, medical insurance, laterality of TKA, preoperative analgesia, preoperative pain, anesthesia types, and postoperative PCA/PCEA . A signip < 0.01). On postoperative days 2 and 3, the difference disappeared. Some other variables showed a similar trend between day 1 and day 3, but did not reach a statistically significant difference in any postoperative day.Similarly, the stratification of MME by baseline variables did not show any significant difference except for PCA versus PCEA . The meaOur study showed that postoperative pain following TKA and its control or opiate amounts are influenced by some baseline variables.This study is not without limitations. The retrospective design of the study limited our access to standardized methods of outcome evaluations; however, the study institution does follow a specific protocol for pain management, which provided comparable and good-quality data. Also, the small sample size decreased the effect size of the study. The exact amounts of PCEA/PCA medication were not available, but its use was based on standardized institutional protocol. Otherwise, the administration of all other pain medications was detailed and accounted for. Additionally, there was a substantial overlap between anesthetics used by different patients with many receiving spinal, epidural, and general anesthetics in their management as this is the model used in the institution.However, our sample was representative of the traditional population undergoing TKA in a specific region of the developing world. The majority of patients were females with a mean age of 58 and underwent unilateral TKA . Based oIn our study, the overall pain following TKA was mild and/or controlled by medications, but certain variables were noted which might affect the postoperative pain score . A signiAdditionally, the pain scores started highest on postoperative day 1 and decreased gradually over postoperative days 2 and 3. Pain levels only reached the significant decline threshold by postoperative day 3 as compared to day 1. Moreover, the statistically and clinically significant difference in pain scores between the preoperative score and postoperative day 3 score disappeared, indicating complete control of surgical pain by day 3 following TKA.One reason for the pain control might be the increased use of opioids by day 3, which was noted to be the highest on postoperative day 3 in our cohort . AssuminThose who received PCA required a much higher amount of opioids on postoperative day 1 than those who received PCEA, but this difference became nonsignificant in later days. Beilin et al.  have preA similar demeanor was also noted across the postoperative days in those receiving spinal anesthesia, epidural anesthesia, or nerve block. Almost three times, the amount of administered opioid was needed on the first postoperative day in those not receiving spinal/epidural anesthesia or nerve block compared to those who did. However, this increase did not level up to a statistically significant difference.In conclusion, postoperative pain and its control following TKA have multifactorial aspects that can affect the success of an opioid-sparing pain control regimen. The pain following TKA was the highest on the first postoperative day with a quick and substantial decrease in subsequent days. Our study revealed that morphine equivalent of around 14 mg is sufficient to control postoperative pain, in the presence of PCA/PCEA. This amount can be an anchor amount for future studies investigating opioid-sparing pain control regimens following TKA. In addition, the anesthesia choice and the presence of PCA or PCEA influence the pain levels during the first postoperative day but not afterward. Hence, spinal anesthesia and PCEA are better options in providing good control of short-term postoperative pain and administering less opiate in TKA patients. Furthermore, thorough studies are needed to evaluate the effect of various variables on postoperative pain and its control following TKA.