Herpes zoster develops when latent varicella zoster virus is reactivated in the trigeminal or dorsal root ganglions. Zoster-associated pain (ZAP) is neuropathic pain caused by the herpes zoster virus. Histological studies of postherpetic neuralgia patients suggest that inflammation is involved in ZAP. The effectiveness of local anesthetic and steroid epidural injections in ZAP patients has been reported. However, most studies included patients with acute herpes zoster, and the safety and therapeutic effects of different doses of epidural steroids in ZAP patients remain elusive. In this study, we randomly assigned 42 patients with severe ZAP beyond the acute phase, as determined by a numeric rating scale (NRS) score ≥7, to receive continuous epidural infusion of local anesthetics with either a one-time 5-mg dose or intermittent repeated doses  of dexamethasone. We found that intermittent repeated epidural dexamethasone bolus resulted in reduced NRS scores and an increased likelihood of complete remission in ZAP patients without any adverse effects. Thus, our results suggest that intermittent repeated epidural dexamethasone administration is safe and effective for treatment of ZAP beyond the acute phase. Herpes zoster is caused by the reactivation of latent varicella zoster virus in the trigeminal and dorsal root ganglion Herpes zoster-associated neuropathic pain is the consequence of inflammatory neural damage secondary to virus reactivation PHN is the most common complication of herpes zoster. Despite the existence of many treatments, PHN remains difficult to manage and is refractory to most treatment modalities In this study, we conducted a randomized controlled trial to compare the analgesic and therapeutic effects of one-time administration of 5 mg epidural dexamethasone with intermittent repeated total 15-mg epidural dexamethasone. We evaluated the efficacy and safety of continuous epidural infusions of local anesthetics with dexamethasone and studied the efficacy of intermittent epidural dexamethasone bolus for zoster-associated pain beyond the acute phase.The Hallym University Kangnam Sacred Heart Hospital institutional review board approved the protocol for this prospective, double-blind, randomized controlled trial (reference number 2019-04-011), and the trial was registered at ClinicalTrials.gov  prior to patient enrollment. Each participant provided written informed consent before undergoing any study-associated procedures. The study was conducted from June 2019 to February 2020 and included patients admitted to our pain clinic for zoster-associated pain rated as ≥ 7 on a numeric rating scale (NRS). We included only those patients who were beyond the acute phase of herpes zoster: specifically, 30 to 180 days after onset of the zoster rash. Patients were excluded if they met any of these criteria: 1) past or present conditions that may influence study participation, safety, or interpretation of the study results, such as cancer, severe diabetes, or a psychological, neurologic, liver, cardiac, hematologic, genitourinary, muscular, or dermatologic disorders; 2) current immunocompromised state; 3) herpes zoster involving the trigeminal nerve; 4) previous epidural block treatment for zoster-associated pain 5) epidural catheter discontinued before completing 10 days of continuous epidural infusion; 6) hemostatic disorder or receiving antiplatelet therapy; and 7) not an appropriate study participant, according to the opinion of the investigators. The study process was explained to all patients, and participants were instructed how to use the NRS for pain (ranging from 0 = no pain to 10 = worst pain imaginable). All participants received oral medications consisting of anticonvulsants, amitriptyline hydrochloride, and analgesics, as needed. Doses of oral medications were adjusted for age and renal function, and the drugs were tapered according to symptoms.www.randomizer.org) to generate a random allocation sequence. Patients were assigned at random in a 1:1 ratio to 1 of 2 groups, which differed according to whether a single dose or repeated doses of dexamethasone were administered. After patients entered the procedure room, another investigator (who had no other role in the conduct of the study) opened a sealed, opaque envelope containing the patient's group assignment. The patients were unaware of the group to which they were assigned.We used a computer-generated randomization schedule  was inserted through the Tuohy needle into the epidural space, and contrast medium was injected to identify placement of the catheter tip in the area of the affected spinal nerve. Then we have confirmed that the level to be targeted was correlated to the affected dermatome by electrical nerve stimulation. After injection of an initial bolus of 0.19% ropivacaine and 5 mg dexamethasone , a continuous epidural infusion of ropivacaine  was begun at a rate of 7 mL/h using the AutoFuser pump , which is a portable balloon infusion device. The catheter was fixed in place with subcutaneous tunneling to minimize infection risk and performed daily dressing changes at the tunneling site. The continuous epidural infusion was maintained for 10 days. During the 10-day period, patients in group A received an 8-mL bolus of 0.19% ropivacaine through the epidural catheter every 5 days. All patients (in groups A and B) were monitored in the recovery room for 30 minutes after each bolus injection.All patients received 1 g cefazolin intravenously prior to the procedure and assumed the prone position on the procedure table. Under fluoroscopic guidance, an 18-gauge Tuohy needle was advanced into the epidural space at the second or third vertebral level below the target level. The target level was identified based on the affected dermatomal distribution of rash and pain. A 20-gauge epidural catheter  was administrated through the epidural catheter. Similar to group A, a continuous epidural infusion of ropivacaine  was begun at 7 mL/h using the AutoFuser pump and maintained for 10 days. Unlike group A, patients in group B received 0.19% ropivacaine and 2.5 mg dexamethasone  via the epidural catheter every 5 days over the 10-day infusion period. They also received a final epidural injection of 0.19% ropivacaine and 5 mg dexamethasone  2 weeks after the epidural catheter was removed  after treatment in each group. NRS pain scores and the percentage of patients with ≥ 50% reduction in severity of pain were compared between the two groups before and at monthly intervals from 1 to 6 months after the treatment. The secondary outcome was complete remission of PHN. Complete remission was defined as an NRS pain score ≤ 2, resolved allodynia and hyperalgesia, and no longer requiring medical treatment. To assess the presence of allodynia or hyperalgesia, we performed a touch/pressure test using a filament brush, a pinprick test using a 26G needle, and a cold swab test using alcohol-soaked cotton. The percentage of patients in each group with complete remission of zoster-associate pain was calculated and compared between groups.Kolmogorov-Smirnov test was used to evaluate the normality of demographic data. Continuous variables are reported as mean ± standard deviation and were analyzed using independent t-tests. Categorical variables are reported as frequency and percentage and were analyzed using Chi-square or Fisher's exact tests. We used logistic regression models to estimate the odds of a ≥ 50% reduction in pain severity (NRS scores) or complete remission of PHN within 6 months of treatment.Based on our experience and data from a pilot study, the sample size was calculated with G*Power software (version 3.0.10) using the z test with a p1 proportion of 0.9, p2 proportion of 0.5, error probability of 0.05, and power of 0.8. Using these parameters, we determined that 20 patients were required in each group to detect a sufficient effect size. We therefore designed the study with 22 patients per group, assuming a 10% drop-out rate. Data were analyzed using SPSS software  or SAS , and P values < 0.05 were deemed statistically significant.A total of 60 patients were screened between April 2019 and February 2020: 10 failed to meet the inclusion criteria, and 6 did not agree to participate. Consequently, 44 patients were randomized (22 per group), and 42 were included in the final analysis  exhibited significantly lower pain scores than patients in group A (one-time 5-mg dexamethasone administration) at each month after treatment (P < 0.05) Figure .The percentage of patients with ≥ 50% reduction in pain severity was not significantly different between groups (P = 0.110). However, the percentage of complete remission of PHN was significantly higher in group B than in group A  (Table No serious procedure-related complications were detected in either group A or group B. Specifically; no patient developed an epidural hematoma, infection, or abscess.In this randomized, controlled trial, continuous epidural local anesthetic infusion with intermittent repeated dexamethasone administration provided excellent analgesia for herpes zoster-associated pain, allodynia, and hyperalgesia beyond the acute phase. Pain relief persisted during the 6 months of follow-up and was not accompanied by adverse effects.The beneficial effects of epidural dexamethasone have been attributed to interruption of neurogenic inflammation and promotion of nerve tissue repair by reducing edema, as well as cytotoxic responses Although the pathogenesis of PHN is not fully understood, herpes zoster is known to affect the central and peripheral nervous systems, resulting in PHN Histopathologic studies in humans indicate that inflammatory processes may be involved in the development of PHN. In a postmortem study, Watson et al. reported that infiltration and accumulation of immune cells occurred around the spinal cord and nerves of patients with PHN Previous studies have shown that intrathecal methylprednisolone relieves PHN-related pain and allodynia In this study, we used continuous infusion of dexamethasone administered epidurally, instead of via the intrathecal route, in patients with zoster-associated pain beyond the acute phase. This treatment reduced NRS pain scores in all 42 patients in our study, and intermittent repeated administration of dexamethasone was more effective in alleviating zoster-associated pain, allodynia, and hyperalgesia than one-time dexamethasone administration. The herpes zoster viral burden settles in the dorsal root ganglion of the affected segment, and it produces nerve and tissue damage. Epidural drug administration targeting the affected spinal root applies the drug directly at the area of the pathologic nerve and effectively controls zoster-associated pain, while avoiding systemic adverse effects and neurotoxicity. There have been no reports of serious complications with epidural steroid administration for zoster-associated pain, unlike the serious adverse effects reported with intrathecal methylprednisolone.There are some limitations in the current study. There was no control group of patients who received no epidural steroids. Because previous reports indicated that neuropathic pain associated with herpes zoster arises from inflammatory neural damage and that epidural steroids and local anesthetics are highly effective for acute herpes zoster pain In conclusion, continuous epidural infusion of local anesthetics with intermittent repeated dexamethasone administration resulted in a greater reduction in pain and likelihood of complete remission than one-time bolus of dexamethasone.


Complex regional pain syndrome (CRPS) is a perplexing painful syndrome of the extremities usually following a harmful event. It is distinguished in two types, mainly depending on the presence of nerve injury. Although its prevalence may vary depending on social and ethnic factors, middle-aged women seem to suffer most often and the upper limb is the most commonly affected extremity. Apart from pain, which is the dominating feature, the clinical picture unfolds across several domains: sensory, motor, autonomic and trophic. This syndrome develops in two phases, the acute (warm) phase, with the classic symptoms of inflammation, and the chronic (cold) phase, often characterized by trophic changes of the soft tissues and even bones. Although the syndrome has been studied for over two decades, no imaging or laboratory test has been established for the diagnosis and recently proposed diagnostic criteria have not yet been validated and are only occasionally applied. Its pathophysiology is still quite obscure, although the most likely mechanisms involve the classic and neurogenic paths of inflammation mediated by cytokines and neuropeptides, intertwined with changes of the autonomic and central nervous system, psychological mechanisms and, perhaps, autoimmunity. Although plenty of treatment modalities have been tried, none has been proven unequivocally efficacious. Apart from information and education, which should be offered to all patients, the most effective pharmacological treatments seem to be bisphosphonates, glucocorticoids and vasoactive mediators, while physical therapy and rehabilitation therapy also make part of the treatment. It is characterized by pain disproportionate to the intensity of the triggering factor and may have a later onset than the time of the harmful event. The syndrome is known to have sensory, motor, autonomic and trophic manifestations, usually lacking a clear dermatomal or peripheral nerve distribution pattern.2 While both types occur typically after trauma, the key distinguishing feature is the presence of a definite nerve injury, which is absent in type 1, but present in type 2 CRPS. This distinction is relevant to the nature of chronic pain, which is considered nociceptive in the former and neuropathic in the latter type, although both types may actually represent different parts of a continuous spectrum. A third type (not otherwise-specified) has also been proposed for those patients partially meeting criteria for either type 1 or 2 and lacking a better explanation for their symptoms and signs.3The term Complex Regional Pain Syndrome was introduced in 1994 by the International Association for the Study of Pain (IASP) in the second edition of the Classification of Chronic Pain. The syndrome was divided into CRPS type 1, formerly known as reflex sympathetic dystrophy (RSD), and CRPS type 2, formerly known as causalgia.4 The first widely accepted set of criteria was proposed in Orlando and endorsed by IASP in 1994 (Table 1).2The diagnosis of CRPS is purely a clinical one. However, several efforts have been made to set diagnostic criteria in order to facilitate clinical communication and standardization for research purposes.5 while up to 37% of patients with diabetic neuropathy meet criteria for CRPS.6 This is probably due to the vague definition of symptoms, which may only be historical, and a degree of subjectiveness in their interpretation . To overcome this, a workshop was held in Budapest in 2003, which resulted in a new, more detailed and likely more specific set of criteria .7An advantage of these criteria is that they are easy to apply in everyday clinical practice and have a high sensitivity (0.98). However, plenty of studies have shown that their specificity is poor (0.36) and other conditions may mistakenly be considered as CRPS. Indeed, in only 40% of cases diagnosed with CRPS the diagnosis is correct,8 In a subsequent Dutch study, the incidence of CRPS was estimated at 26.2 per 100,000 person-years, again with a female predominance.9 Both studies also showed that the upper extremity is the most commonly affected. In a more recent study from the US, the diagnosis of CRPS emerged at a rate of 70 per 100,000 hospital discharges over a 4-year period.10 The most likely causes for those variations (Table 3) are differences in the type of source data and the methods of case ascertainment. Indeed, in a literature search aiming to assess the use of the IASP criteria, only 38% of the publications mentioned the application of the criteria and only 15% of the referenced publications satisfied them.11 Apart from female gender, other epidemiological risk factors are Caucasian race, high household income and private insurance. It is not yet clear how these factors are related to CRPS and whether there is a biological factor involved. It is suggested that patients with a higher socioeconomic status have access to better healthcare services and a closer follow up. Various comorbidities also seem to affect the occurrence of CRPS, including depression, headache and drug abuse.10 In a prospective study by Bean et al. investigating how psychological factors influence the recovery of patients with CRPS, it was concluded that anxiety, pain-related fear and disability have a negative effect, thus implicating psychological parameters for poorer recovery.12 In contrast, some diseases do not appear to associate with the syndrome, such as diabetes, anemia, obesity and hypothyroidism.10A population-based study in Olmsted County, Minnesota, over the period 1989–1999, applying the IASP criteria resulted in an incidence rate for CRPS type 1 of 5.46 per 100,000 person-years and a period prevalence of 20.57 per 100,000. On the other hand, CRPS type 2 incidence rate was just 0.82 per 100,000 person-years. The female-to-male ratio was 4:1, while the median age of onset was 46 years.13Inciting events may be a fracture, particularly distal radius or Colles’ fracture, which has been associated with a CRPS incidence up to 36.7%. Orthopaedic surgery of the extremities has also been associated with the occurrence of CRPS, as well as other types of trauma, immobilization and stroke.calor, dolor, rubor, tumor.1 The symptoms usually appear distally to the area of trauma like a glove or stocking.14 Patients describe a constant, deep pain that exacerbates with movement or temperature changes.15Two phases of the syndrome have been described: first, the acute or “warm” phase, during which the affected limb shows classical signs of inflammation - 14 Atrophies may occur in the skin, subcutaneous tissue and muscles, even local osteoporosis of the underlying bones.14 Nail and hair growth are altered, either increased or decreased with quality changes.16The second, chronic or “cold” phase starts about 6 months later, as the inflammation subsides. The quality of the pain is different, more persistent while resting and difficult to treat. Some patients experience muscular spasms.15 Motor disorders appear in most cases with CRPS: in the initial phase, movement is reduced because of edema and fear of inducing pain with movement (kinesiophobia); in the chronic stage, fibrosis ensues limiting movement.1 Although the key distinguishing feature between type 1 and type 2 CRPS is the presence of nerve injury in the latter, the symptoms in type 2 still exceed the territory of the injured nerve and are far more complex than expected for neuropathic pain, resembling, thus, to the symptoms of CRPS type 1.17 Besides, in the paper proposing the Budapest criteria, it is questioned whether there is a clinical utility in the differentiation between type 1 and 2, although the distinction was maintained.7Autonomic symptoms include hyper- or hypohidrosis and skin colour changes, mainly the limb turning red.7 No serum markers or imaging findings with high diagnostic value have been identified. Plain radiographs may show bone demineralization, although this occurs relatively late and is not specific.17 Magnetic resonance imaging (MRI) may show spotted bone-marrow edema, cutaneous edema, joint effusion or contrast uptake in the skin and the synovium. However, these findings have a low overall sensitivity (35%) and a low-moderate predictive value for CRPS, although the specificity is quite high (91%).18 Some researchers have proposed the use of three-phase bone scintigraphy (TPBS), which shows alterations in the peri-articular bone metabolism.19 This test, particularly phase 3, is highly specific, especially for the upper limb,19 but when applied in patients with CRPS diagnosed with the Budapest criteria, the sensitivity is quite poor (0.551).20 In conjunction with the TPBS imaging, serum osteoprotegerin, an osteoblast activity marker, could be used as a diagnostic tool with a sensitivity about 0.74 and a specificity of 0.8.21 There was a significant positive correlation between increased radiotracer uptake in TPBS phase 3 and serum osteoprotegerin in patients with CRPS suggesting an increased osteoblast activity.21As no gold-standard tests for CRPS exist, the diagnosis is essentially clinically assisted with the application of proposed criteria.23Functional brain MRI has been used to investigate the role of the central nervous system in CRPS. Abnormalities in central motor function and changes in cortical paths could be used in the future as possible biomarkers.In conclusion, the diagnosis of CRPS is purely clinical, based on the history, symptoms and signs. Classical radiographs should always be performed to assess bone integrity, given the strong association with trauma. More elaborate studies, such as TPBS and MRI of the affected extremity may assist by revealing findings compatible with CRPS and by excluding other diagnoses, such as synovitis, infections or tumors.Figure 1).The pathogenesis of the disorder remains obscure. It is considered a multifactorial condition with several contributors: classic inflammation, neurogenic inflammation, impairment of the autonomic nervous system and changes of the central nervous system (CNS) , IL-2, monocyte chemoattractant protein-1 (MCP-1) and bradykinin are raised during the chronic phase. Increased IL-6, MCP-1 and macrophage inflammatory protein 1β (MIP-1β) were also found in the blister fluid from the affected limb.25 Although classic inflammation seems more relevant to the warm phase of CRPS, some studies have suggested that even in the cold stage inflammation may play a role, as well.26 For instance, it has been shown that the levels of pro-inflammatory cytokines IL-6 and TNFα in the affected extremity are comparably disturbed between cold and warm CRPS. A hypothesis might be that in some patients increased vasomotor activity masks a parallel inflammatory process, which is, though, revealed after vasodilatory treatment. Besides, vasoconstriction results from an imbalance of vasodilating  and vasoconstricting substances (e.g. endothelin-1), which, in turn, may be induced by pro-inflammatory cytokines.24The acute phase of CRPS implies that classic inflammatory mechanisms are likely involved in its pathophysiology. Tissue trauma is considered to trigger an exaggerated and persistent release of pro-inflammatory cytokines such as tumour necrosis factor-α (TNFα), interleukin (IL) 1β and IL-6, which activate the cascade of inflammation that results in a painful, red and swollen extremity.27 CGRP activates CGRP1 receptor in smooth muscles and endothelial cells inducing vasodilation of arterioles, while substance P and neurokinin A promote vascular permeability by activating neurokinin A1 receptors in endothelial cells.27 These changes result in hyperemia, tissue edema and exudation of leukocytes. Besides, CGRP and substance P activate resident cells, such as mast and dendritic cells. These, in turn, release inflammatory mediators including histamine, serotonin, TNFα that attract inflammatory cells and further promote inflammation, but also act upon local nociceptive Aδ-fibers inducing peripheral nerve sensitization.28 Finally, CGRP promotes sweat gland function, as well as hair growth.27Neurogenic inflammation probably plays a central part in the development of CRPS. It begins with the stimulation of the peripheral endings of the nociceptive C-fibres, which, subsequently, conduct the stimulus not only afferently to the dorsal ganglia, but also efferently through branches extending back into the afflicted tissue. This backward firing results in the release of several pro-inflammatory neuropeptides the most important being substance P, calcitonin gene-related peptide (CGRP) and neurokinin A, as well as others including adrenomedullin, neurokinin B, vasoactive intestinal peptide, neuropeptide Y and gastrin-releasing peptide.29 Systemic manifestations of sympathetic dysfunction have even been observed, such as increased heart rate, reduced heart rate variability and impaired orthostatic response.30 In the warm phase of CRPS, local norepinephrine release from sympathetic fibers is decreased leading to increased cutaneous blood flow. However, in the chronic cold phase, α-adrenoreceptors are more sensitive to circulating catecholamines leading to vasoconstriction and decreased blood flow.31 Expression of adrenoreceptors on nociceptive fibers leads to sympatho-afferent coupling producing sympathetically mediated pain. Indeed, under conditions of sympathetic activation, there is a considerable increase of pain intensity in patients with CRPS.33Several factors indicate the role of the sympathetic nervous system in the appearance of CRPS. Those include changes in skin colour, hyper- or hypohidrosis and changes in the extremity temperature.34 The brain areas that seem to participate in the motor dysfunction are the primary motor cortex, supplementary motor cortices and posterior parietal cortices. The reorganization of the central motor circuits is thought to lead to an increased activation of the motor cortex and to motor dysfunction of the affected extremity.35 However, a systematic review published in 2013 concluded that there was no significant impairment in the representation of the affected limb on the motor cortex.36Some studies suggest maladaptive neuroplasticity of the motor and somatosensory cortex. In 2000 Birklein et al. published an analysis of 145 cases studying the neurological findings in CRPS. Ninety-seven percent of patients manifested motor dysfunction such as tremor, exaggerated reflexes, dystonia and myoclonic jerks.37 Sensory stimuli on the affected extremity trigger a complex cortical network, including areas of nociceptive, cognitive and motor processing different than the pattern triggered by similar stimuli on the unaffected side. Consequently, the patient does not only feel pain during the movement of the hand or leg, but also with the thought of movement.38 Furthermore, it is hypothesized that the continuous nociceptive stimulation induces plastic changes in the motor and somatosensory networks, so that hyperalgesia and chronic pain is not only the consequence of changes in the CNS, but also the cause.39Changes in the somatosensory cortex have been investigated by several researchers in order to explain hyperalgesia. The affected body part seems to be represented on a smaller area on the primary somatosensory cortex.40 Another prospective multicentre study investigated the effect of various psychological factors  on the risk of CRPS development in 596 patients with a single fracture. Although 7% of patients eventually developed CRPS type 1, none of the psychological scores were significantly different from those of the general population, nor could any psychological factor be identified as a predictor of CRPS.41 Similarly, in a systematic review no association between psychological factors and the occurrence of CRPS could be demonstrated, except that patients with more life events were found to carry a higher risk of developing CRPS.42A cross-sectional study comparing psychological factors between patients with CRPS or low back pain showed that in the CRPS group pain intensity correlated with anxiety. Moreover, pain and, particularly, depression were the couple of factors that significantly predicted disability.43 as were autoantibodies against α-1a adrenoreceptors.44 Another study by Kohr showed that 30–40% of patients who suffered from CRPS had surface-binding autoantibodies against an autonomic nervous system autoantigen.45 The autoimmune nature of CRPS was further upheld by Goebel and his colleagues who performed a randomized, double-blind, placebo-controlled crossover trial of intravenous immunoglobulin (IVIG) including 13 patients with moderate to severe pain due to CRPS. The average pain intensity significantly reduced following IVIG treatment compared to placebo.46 However, this result was not replicated in a larger study.47There is evidence that CRPS might involve an autoimmune component, as well. In some cases, IgG autoantibodies with agonist-like properties on the β2-adrenergic and muscarinic-2 receptor were present,As CRPS is a multifactorial syndrome, its management extends over several domains and treatment modalities, such as patient information and education, pharmacological treatments, physical and occupational therapy and psychological support. The aim of treatment is to relieve pain and restore the functionality of the affected limb. Although the course of the disease is variable and there is no strong evidence that it is modified by treatment, therapy should not be delayed, as patients with a more chronic course carry a worse prognosis.48 Education will also allow a more active participation of the patients in the management of their disease by enabling them to form their own understanding of the therapeutic strategy proposed by the physician, to build the knowledge and skills required for the rehabilitation process and to gain trust into this process, improving eventually their adherence to the treatment plan.As in every chronic disease, patients and their families should be informed about their condition, in order to realize the nature of their symptoms and the course of the disorder.49 Similarly, a randomized trial including 60 patients with CRPS following stroke compared the effectiveness of a one-month treatment with either a tapering dosage of prednisolone starting from 40mg daily or piroxicam 20mg daily. At the end of treatment there was a significant improvement of the CRPS score in patients on prednisolone, but no improvement in those on piroxicam.50 Hence, currently there is no evidence supporting the use of NSAIDs for the treatment of CRPS.Non-steroidal anti-inflammatory drugs (NSAIDs) have been used to treat pain and inflammation. However, a randomized double-blind placebo-controlled trial of pare-coxib, 80mg on two consecutive days including only 20 patients with CRPS 1 and 2 of the upper limb, showed no benefit of parecoxib on pain or edema.51 In another prospective study, treatment of patients with shoulder-hand syndrome post stroke with 32 mg of oral methylprednisolone daily for 14 days followed by a 14-day taper resulted in 31 out of 36 patients being almost asymptomatic within 10 days of treatment.52 Moreover, a case series revealed that, in patients with RSD who had failed exercise therapy, long-acting glucocorticoids (80mg of Depo-Medrol administered no more frequent than fortnightly for up to 4 injections) resulted in improvement of limb mobility, pain, swelling and strength.53 Finally, in a more recent case series including 31 patients with CRPS, a short course of prednisone with a starting dose of 40–60 mg per day and a quick tapering showed both short- and long-term benefits across various outcomes, such as pain, swelling, mobility, strength and limb functionality.54 On the other hand, in a prospective study including 31 patients with CRPS of more than 3 months duration who had failed standard treatments, administration of high-dose prednisolone (60–100mg/day) with a rapid taper-off over 16–22 days showed that the reduction in average pain intensity missed statistical significance, although borderline. This study showed that in chronic CRPS high dose glucocorticoids may not be as effective as in the acute phase, while the associated adverse events should also be taken into account.55As classic inflammation is likely involved at least in the early stages of the disease, glucocorticoids might be beneficial. However, relevant studies are heterogeneous as regards CRPS definition, patient characteristics, glucocorticoid formulations and dosages employed, while practically all of them included low numbers of patients. In an early randomized placebo-controlled trial including 23 patients with CRPS type 1, 10 mg of oral prednisone three times daily for up to 12 weeks were proven more effective than placebo in producing clinical improvement.29 More importantly, several, mainly small-scale, studies support the effectiveness of bisphosphonates in CRPS. The earliest was a randomized double-blind trial of intravenous alendronate (7.5mg daily for 3 days) or placebo, which showed a significant improvement of pain, tenderness, swelling, and motion.56 These results were later confirmed in another double-blind placebo-controlled trial, which used a more convenient dosing regimen of alendronate, 40mg daily per os for 8 weeks. Throughout 12 weeks, significant benefits were observed in patients on alendronate as regards spontaneous pain, pressure tolerance and mobility compared to the control group. In a further 8-week extension of the study, patients continuing alendronate showed additional improvements in the same outcomes. Apart from two patients reporting upper gastrointestinal symptoms, no unexpected adverse events emerged with this increased dosage of alendronate, making it therefore a potentially effective, safe and feasible pharmacological modality for CRPS.57Bisphosphonates were recently introduced in the treatment of CRPS, although the exact therapeutic mechanism still remains unclear. Plenty of suggestions have been proposed, the most common being through the regulation of inflammatory mediators and the inhibition of proliferation and migration of bone marrow cells.58 intravenous neridronate,59 and intravenous pamidronate,61 all types of bisphosphonates, though, not widely available. Notably, a randomized study comparing intravenous pamidronate (three infusions of 60mg each) to oral prednisolone (1mg/kg tapered off over 14 days) in CRPS post stroke showed that pamidronate was as effective as prednisolone in pain control.61Similar beneficial effects were reported for intravenous clodronate,62 In an early study, Gobelet et al. randomized 24 patients with RSD undergoing physical therapy to additional subcutaneous calcitonin 100 mg daily for 3 weeks, or no additional treatment and showed that the group on calcitonin had more rapid pain relief.63 The same group subsequently performed a similar study with intranasal calcitonin (300UI daily) and background physical therapy showing greater improvement of pain, range of motion and the ability to work with calcitonin compared to placebo.64 However, another prospective randomized double-blind study demonstrated no effect of intranasal calcitonin (400UI daily) on clinical progression of CRPS.65 Finally, other investigators showed that calcitonin was no more effective than paracetamol, both administered to patients undergoing physical therapy.66 In conclusion, the scientific evidence supporting the use of calcitonin for the treatment of CRPS is rather weak and, given the recent safety concerns regarding its use, it is no longer recommended.67Calcitonin is thought to reduce pain in CRPS through release of β-endorphin in CNS and inhibition of bone resorption.62 Three free radical scavengers have been used so far: dimethylsulfoxide (DMSO), N-acetylcysteine (NAC) and mannitol. DMSO 50% cream was applied locally to patients with acute CRPS in combination with physiotherapy. After 2 months, the visual analogue score for pain and RSD scores were improved.68 When DMSO 50% (5 times per day) was compared to NAC (600 mg 3 times per day), DMSO treatment was more efficacious for warm CRPS type 1 and for treating dysfunctions of the lower extremity, while NAC was more effective for cold CRPS type 1.69 Moreover, DMSO 50% cream seems favourable compared to ismelin block treatment for CRPS in early stages.70 Regarding mannitol, a randomized double-blind placebo-controlled trial showed no significant benefit of mannitol 10% infusions compared to placebo in patients with CRPS type 1.71Therapy of CRPS with free radical scavengers is based on the hypothesis that in CRPS toxic oxygen and hydroxyl free radicals are overproduced.46 A meta-analysis of three randomized placebo-controlled trials showed that 500 mg of vitamin C per day for 50 days decreases the one-year risk of CRPS after wrist fracture.72Vitamin C has been used for the prevention of CRPS based on the concept that it inhibits local inflammatory pathways via antioxidant mechanisms.13Although opioids constitute the second-line treatment for neuropathic pain, their effectiveness is not yet established in CRPS and their multiple side effects limit their use.73 There is still no evidence on the effectiveness of pregabalin, carbamazepine or phenytoin in CRPS.Anticonvulsants, such as gabapentin and pregabalin, have been proven to relieve pain in some neuropathic pain syndromes. With this assumption, Van de Vusse et al. conducted a randomized placebo-controlled crossover trial using gabapentin to treat CRPS type 1. They concluded that the pain relief was not significant with gabapentin, but there was a greater reduction of the sensory deficit in the affected extremity.13 The α-sympathetic blocker phenoxybenzamine has shown positive results in reducing pain in the acute stage.75 Clonidine, an α2-adrenergic agonist, administered locally via a transdermal patch, has also been shown to be efficacious in treating hyperalgesia.76 The effectiveness of phenoxybenzamine, as well as nifedipine, a calcium-channel blocker, in the treatment of CRPS was reported in a series of 59 patients.77 Both treatments produced beneficial effects, when administered in the early stages of the syndrome, but their effectiveness was less evident, when the treatment started in the chronic stage.Sympatholytic drugs have been tried in patients with CRPS, in order to inhibit the sympathetically mediated pain.78In conclusion, although plenty of pharmacological treatments have been tried for the treatment of CRPS, the published studies are mainly underpowered and heterogeneous in terms of patient characteristics and drug dosages. Therefore, safe conclusions are difficult to draw. A recent network meta-analysis focusing on pain management in CRPS concluded that for CRPS with symptom duration less than 12 months the best treatment are bisphosphonates followed (by far) by glucocorticoids. For CRPS with symptom duration of at least 12 months the best treatment was calcitonin followed by bisphosphonates and vasodilators.79 Physical therapy is more efficacious in reducing pain and improving active mobility,80 while use of the affected limb in daily activities is improved through occupational therapy.13 Given that neuroplasticity is an important part of the CRPS pathophysiology, graded motor imagery is one of the most beneficial tools of physical therapy for reducing pain.81 Particularly, mirror therapy, which has been used to reduce the pain of amputated ghost limb, is beneficial in alleviating pain and improving functionality in CRPS as well. Having a mirror placed between the healthy and the affected limb, the patient is encouraged to move the healthy limb in front of the mirror and at the same time watch the movement through the mirror. In this way, an illusion is created that the affected limb is also moving, although without feeling pain. Several studies gave positive results using this cost-free and easily applied therapeutic method.82Physical and occupational therapy, with or without medical therapy, are first-line treatments of CRPS in order to avoid kinesiophobia. Although initiation of physiotherapy in the early stages has been proven more beneficial, it may also help in chronic CRPS.79When medication has failed to relieve pain in CRPS, several invasive procedures have been employed, such as sympathetic blockade, surgical sympathectomy, spinal cord stimulation and even amputation. However, research is still required, in order to assess their cost-benefit balance and their indications and place in the treatment of CRPS.Complex regional pain syndrome is a chronic and multifactorial pain syndrome, emerging after trauma and causing various degrees of disability. Inflammation, both classic and neurogenic, plays a major role in the pathogenesis of the disease, coupled with disorders of the autonomic nervous system, CNS plasticity and, possibly, psychological factors. As there is no objective test, the diagnosis is reached on clinical grounds. The treatment is multidisciplinary, involving patient education, medications , physical and occupational therapy. More research is needed in order to elucidate its pathogenesis, which will allow the design of targeted treatments to be tried in large prospective studies.


The identification of central sensitization (CS) is an important aspect in the management of patients with chronic musculoskeletal pain. Several methods have been developed, including clinical indicators and psychophysical measures. However, whether clinical indicators coincide with the psychophysical test of CS-related sign and symptoms is still unknown. Therefore, the present study aimed to analyze the diagnostic accuracy of the clinical indicators in identifying CS-related sign and symptoms in patients with musculoskeletal pain.One-hundred consecutive patients with musculoskeletal pain were included. Clinical indicators (index method) based on a combination of patient self-report pain characteristics and physical examination were used to identify the phenotype of patients with musculoskeletal pain and the predominance of the CS-related sign and symptoms. Conditioned pain modulation (CPM) was assessed by the Cold Pressor Test (reference standard), which is a psychophysical test used to detect impairment of CPM. Measurements of the diagnostic accuracy were performed.Twenty-seven patients presented predominance of CS-related sign and symptoms in the assessment of the clinical indicators, and 20 had impairment of CPM. Clinical indicators showed high accuracy , high specificity , high negative predictive value , and a relevant positive likelihood ratio  when compared to the Cold Pressor Test.Clinical indicators demonstrated a valuable tool for detecting the impaired CPM, which is a remarkable feature of the CS-related sign and symptoms. Clinicians are encouraged to use the clinical indicators in the management of patients with musculoskeletal pain. Musculoskeletal health conditions are a common cause of pain in the general population, and the central sensitization (CS) is linked with a number of these patients. Musculoskeletal pain is present in approximately half of the population of Europe , the UniIdentifying the pain related to CS is a clinical challenge for health professionals because there is no gold standard assessment method . BesidesThe relevant frequency of the patients with chronic musculoskeletal pain and the predominance of the CS phenotype  led reseThe lack of robust terminology to identify clinical features and neurophysiological mechanisms hamper definite decision-making in patients with chronic musculoskeletal pain. Clinical indicators have the potential to be a suitable tool for screening purposes and helpful for guiding the management of patients with different pain. Still, an investigation of the criterion validity of the clinical indicators (index method) to detect the impairment of CPM using a psychophysical test (reference standard) is needed to ensure an adequate classification of the patients. Therefore, the present study aimed to analyze the diagnostic accuracy of the clinical indicators in identifying impairment of CPM in patients with musculoskeletal pain. We hypothesized that patients with musculoskeletal pain with the clinical phenotype of the CS-related sign and symptoms would present impairment of the CPM.This diagnostic accuracy study followed the Standards for Reporting Studies of Diagnostic Accuracy (STARD) . The stuConsecutive patients with musculoskeletal pain (aged 18 years and over) of the outpatient physiotherapy of Gaffrée and Guinle University Hospital were enrolled when they sought treatment between November 2015 and May 2016. The study included patients with acute pain (pain duration less than 3 months) and chronic pain (pain duration greater than 3 months). Musculoskeletal pain was defined as pain perceived in a region of the body with muscular, ligament, bone, or joint origin , as well as in the anterior tibial region . Consequently, the within-group comparison was also statistically significant , high accuracy , high negative predictive value  and a relevant positive likelihood ratio , but low values of sensitivity  and positive predictive value  when compared to the CPT. Measurements of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of central sensitization are presented in Table This study investigated the diagnostic accuracy of the clinical indicators in identifying patients with musculoskeletal pain and CS-related sign and symptoms, considering the impairment of the CPM as a standard measured. Clinical indicators exhibited high values of diagnostic accuracy, specificity, the negative predictive value of the clinical diagnosis of impairment of CPM in patients with musculoskeletal pain. Besides, the positive likelihood ratio found in the current study represents a relevant increase in odds favoring a rule in patients with the impairment of the CPM. The clinical indicators demonstrated to be useful to detect impairment of CPM in patients with musculoskeletal pain, specially ruled out those patients who do not have impairment of CPM.We acknowledge strengths and limitations in the current study. The first strength is the novelty to validate the use of a practical and straightforward system of clinical identification of the phenotype of patients with CS-related sign and symptoms. The second strength was the use of a psychophysical method for impairment of CPM identification using two different anatomical sites for its classification. Ultimately, we enrolled target-positive and target-negative patients , the negative likelihood ratio was not small enough to rule out the CS-related sign and symptoms with confidence. Predictive values provide probabilities of abnormality for a particular test, but the prevalence of the abnormality in the study sample interferes with the results. In the current study, the prevalence of the CS-related sign and symptoms was 27%, corroborating a previous Brazilian study  and otheOur findings indicate that clinical indicators are an accurate tool for the identification of the CS-related sign and symptoms. Although the majority of patients with impaired CPM presented CS-related sign and symptoms, there were 20% of participants who presented divergent results. Therefore, the clinical presentation of the CS-related sign and symptoms in patients with musculoskeletal pain may be disparate from the psychophysical test, which can reveal the neurophysiological impairment. The conflicting diagnosis of the CS-related sign and symptoms in the clinical presentation and the neurophysiological test preclude adequate decision making in patients with musculoskeletal pain. Additionally, the clinical indicators were developed to identify the predominance of pain in patients with low back pain  demonstrFew studies have investigated the validity of the clinical tools to identify patients with CS-related sign and symptoms. For instance, Gervais-Hupe et al. observed sensitivity of 87.2% and specificity of 34.2% in the identification of CS using the Central Sensitization Inventory (CSI) with a cut-point of 22 in patients with knee osteoarthritis when compared to CPT . The samClinical indicators demonstrated a valuable tool for detecting the impaired CPM, which is a remarkable feature of the CS-related sign and symptoms. Clinicians are encouraged to use the clinical indicators in the management of patients with musculoskeletal pain.


Chronic postoperative inguinal pain (CPIP) is defined as pain impacting daily activities lasting at least 3 months. With an incidence of 0.5–6.0%, chronic pain affects many patients who underwent inguinal hernia repair (IHR). Early severe postoperative pain has been described as a risk factor for CPIP. Thus, we aim to investigate the impact of the transversus abdominis plane (TAP) block on CPIP.From 2013 to 2019 we collected data from individuals who were operated on electively in TAPP technique and who received a preoperative TAP block.Data from 289 patients were selected. 259 patients were male. The mean age was 59.93 years and the mean BMI was 25.72 kg/m2. 252 patients suffered from a primary inguinal hernia. No mesh fixation was conducted. 21 patients reported pain at rest, 26 pain under physical exertion and 13 patients required treatment of their pain. In 6.25% of cases patients reported CPIP. We compared our findings with data from the German Herniamed Registry , because we assume that the majority of these patients did not receive a TAP block. The rate of pain under physical exertion (9.2% vs. 10.05%) and pain requiring treatment (2.45% vs. 2.95%) one year after surgery slightly differs without a statistical significance.We assume that the TAP block may reduce CPIP, postoperative pain during physical exertion and pain requiring treatment following IHR in TAPP technique. Additional randomized clinical trials are mandatory to evaluate the hypothesis. •The TAP block may reduce the rate of chronic postoperative inguinal pain.•The TAP block may reduce the rate of pain requiring treatment and on exertion one year after IHR.•The TAP should further implemented into daily hernia surgery routine. With To reduce the analgesic medication, pain in the Post-Anesthesia Care Unit (PACU) and to accelerate the physical recovery time, the administration of local and regional anesthetic agents has been implemented in parts into the daily routine of hernia surgery. Like it has been recently published by different authors the transversus abdominis plane (TAP) block prior to IHR in TAPP technique reduces the cumulative analgesic need medication and the pain level in the PACU . This apWe hypothesize, that the reduction of early postoperative pain, a CPIP risk factor, after TAP block administration may reduce postoperative painn following IHR in TAPP technique.2A monocentric retrospective observational study investigating the TAP block impact on chronic postoperative inguinal pain (CPIP) was conducted. According to International guidelines CPIP was defined as pain impacting daily activities lasting at least 3 months postoperatively ,2.The data of individuals who underwent elective IHR in TAPP technique from January 2013 to January 2019 were taken from their electronic files.The study has been performed at the xxx hospital (Germany) between January 2020 and March 2020. The study was approved by the Ethics Committee of the ‘Ärztekammer xxx’  in September 2019 (Eth-12/19) and conducted in accordance with the ethical standards of the Helsinki Declaration 1975.The study was registered with the German clinical trial registry DRKS (DRKS00020539). No funding has been received.The time of patient's hospital stay has been analyzed. The study is based on the patients' data available from their files.The study was conducted in accordance to the STROCSS 2019 Guidelines [2.1Patients who underwent elective laparoscopic IHR in TAPP technique and TAP block conduction were included.2.2Patients who underwent a conversion to an open IHR, as well as patients undergoing primary open IHR were excluded. No individuals with femoral hernias were included.Individuals with a lack of one-year-follow-up in the electronic file were excluded.2.3The TAP block was performed either under direct visualization or with ultrasound imaging.2.4The TAP block was performed under direct visualization using the laparoscope at the beginning of the operative procedure. While the abdominal cavity is insufflated, the surgeon palpated the lateral border of the rectus sheath to ensure adequate lateral placement. Then a 19 G needle was inserted percutaneously just above the iliac spine, inferior to the costal margin at the lateral end of the surgical field. By using the laparoscope to ensure that the peritoneum is not penetrated, the needle was advanced through the internal and external oblique and a small amount of local anesthetic was injected into the layer between the internal oblique and transversus abdominis. The appropriate dispersal along the layer was confirmed visually prior to the injection of the entire amount of local anesthetic. The same procedure was conducted on the contralateral side in case of a bilateral inguinal hernia (IH).The amount of local anesthetic for unilateral tap block consisted of 75 mg ropivacaine mixed with 20 cc of normal saline. We used double the amount in a bilateral IH.2.5A TAP block conducted under anesthesia through ultrasound guidance  using a 22G needle and standard lateral approach was performed prior to the beginning of the operation.2.6The TAPP procedure has been performed by several different surgeons (n > 10). Next to an umbilical 10-mmport for the 30° telescope two 5-mm ports, 5 cm from umbilicus at the lateral borders of the rectus abdominis muscle were inserted. We insufflated CO2 to a pressure of 15 mmHg. The hernial sac was reduced. A Polypropylene mesh (Medtronic®) was inserted through the 10-mm port to cover the entire myopectineal orifice. The mesh was not fixated. While lowering the intra-abdominal pressure to 8 mm Hg, the peritoneum was closed by a running dissolvable non-self-locking suture.2.7t-test a power calculation has been performed.Analysis was done using R (ver. 3.6.1). Data were presented as number (percentages) for nominal or mean ± SD/median (min-max) for metric variables. For the comparison of nominal variables between groups Fishers exact test was used, for metric variables normality was tested by using the Sapiro-Wilk test and hence the T-test or the Wilcoxon-test. A p-value < 0.05 was considered as statistically significant. No corrections for multiple testings were done. Using a two-sided two-sample In order to identify patients from the TAP group who benefit most from the therapy, as multivariate analysis we defined a decision tree regression model by using the R package “rpart".3The primary endpoint was the rate of CPIP revealed one year after surgery. CPIP was defined as pain impacting daily activities lasting at least 3 months postoperatively.The secondary endpoints were relevant complications according to clavien-dindo-classification  during t3.1In October 2019, an MS Excel data sheet was provided. This data was imported into R (ver. 3.6.1), and multiple plausibility checks were performed. In November and December 2019, updates of this data were provided while inconsistencies were resolved.3.2In order to compare the revealed data with published data from the German Hernia registry  a selectExclusion criteria were women, emergency surgery, femoral, bilateral and recurrent hernias.44.12 (SD 2.16).In this study 289 patients were enrolled . The mea4.2The perioperative baselines are illustrated in 4.3The endpoints one year after surgery are summarized in 4.42 (SD 2.4). 92 (56.44%) individuals suffered from preoperative pain, 10 (6.13%) from pain at rest, 15 (9.2%) from pain under physical exertion, 4 (2.45%) from pain requiring treatment, 8 (4.9%) from chronic pain and 7 (4.29%) from ingunial dysaesthesia. In terms of pain under physical exertion, pain at rest and pain requiring treatment both groups did not statistical significant differ from each other.The data from 163 patients were analyzed and compared with these from the German Herniamed Registry (n = 8799)  Table 4Table 4. 4.5t-test.To reveal differences regarding the CPIP one year after TAPP IHR with and without TAP block administration a group sample sizes of 334 (each) would achieve 90% power to detect a difference of 5% of CPIP between the null hypothesis that both group means CPIP rate is 5% and the alternative hypothesis that CPIP rate of group 2 is 10% with known group standard deviations and with a significance level  of 0,05 using a two-sided two-sample 5Chronic postoperative inguinal pain (CPIC) following inguinal hernia surgery is a major issue, which effects many patients ,11. The Due to different definitions, different assessment times and measurement methods the incidence of CPIP after open and laparoscopic IHR is heterogeneous reported in literature. It ranges from 0.7 to 43.3% . AccordiEarly postoperative pain has been described as one risk factor for CPIP ,2,15. ToWe recently revealed the positive effect of the TAP block on postoperative pain and cumulative analgesic need medication after TAPP IHR (n = 766). The individuals, who received a TAP block reported a reduced VAS-Score in the post-anesthesia care unit ; TAP block group, n = 364, 0.75 (1.25); p < 0.001) following TAPP IHR ,17.We compared our results in terms of pain at rest, pain under physical exertion and pain requiring treatment with those from the Herniamed Registry. The patients were selected  would be needed to confirm our hypothesis that the TAP block leads to a reduction of CPIP one year after IHR in TAPP technique ,21.It has been reported by several authors, that the TAP block sufficiently reduced early postoperative pain and cumulative analgesic need medication following laparoscopic IHR . AnotherNaturally when patients are suffering less from chronic pain, it likely will lead to an overall reduced opioid consumption. Severe opioid side effects such as nausea, vomiting, constipation and especially the addiction potential with increasing numbers of opioid related deaths could be prohibited ,25.As limitations the retrospective study design and the small sample size have to be mentioned. Moreover, several surgeons performed the IHR. In addition, the TAP-block has been administrated ultrasound-guided preoperatively and visual guided intraoperatively. Although recent literature did not indicate differences in terms of analgesic potency it might be an issue. Further trial should focus on one decent approach. Due to a lack of documentation in patients files we were unable to clearly identify ultrasound-guided preoperatively and visual guided intraoperatively TAP block administration.6Due to our findings we assume that the TAP block may reduce CPIP, postoperative pain under physical exertion and pain requiring treatment following IHR in TAPP technique. The TAP block should be further implemented into daily routine. Further randomized clinical trials are mandatory to evaluate the hypothesis.Ethical approval has been received.All authors have no source of funding.CP (corresponding author): Contribution to the paper: author, data collection, data analysis and interpretation, writing the paper, examination and treatment of patients.GD (co-author): Contribution to the paper: data extraction.SA (co-author): Contribution to the paper: data extraction.SA (co-author): Contribution to the paper: data analysis, treatment of patients.JF (co-author): Contribution to the paper: data extraction.KB (co-author): Contribution to the paper: data analysis, grammatical correction.UG (co-author): Contribution to the paper: data analysis.MS (senior-author): Contribution to the paper: data analysis, examination and treatment of patients.Due to the sensitive nature of the revealed data in this study, they will not be shared.The data that has been used is confidential.Not commissioned, Editor reviewed.None.


Bone marrow aspiration and biopsy (BMAB) is a painful procedure, and the routinely used local infiltration anesthesia (LIA) with lidocaine is unable to provide pain relief during the most uncomfortable phases. The primary endpoint of the present randomized, patient-blinded trial was to evaluate the efficacy of an opioid and benzodiazepine combination plus LIA  in patients undergoing BMAB for hematological malignancies. The secondary endpoint was the safety of the procedure in an outpatient setting. Ancillary assessments were anticipatory anxiety related to pain recall in the event of re-biopsy, and adequacy of bone tissue harvested. Patients were randomly assigned to one of 2 arms to receive either sedoanalgesic placebo plus LIA (standard group) or oral fentanyl citrate 200 μg plus oral midazolam 5 mg plus LIA (combo group) during BMAB. Pre-procedural anxiety and procedural pain were assessed according to the Numerical Rating Scale (NRS: 0–10), dividing the time of the procedure into five intervals  and evaluating the degree of discomfort at each time (T) in both groups. One hundred and sixteen patients were eligible for the study. At T2b (time of biopsy) and T3 (time after biopsy), a significantly lower perception of pain was registered in the combo group. Moreover, there were no significant sedoanalgesia-related side-effects. Finally, histological specimens were higher in quality in the combo group. Sedoanalgesia was highly effective in reducing pain during biopsy, diminished anticipatory anxiety in patients undergoing re-biopsy and led to fewer non-diagnostic specimens being harvested. Bone marrow aspiration and biopsy (BMAB) is a medical procedure commonly used for the diagnosis and follow-up of several hematological and non-hematological diseases ,2. In adIn the setting of hematological malignancies, BMAB provides comprehensive data on cytological and histological morphology, cytogenetics and molecular biology, all of which are useful for diagnosis, therapeutic decision-making and the formulation of prognosis. The 2008 World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues recommends that 500 nucleated cells be counted on bone marrow smears in an area as close to the particle and as undiluted with blood as possible, and that bone trephine biopsy be taken at the right angle from the cortical bone and at least 1.5 cm in length to enable the evaluation of at least 5 partially preserved intertrabecular areas ) to those of the standard group (median measured length 17.9 mm [range 10.6–21.8 mm]). The longer specimens harvested in the combo group also resulted in a higher quality of the diagnostic process: all 55 combo patients (100%) had a fully conclusive pathological diagnosis compared to 48 (92.3%) in the standard group. Primary and secondary endpoint results are summarized in A cost-effectiveness analysis has also been performed : This coThere is no clear evidence indicating a single effective method of premedication before BMAB in adults, and no formal guidelines for using analgesia/anxiolysis in this setting. Our preliminary results confirmed the different subjective perception of pain in the 2 patient groups, one treated with the LIA plus sedoanalgesia and the other with LIA alone, also underlining a high level of satisfaction and general comfort in patients in the combo group. The primary endpoint of this superiority study was thus reached: the degree of pain reduction in sedoanalgesia patients compared to those receiving standard premedication differed significantly. Given that a less painful experience associated with BMAB can notably improve the quality of life in patients with a chronic disease, sedoanalgesia can be considered superior to LIA alone as a pre-procedural anesthetic method. Compared to others papers, the presence of a single operator performing the procedure in our study overcame the problem of different pain perception deriving from different experience levels of the physician performing the BMAB. Hence, the result of a different degree of discomfort can only be ascribed to the efficacy of the medications. In addition, having the same operator perform the procedure each time overcame potential operator-dependent bias.n = 21) in the combo group , when given the choice of sedoanalgesia or standard LIA, chose to repeat the combination premedication.The clinical importance of our data is evident because all of the patients  and 21.2 mm in the combo-group (range 16.4–23.9 mm), which is above the optimal threshold of 20 mm [Some authors have used various methods and combinations of analgesia and anxiolysis in an attempt to reduce the pain from BMAB, obtaining different results. Several combinations of sedoanalgesia have been used with different administration modalities, together with different pain measuring scales, timing to monitor parameters and number of operators. In one of the first large studies focusing on the contribution of a single anxiolytic agent  added to LIA, pre-medication significantly reduced the perception of pain after 24 h and the memory of the uncomfortable event . A combi2 and female gender [Pain is common in cancer patients and physicians should not neglect this component of the disease because of its potentially dramatic effect on quality of life. Although there are some known non-modifiable factors associated with higher pain levels, such as younger age, body mass index > 30 kg/me gender ,19, there gender , suggest


Emergency Department (ED) crowding reduces staff satisfaction and healthcare quality and safety, which in turn increase costs. Despite a number of proposed solutions, ED length of stay (LOS) - a main cause of overcrowding - remains a major issue worldwide.This retrospective cohort study was aimed at evaluating the effectiveness on ED LOS of a procedure called “Diagnostic Anticipation” (DA), which consisted in anticipating the ordering of blood tests by nurses, at triage, following a diagnostic algorithm approved by physicians.In the second half of 2019, the ED of the University Hospital of Ferrara, Italy, adopted the DA protocol on alternate weeks for all patients with chest pain, abdominal pain, and non-traumatic bleeding. A retrospective cohort study on DA impact was conducted. Using ED electronic data, LOS independent predictors  were evaluated through multiple regression.p < 0.001).During the weeks when DA was adopted, as compared to control weeks, the mean LOS was shorter by 18.2 min for chest pain, but longer by 15.7 min for abdominal pain, and 33.3 for non-traumatic bleeding. At multivariate analysis, adjusting for age, gender, triage priority, specialist consultations, imaging test, hospitalization and ED crowding, the difference in visit time was significant for chest pain only (The impact of DA varied by patients’ condition, being significant for chest pain only. Further research is needed before the implementation, estimating the potential proportion of inappropriate blood tests and ED crowding status. The American College of Emergency Physicians defines crowding as a need for emergency services exceeding available resources for patient care in the Emergency Department (ED), hospital or both . In partThe causes of crowding are multifactorial and include, among the major contributors, the length of stay (LOS) of ED patients . EvidencMany interventions have been tested to improve ED waiting times and LOS , includiGiven that the Italian and Regional healthcare government recommended a maximum threshold of 6 hrs for ED LOS, the Ferrara University Hospital introduced nurse-initiated diagnostic ordering at triage at alternate weeks, thus allowing an evaluation of the impact and feasibility.This retrospective cohort study was aimed at evaluating the impact on ED LOS of a procedure called “Diagnostic Anticipation” (DA), which consisted in anticipating the ordering of blood tests by nurses, at triage, following a diagnostic algorithm approved by physicians.The study protocol was approved by the Independent Ethical Committee of Area Vasta Emilia Centrale  and the study had an administrative permission by General Direction of Ferrara University Hospital.This retrospective cohort study was performed at the ED of the Ferrara University Hospital, a tertiary care hospital in Emilia-Romagna Region, Northern Italy, from July 1st, 2019 to December 31, 2019. All participants were monitored during the ED stay, from triage registration to physician’s decision .Inclusion criteria were hour of visit between 8:00 am to 8:00 pm, a presenting complaint of chest pain, abdominal pain or non-traumatic bleeding and a triage priority color code yellow or green. In Italy, triage involves assigning a priority color code to patients arriving at the hospital ED: white ; green ; yellow ; red  .Exclusion criteria were an age < 18 years and patient’s death or leave of ED before physician’s decision.The DA protocol was implemented on alternate weeks and between 8:00 am to 8:00 pm to evaluate its impact before full implementation . During the weeks in which the DA was adopted, following an algorithm made by the physicians, the nurses at triage ordered the blood tests listed in Table A multidisciplinary team including the hospital risk manager, ED physicians and nurses, laboratory physicians and IT technicians defined the standard operating procedure . ED crowding was estimated for each visit through the National ED Overcrowding Study (NEDOCS) score . The NEDFrom July 1st 2019 to December 312,019, 3224 visits were included in the study , out of a total of 30,532 ED visits ;327 ± 123 versus 345 ± 157 min for the patients with chest pain (univariate p = 0.053);356 ± 149 versus 341 ± 167 min for the patients with abdominal pain (p = 0.023).337 ± 166 versus 304 ± 147 min for the patients with non-traumatic bleeding . In contrast, ED LOS did not significantly differ during DA and control weeks for the patients with abdominal pain (p = 0.41) and non-traumatic bleeding (p = 0.20). The other higher independent predictors of ED LOS were NEDOCS score, number of specialist consultations (at least 1), number of imaging tests, hospitalization , age and yellow priority code , and male gender   Table .Table 3In this field, retrospective cohort study, the introduction of protocol of DA in ED showed contrasting results: although the ED was reduced by approximately 30 min for the patients presenting with chest pain, no impact was observed for the patients with abdominal pain and non-traumatic bleeding. Also, with regard to chest pain, the observed reduction in LOS was shorter than the mean difference of 51 min reported in a systematic review on triage-nurse ordering . The potThe other results of the multivariate analyses were straightforward: a longer ED LOS was observed for patients, with upper priority code, during the periods of higher ED crowding (higher NEDOCS score). Noteworthy, female patients with abdominal pain showed a significantly longer LOS than males. This could be explained by the fact that abdominal pain has gender-specific diagnostic differences . Again, further, specific studies are warranted to investigate the potential gender difference on LOS and its potential organizational consequences.First, in this study the DA protocol was limited to the daily hours of service from 8:00 am to 8:00 pm, due to a limited availability of resources (nurses in service) during night shifts. However, during the nights, ED crowding is typically lower.Second, triage-initiated blood testing requires a crowded ED in order to detect a positive impact on LOS: in uncrowded ED patients are immediately, or after a very short waiting time, addressed to physician’s evaluation, and it may not be observed any LOS reduction from anticipated testing. In this study, the mean NEDOCS score ranged from 120 (overcrowded) to 160 (severely overcrowded). Thus, the findings of this study cannot be generalized to ED with low crowding status and short waiting times before physician’s evaluation.The introduction of a protocol of DA of blood tests at triage, into a crowded ED, showed contrasting results: the LOS was significantly reduced, by approximately 30 min, for the patients reporting chest pain, whereas no impact was observed for the patients with abdominal pain or non-traumatic bleeding. Although the impact of diagnostic anticipation could be substantial in reducing the ED waiting time, further research is required to confirm the positive findings and investigate the potential reasons of the observed discrepancies by clinical condition.Additional file 1.


Background: Activation of TRPM8, a cold-sensing receptor located on the cornea and eyelid, has the potential to relieve the neuropathic ocular pain (NOP) in dry eye (DE) by inhibiting other aberrant nociceptive inputs. We aimed to investigate the effect of a topical TRPM8 agonist, cryosim-3 (C3), on relieving DE-associated NOP. Methods: We conducted a prospective pilot study of 15 patients with DE-associated NOP. These patients applied topical C3 to their eyelid, 4 times/day for 1 month. The patients underwent clinical examinations. They also completed the Ocular Pain Assessment Survey (OPAS), which is a validated questionnaire for NOP, at baseline, 1 week, and 1 month after treatment. Result: At 1 week, the OPAS scores of eye pain intensity, quality of life , and associated factors  improved. The total OPAS scores of eye pain intensity, quality of life, and associated factors remained improved at 1 month. The Schirmer test scores also improved at 1 month. Conclusion: TRPM8 agonist (C3) could be a novel agent for treating patients with DE-associated NOP who are unresponsive to conventional treatments. Dry eye (DE) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanying ocular symptoms . It has Transient receptor potential (TRP) cation channels are associated with the perception of chemical and temperature stimulations . Within This prospective nonrandomized pilot study was conducted in accordance with the tenets of the Declaration of Helsinki. Ethical approval was obtained from the Chonnam National University Hospital Institutional Review Board (CNUH-2018-274). Informed consent was obtained from all included patients. The sample size was calculated using the G*Power software  with a level of α = 0.05 and a power of 95% to detect a 2-point difference in pain scales. Accordingly, a total sample size of 13 patients was found sufficient.Patients with DE accompanied by NOP features, who underwent evaluation between January and December in 2018, were enrolled. DE was diagnosed based on ocular surface disease index (OSDI) score ≥13 and tear break-up time (TBUT) ≤7 s. The inclusion criteria were as follows: (1) chronic ocular pain that was unresponsive to conventional topical agents  for >3 months; (2) discordance between the painful DE symptoms and signs and specific descriptors, including burning or stinging; and (3) a Wong–Baker FACES Pain Rating Scale (WBFPS) score ≥4. Patients who had a history of ocular diseases other than DE and those receiving systemic medications that alter the pain and mood statuses were excluded.The patients were treated with add-on C3 while undergoing conventional topical treatment. C3 samples (2 mg/mL) were diluted in purified water, soaked in gauze, and packaged using automated equipment. The patients applied topical C3 by wiping the gauze on the closed eyelid margin, 4 times/day for 1 month B.The OSDI questionnaire, which ranged from 0 to 100, was used to quantify the vision-related QoL. TBUT, the time interval between the last complete blink and the first appearance of disruption of the tear film, was measured thrice, and the mean value was used for analysis. Corneal staining scores were assessed using the area-density index, by multiplying the area and density score. The Schirmer test score represented the length of wetting, and was measured using a calibrated sterile strip placed at the lateral canthus for 5 min under topical anesthesia (0.5% proparacaine). Only the score of the right eye was assessed.The WBFPS was chosen to screen the pain severity in the patients with DE. The patients chose the face that best depicted the pain they were experiencing. At baseline, 1 week, and 1 month after treatment, the patients also completed the OPAS, which is a validated questionnaire for neuropathic pain as previously described . The quep-value <0.05 was considered statistically significant.Statistical analyses were conducted using PASW Statistics for Windows, Version 18.0 . The normality of distribution was assessed using the Shapiro–Wilk test. The Wilcoxon signed-rank test and repeated-measures analysis of variance with Bonferroni’s post hoc test were used for comparing parameters before and after treatment. A This study enrolled 20 patients with DE accompanying NOP features. Five patients (25.0%) discontinued the treatment because of drug ineffectiveness or intolerance. The remaining 15 patients (75.0%) were included in the analysis. Their mean age was 59.5 ± 13.0 years, and nine patients (60.0%) were women. Five patients had a history of intraocular surgery, and one patient had a history of ocular trauma. At 1 week after treatment, eye pain intensity, QoL , and associated factors  were improved. The total Ocular Pain Assessment Survey (OPAS) scores of eye pain intensity, QoL (sleep), and associated factors (burning sensation and light sensitivity) remained improved at 1 month. However, the score of non-eye pain and aggravating factors did not change after treatment . Among tDE is a multifactorial disease of the ocular surface that is accompanied by ocular symptoms . The preHowever, chronic NOP associated with DE is a challenging clinical problem that is difficult to treat with conventional medications ,13. ConvSeveral members of the TRP super family have emerged as important targets for pain control owing to their critical role in nociception, especially, in chronic states . TRP recThis pilot study showed that the topical application of a TRPM8 agonist (C3) to the eyelid was safe and effective in relieving NOP in patients with DE. We previously showed that the topical application of C3 stimulates basal tear secretion and relieves ocular discomfort in patients with mild DE . The senTopical delivery of C3 to the eyelid margins could minimize corneal exposure that induces side effects, such as discomfort or paradoxical ocular pain . In addiThis study included a short follow-up period of 1 month and a small sample size. In our study, 15 patients who were included in the analysis showed improved symptoms after treatment; however, a larger sample size would have yielded a more accurate response rate. The number of enrolled patients was too small to perform a subgroup analysis. This was a single-center study, and hence, the findings should be verified in future multicenter prospective randomized control studies evaluating the objective signs. In addition, we did not strictly control for previous medications for DE when enrolling the patients. This might have induced a bias during analysis. However, patients in our study did not respond to conventional treatment for a long period of time (122.7 days), but they showed an improvement of ocular pain within 1 week after C3 treatment. This improvement suggests a direct effect of C3 treatment rather than a delayed effect of previous conventional treatment. We believe that including patients with varying histories of medical treatments may likely emulate the actual use of this drug. Despite the aforementioned limitations, the TRPM8 agonist (C3) could be a novel agent for treating NOP in patients with DE who are unresponsive to conventional topical treatment.


The increased recognition of the high prevalence and important burden of cancer pain and the documentation of a large proportion of patients receiving inadequate analgesic treatment should have reinforced the need for evidence-based recommendations. The World health Organization (WHO) guidelines on cancer pain management—or palliative care—are traditionally based on a sequential, three-step, analgesic ladder according to pain intensity: nonopioids  to mild pain in step I; weak opioids  to mild-moderate pain in step II; and strong opioids to moderate-severe pain in step. III. Despite the widespread use of this ladder, unrelieved pain continues to be a substantial concern in one third of patients with either solid or hematologic malignancies. The sequential WHO analgesic ladder, and in particular, the usefulness of step II opioids have been questioned but there are no universally used guidelines for the treatment of pain in patients with advanced cancer and not all guideline recommendations are evidence-based. The American Society of Clinical Oncology and the European Society of Medical Oncology have recommended the implementation of early palliative care (EPC), which is a novel model of care, consisting of delivering dedicated palliative service concurrent with active treatment as early as possible in the cancer disease trajectory. Improvement in cancer pain management is one of the several important positive effects following EPC interventions. Independent well-designed research studies on pharmacological interventions on cancer pain, especially in the EPC setting are warranted and may contribute to spur research initiatives to investigate the poorly addressed issues of pain management in non cancer patients. The percentage of responder patients was higher in the low-dose morphine group, as early as at 1 week, and clinically meaningful (≥30%) and highly meaningful (≥50%) pain reduction from baseline was significantly higher in the low-dose morphine group (p < 0.001). A change in the assigned treatment occurred more frequently in the weak-opioid group, because of inadequate analgesia. Also, the general condition of patients, based on the Edmonton Symptom Assessment System overall symptom score, was better in the morphine group and adverse effects were similar in both groups [Approximately one third of cancer patients still do not receive pain medication proportional to their pain intensity . A recenh groups . Our stuh groups . Unfortuh groups . Despiteh groups . Consisth groups , which hh groups  indirecth groups , with a h groups . Similarh groups .In conclusion, based on a revision of several guidelines, and especially the most recent ESMO, NCCN, and WHO guidelines ,17,18, sOne of the possible reasons for the successful completion of our RCT study, in due time , may resWe think that the implementation and dissemination of evidence-based knowledge on the use of drugs in cancer pain management, especially in the favorable and clinically relevant context of EPC interventions, may be a pragmatic and effective way to counteract the opioid misuse and abuse, in the oncology and hematology wards and among patients and their caregivers. The further dissemination of scientific results, leading to a robust knowledge on cancer pain management, may, in turn, spur a broad scientific interest and multiple novel research initiatives and well-designed studies on the management of pain in non-cancer patients and contribute to generate new insights on such themes either in the scientific community or in the clinical care wards or in the general population.


To assess associations between preserved spinal cord tissue quantified by the width of ventral and dorsal tissue bridges and neuropathic pain development after spinal cord injury.This retrospective longitudinal study includes 44 patients  age, 50.05 (18.88) years) with subacute  spinal cord injury  and neuroimaging data who had a follow-up clinical assessment at 12 months. Widths of tissue bridges were calculated from midsagittal T2-weighted images and compared across groups. Regression analyses were used to identify relationships between these neuroimaging measures and previously assessed pain intensity and pin-prick score.Pin-prick score of the 25 patients with neuropathic pain increased from 1 to 12 months , while it stayed similar in pain-free patients . They also had larger ventral tissue bridges  at 1 month when compared with pain-free patients. Conditional inference tree analysis revealed that ventral tissue bridges’ width (≤2.1 or >2.1 mm) at 1 month is the strongest predictor for 12 months neuropathic pain intensity  and 12 months pin-prick score .Larger width of ventral tissue bridges—a proxy for spinothalamic tract function—at 1 month post-spinal cord injury is associated with the emergence and maintenance of neuropathic pain and increased pin-prick sensation. Spared ventral tissue bridges could serve as neuroimaging biomarkers of neuropathic pain and might be used for prediction and monitoring of pain outcomes and stratification of patients in interventional trials. Spinal cord injury (SCI) is a devastating and life-changing event. In most cases, it produces immediate and permanent sensory, motor and autonomic dysfunction below the level of injury, resulting in a reduced quality of life.16Based on neuroimaging, the location and width of spared midsagittal tissue bridges have been shown to be critically involved in the recovery of sensorimotor function.This study aimed to explore the value of spared midsagittal tissue bridges  derived from conventional T2-weighted (T2w) serial scansIn this retrospective study, we included 44 patients with subacute SCI (28 tetraplegic and 16 paraplegic patients) who were admitted consecutively to the Balgrist University Hospital  between May 1996 and January 2019. Of these 44 patients, all had a follow-up clinical assessment and 32 had a neuroimaging follow-up visit at 12 months post-SCI .We used 1 month and 12 months neuroimaging, neuropathic pain and clinical data from these patients to investigate group differences and clinicopathological relationships as well as outcome predictions by means of regression analysis and unbiased recursive partitioning (URP). Variables of interest included were lesion parameters as well as pain and clinical outcome measures at 1 month and 12 months follow-up.We excluded patients with pre-existing neurological or mental disorders or brain lesions, as well as patients with MRI contraindications.Tissue bridge data from a small subset of the study population was previously reported in a different context.9–11http://www.emsci.org/). On the EMSCI questionnaire, patients rate various aspects of pain . The pain intensity was quantified using an 11-point numeric rating scale with ‘0’ indicating no pain and ‘10’ indicating the worst imaginable pain. Data from the EMSCI pain questionnaire was available for 43 patients with SCI at 1 month  and 42 patients at 12 months post-SCI . One patient and two patients without EMSCI pain questionnaire at 1 month and 12 months, respectively, reported to suffer from NP.All patients were clinically examined using a comprehensive clinical protocol including 1) the International Standards for Neurological Classification of Spinal Cord Injury protocolAll study participants underwent MRI on 1.5 or 3 T Philips , Siemens  or GE  scanners. A 32-channel receive spine coil integrated in the table was used with all scanners. The anatomical MRI protocol consisted of standard sagittal T1-weighted, sagittal T2w and axial T2w clinical scans obtained at the lesion level. Repetition time (TR), echo time (TE) and flip angle (FA) of the sagittal T2w clinical sequences were used as follows: at 1.5 T  and at 3 T . The echo train length was 19 at 1.5 T and 17 at 3 T. At 1.5 and 3 T, the field of view9 was set to 330 mm×330 mm and 220 mm×220 mm, respectively. To reduce metal artefacts, readout bandwidths were increased at 1.5 T (415 Hz/pixel) and at 3 T (751 Hz/pixel). The spatial resolution of sagittal T2w images was 0.55 mm×0.55 mm×2.75 mm at 1.5 T and 0.57 mm×0.57 mm×2.75 mm at 3 T. The midsagittal slices of sagittal T2w scans were the ones used for lesion segmentation analysis.9–11Together with oedema and haemorrhage, intramedullary damage manifests as changes of signal intensity on T2w scans.Lesion segmentation was performed manually and blinded to patient identity and scan time point by rater DP. We used the Jim software  to delineate the lesion on the midsagittal slice from sagittal T2w scans. This enabled us to assess the lesion area, its rostro-caudal lesion length, anterior-posterior lesion width and ventral and dorsal tissue bridges, the sum of both reflecting the total width of tissue bridges .9 10Statistical analysis was performed using Stata software . We used unpaired two-tailed t-tests to compare patients with SCI with NP and pain-free patients with SCI regarding their age at 1 month scanning time point and the time interval between injury and 1 month scan. Paired two-tailed t-tests were used for comparison of midsagittal tissue bridges , pin-prick score and mean pain intensity at 1 month and 12 months post-SCI.We applied Mann-Whitney U tests for pairwise comparisons of patient groups regarding their pin-prick score and width of midsagittal tissue bridges  at 1 month and 12 months post-SCI as well as rate of change in pin-prick score from 1 month to 12 months.We used multivariable linear regression analysis to investigate associations between imaging measures  and mean pain intensity at 1 month. One month quantitative lesion measures were also used with the same model to predict mean NP intensity and recovery of pain sensation  at 12 months follow-up. Age and sex were included as covariates of no interest in the regression models to adjust for linear age and sex dependency. Models including ventral tissue bridges were also corrected for dorsal tissue bridges. Prediction models were furthermore adjusted for 1 month clinical scores . Potential confounders were only retained if the covariates were significant or if they had a substantial effect on the correlation coefficient of interest. Results were regarded as significant when the p values were ≤0.05 and CIs were set to 95%.We further used a widely usedAnonymised data of this study are available on request from the corresponding author.Forty-four patients with SCI (n=35 men (79.5%)) with a mean (±SD) age of 50.05±18.88 years were included. Patients with NP  and pain-free patients  did not differ in their age at 1 month . The patients’ time interval between injury and 1 month scan  was 32.95±16.85 days. There was no difference in time since injury  between patients with NP  and pain-free patients .Over time, NP developed in six initially pain-free patients whereas one patient with NP at baseline reported to be NP-free at follow-up. Patients with NP at 1 month (56.8%) and 12 months follow-up (68.2%) reported a similar mean NP intensity of 3.67±1.61 and 3.68±1.61 , respectively. Pin-prick score of patients with SCI with NP was 70.08±28.40 at 1 month and increased to 80.16±27.88 at 12 months post-SCI . In pain-free patients, 1 month pin-prick score was 57.84±25.02 and did not significantly change over time ). Between both patient groups, there was no difference in pin-prick score at 1 month  and the rate of change in pin-prick score from 1 month to follow-up at 12 months did not differ .Of 44 patients, 8  A patients) had no midsagittal tissue bridges (18.2%) while the remaining 36  did have midsagittal tissue bridges (81.8%) with an average width of 2.21±1.65 mm. Thirty-one of 44 (70.5%) patients had ventral tissue bridges with an average width of 1.17±1.18 mm and 29 of 44 (65.9%) had dorsal tissue bridges with an average width of 1.03±1.20 mm. Twenty-four patients had both ventral and dorsal tissue bridges while seven and five patients had only ventral or dorsal bridges, respectively.At 1 month, width of total midsagittal tissue bridges was larger  and higher pin-prick score at 12 months , independent of dorsal tissue bridges, age and 1 month clinical score. When looking at subgroups separately, patients with NP  showed a positive relationship between width of ventral tissue bridges at 1 month and pin-prick score at 12 months.Larger ventral tissue bridges at 1 month were associated with a higher mean NP intensity  into two terminal nodes with regard to the patients’ mean pain intensities at 12 months, according to the 1 month width of ventral tissue bridges being ≤2.1 mm  or >2.1 mm . The two subgroups presented 12 months mean pain intensities of 1.90±2.26 and 3.83±1.19, respectively. The URP-CTREE algorithm also identified 1 month ventral tissue bridges as a predictor for 12 months pin-prick score, its width separating the initial group (p=0.025, n=44, This study demonstrates the potential involvement of spared ventral tissue bridges in the development and maintenance of NP following SCI. In particular, patients with NP had larger total and ventral tissue bridges when compared with pain-free patients, their width at 1 month being a predictor for a higher NP intensity and higher pin-prick score at 12 months post-SCI.et alet al8 16 32–34As expected,et al38–40Ventral tissue bridge measures are likely to cover the anterior spinothalamic tract.This study has limitations. First of all, this study is a retrospective monocentric study with specified inclusion criteria. This likely represents a bias source as the study design resulted in a homogeneous data set, but might not reflect the general SCI population. Future studies would therefore benefit from a prospective multicentric design including larger patient numbers. Furthermore, women and men were not equally distributed in our patient cohort. However, this is also not the case for the general SCI population.This study identifies spared tissue bridges as quantifiable neuroimaging biomarkers assessed by conventional MRI predicting the emergence and maintenance of NP. Specifically, we identified 1 month width of ventral tissue bridges as the strongest predictor of NP intensity and pin-prick score at 12 months post-SCI. Thus, ventral tissue bridges represent MRI metrics, which could be readily implemented in the daily clinical routine to serve as promising, reliable and time-saving neuroimaging biomarkers for the monitoring of NP and for stratification of patient subgroups in interventional clinical trials.