Minimal pain at D1  and maximal pain at M6  were independent predictors for CPSP at M12. CPSP is an important issue after otorhinolaryngological surgery. Better instrument for perioperative assessment should be defined to identify patients at risk for CPSP.Data on chronic postsurgical pain (CPSP) after otorhinolaryngological surgery are sparse. Adult in-patients treated in 2017 were included into the prospective PAIN OUT registry. Patients’ pain on the first postoperative day (D1), after six months (M6) and 12 months (M12) were evaluated. Determining factor for CPSP was an average pain intensity ≥ 3  at M6. Risk factors associated with CPSP were evaluated by univariate and multivariate analyses. 10% of 191 included patients , had CPSP. Average pain at M6 was 0.1 ± 0.5 for patients without CPSP and 4.2 ± 1.2 with CPSP. Average pain with CPSP still was 3.7 ± 1.1 at M12. Higher ASA status (Odds ratio [OR] = 4.052; 95% confidence interval [CI] = 1.453–11.189;  It has been shown for several types of the surgery, that patients with CPSP have a significantly lower physical and mental health, show higher fatigue levels, and less social functioning than patients without CPSP4. The risk for the development of CPSP still is underestimated in clinical routine and a largely unrecognized clinical problem5. Up to and including the International Classification of Diseases (ICD), 10th revision  did not offer a diagnostic category for the classification of CPSP. The 11th revision of the ICD (ICD-11) will come into effect on 1 January 2022. The International Association for the Study of Pain (IASP) defined CPSP for the ICD-11 as chronic pain that develops or increases in intensity after a surgical procedure or a tissue injury and persists beyond the healing process, i.e., at least 3 months after the surgery6. Furthermore, other causes for the pain have been excluded; and the possibility that the pain is from a pre-existing condition has been excluded7.Chronic postsurgical pain (CPSP) is an important clinical problem which significantly influences recovery after surgery and patients’ quality of life8. Severe CPSP is reported for 2–15% of the surgical patients5. One Norwegian population-based study has been published reporting that 10.5% of surgical patients developed CPSP and still 6.2% after excluding all patients with any pain before surgery9.It is said that CPSP occurs in 10–86% of patients after common operations, such as groin hernia repair, breast and thoracic surgery, leg amputation, and coronary artery bypass surgery10. ORL and head and neck surgery is underrepresented and neglected as a specific entity in studies on CPSP. Assessment of the multifactorial nature and subjective experience of CPSP has proved challenging for researchers although a number of tools and pain questionnaires are available for the assessment of pain. The assessment should also include the major psychosocial dimensions of pain11. Beyond acute postoperative pain, several demographic, psychosocial, genetic factors, as well as preoperative pain, surgical factors, and perioperative anesthesia and analgesia take influence on the risk of development of CPSP12.It is well known that otorhinolaryngological (ORL) and head and neck surgery can lead to severe acute postoperative pain. Even a so-called minor surgery like tonsillectomy is ranked among the 25 procedures with highest pain intensitieswww.quips-project.de) in Germany, the present prospective study used QUIPS data in combination together with questionnaire-based follow-up data to investigate postoperative pain, pain medication use, and pain-related interference up to 12 months after ORL and head and neck surgery.Using our well-established prospective registry structure of the nationwide project Quality Improvement in Postoperative Pain Treatment . Patients’ and surgical characteristics as well as the postoperative pain scores were not different between patients of the final study groups and patients lost to follow-up  had no CPSP and 19 (10%) had CPSP at M6. The pain at M6 was always localized to the surgical site or referred area, i.e. in the head (11 patients), neck (7 patients), and thorax (1 patient). 5 patients were lost for follow-up at M12. 168 patients had no CPSP (90%) and 18 had CPSP at M12 (10%). At M12, the pain was localized in the head (12 patients), neck (5 patients), and thorax (1 patient). Half of the patients (9 patients) with CPSP at M6 and M12, respectively, had chronic pain before ORL surgery. The localization of the chronic pain before surgery was different from CPSP localization in all cases. At M6 still 22 patients (11.5%) and at M12 still 20 patients (10.5%) took pain analgesics , higher ASA status (p = 0.006), chronic pain before surgery (p = 0.015), and pain medication intake before surgery (p = 0.026). All functional interference parameters were worse in patients with CPSP . Age, gender and other patient factors had no influence . From all pain parameters at D1 , minimal pain showed the largest difference between patients without versus with CPSP. Table p = 0.007). Still all functional interference parameters were worse in patients with CPSP . From all pain parameters measured at D1, still minimal pain was the best distractor between patients without versus with CPSP. Beyond average pain (defining CPSP), also minimal and maximal pain at M6, were significantly different between patients without versus with CPSP at M12.Table y p = 0.06. All fup = 0.007), only thyroid surgery , and minimal pain at D1  remained independent risk factor for CPSP at M6 (Table p < 0.001). In model 2, minimal pain at D1  and maximal pain at M6  remained independent predictors for CPSP at M12. Also at M12, chronic pain before surgery was not an independent risk factor for CPSP.In the multivariate analysis, the ASA status  reported in 17–22% of persistent mild to severe pain (not differentiated). In the present study, patients with pharyngeal surgery were the largest group of patients with CPSP at M6. It is well known that pharyngeal surgery can be followed by sever postoperative pain14. Hence, it fits together that pain at D1 was associated to CPSP at M6 and M12. In conclusion, the presented series seems to be the largest study exclusively for ORL and head and neck surgery, and a CPSP rate of about 10% seems to be plausible.ORL and head and neck surgery were so far underrepresented in CPSP studies. A data analysis of 3120 patients from the European registry included 60 patients after thyroidectomy15. Hence, opioid dependence got much attention in the media. In contrast, not much is known about long-term postoperative non-opioid dependence. In the present study, three patients (1.6%) still took opioids. None of these three patients was a head and neck cancer patient. Nearly to one-third of head and neck cancer patients still is taking opioids 6–12 months after surgery17. In a recent population-based cohort study among patients undergoing plastic and reconstructive surgery, a persistent opioid use occurred in 6.6% of the patients15. A recent analysis of a U.S. nationwide insurance claims dataset from 2013 to 2014 analyzed persistent opioid use after minor and major surgery18. From head and neck surgery, thyroidectomy patients were included. Thyroidectomy patients had an incidence of 5.1% of new persistent opioid use within 90–180 days after surgery. In comparison to the U.S. American data, the incidence of long-term opioid dependence was low in the present study. This may be due to a more restrictive prescription of opioids in Germany. The present study did not include children. Tonsillectomy is one of the most painful ORL surgeries and is mainly performed in children and young adults. A recent analysis of a database of a large national private insurer in the U.S. showed that many children receive postoperative opioid prescription fills19. Therefore, it would be worthwhile to investigate the incidence of CPSP after pediatric ORL and head and neck surgery.At M6 and M12 still 11.5% and 10.5%, respectively, of the patients , took pain medication. There is increasing data that perioperative opioid use is an important risk factor for long-term opioid dependence. In the present study, only 11.8% of the patients received perioperative opioid use and the application was not a risk factor for CPSP. It is reported that 5–10% of surgical patients exhibit a persistent postoperative opioid use1. Younger age, body mass index, psychological distress were predictors for persistent post-surgical pain (NRS ≥ 1) in the already mentioned cross-sectional survey9. This makes clear that the immediate postoperative pain and probably many psychosocial factors that were not analyzed so far, have a major impact on the risk to develop CPSP. It is well known that psychological factors like preoperative anxiety, the pain catastrophizing level, and resilience have a major impact on postoperative pain after ORL surgery20. It is likely that these factors have direct or indirect impact also on the risk to develop CPSP. Furthermore, pain intensity can be considered as one determining key factor for CPSP. Many of the mentions psychosocial factors contribute to the bio-psycho-social model of chronic pain. This should be analyzed in future studies. The characteristics and quality of the chronic postoperative pain should be analyzed in more detail as well as the impact of chronic pain on physical and mental health.Higher comorbidity as reflected by the ASA status, higher pain at D1, persisting pain at M6 were independent predictors for CPSP at M12. Preoperative chronic pain was not an independent predictor in the present series. The multivariate analysis of the PAIN OUT trial identified orthopedic surgery, preoperative chronic pain and percentage of time in severe pain on D1 as risk factors for M1221. Older patients seem to need specific chronic post-surgical pain treatment and prevention strategies.In the present study, the patients in the CPSP group were older. The difference was not statistically significant but a trend was seen. The ratio of the elderly patients scheduled for ORL surgery is presumably growing in the future. Frailty, delirium, and cognitive deficit are regarded as further important factors in the development of chronic post-surgical pain in older adultsAs usual the present study was based on patient self-report, the outcomes assessed by validated questionnaires. Although this work was not a randomized controlled study and the authors did not focus on the exact analgesic dose regimens, moreover, the pain management was not standardized because of the vast diversity of patients, illnesses, and surgical interventions which can be a limitation of this research, the results are consistent with former investigations regarding the effective pain management, lower opioid use, greater patients’ satisfaction, and low CPSP rate.23. Future trials should therefore focus on the principles of opioid-free anesthesia in ORL surgery for preventing adverse side effects of opioids and dependence. The presented study based on the assessment of the pain intensity and analgesic medication can be the basis for further investigations for a better understanding of the development of CPSP after ORL surgery. These studies should standardize or randomize the perioperative and postoperative opioid prescription to analyze the effects on chronic postsurgical pain. The effective and satisfactory pain management seems to be the most important factor in the prevention of CPSP since the intensity and duration of the pain can be considered as the main determining key factors for the development of CPSP.Only 5% of patients remained with CPSP due to the multimodal perioperative pain management, which seems to be one of the most important factors in the prevention of CPSP. In the present study, only 11.8% of the patients received perioperative opioid medication. Opioid-free anesthesia has gained in popularity as a way to enhance early recovery and to spare opioids for the postoperative period18. Assessment of such preoperative factors should be included in future trials.Data on the course of the individual (acute versus chronic) diseases were not analyzed. Especially, pain characteristics in patients with head and neck cancer or other severe chronic ORL diseases may have affected the results at M6 and M12. Moreover, preoperative psychosocial factors like tobacco, alcohol and substance abuse disorders, mood disorders, and anxiety are known risk factors especially for persistent opioid use after surgery24. Such special perioperative and postoperative pain services are so far offered only at a few places25.In conclusion, this prospective cohort register-based study on 191 patients representing everyday clinical practice after otolaryngological and head and neck surgery showed that a considerable number of patients develop CPSP and therefore take analgesics. Patients at high risk for CPSP need to be identified early and offered coordinated and comprehensive prevention and perioperative care at best by a multidisciplinary team consisting of pain physicians, advanced practice nurses, psychologists, and physiotherapistswww.pain-out.eu) project and theGerman-wide Quality Improvement in Postoperative Pain Treatment  registry . The ethics committee of the Jena University Hospital, Jena, Germany, approved the study protocol for a data collection of routine and anonymized hospital data as well as the QUIPS questionnaires. The study followed all relevant guidelines of the institutional ethics committee and the principles of the Declaration of Helsinki. By completing the patient questionnaire, a patient gave written informed consent for study participation.The present prospective cohort study was part of the PAIN OUT  in the ENT department of Jena University Hospital were included. Other inclusion criteria were age ≥ 18 years, oriented and awake, linguistic and intellectual understanding of German language, written consent.26. Briefly, the QUIPS questionnaires consisted of two parts: This first part was covering the patient-reported outcome (PRO) parameters and comprised a validated 15-item questionnaire, whereas the second part was filled by the investigator. After a standardized instruction, the patient herself or himself completed the first part at the first postoperative day (D1). QUIPS used 11-point NRS to estimate the patient’s pain intensity during activity, minimal and maximal pain. Generally, higher numbers were indicating more pain . Furthermore, the patient was asked by dichotomized (yes/no) questions about pain-related impairments , side effects of pain treatment , and satisfaction with the pain management. The second part, which was filled by the investigators, was covering the relevant demographic and clinical parameters like age, gender, type of surgery including coding of the surgical procedures (OPS codes) due to the German procedure classification (OPS-301), anesthesia, pain management, and was collected from the patients’ charts. The patients’ pre-anesthesia overall health status was preoperatively assessed by The American Society of Anesthesiologists physical status classification system (ASA status)27. The Charlson comorbidity index (CCI) was utilized to assess the patients’ comorbidity28.The QUIPS questionnaires are presented in detail elsewherehttp://www.quips-projekt.de). Here, the patients answered the same questionnaire. If a patient was not reached via telephone or email, the questionnaire was sent to the patient by regular post. To assess the postsurgical pain, i.e. explicitly related to the ORL surgery, again 11-point NRS were used to estimate the patient’s minimal, maximal pain, and average pain within the last 24 h as well the actual pain. Again, higher numbers were indicating more pain . All pain drugs taken were listed. Finally, German version of the Brief Pain Inventory (BPI) was used to estimate the functional interference within the last 24 h with three domains: physical interference , affective interference , and sleep was assessed also using 11-point NRS 29. Patient with any intensity of persistent pain (NRS ≥ 1) were differentiated from patient with CPSP: All patients who indicated average pain with NRS ≥ 3 at M6 and/or M12 were defined as patients with CPSP. Patients with average pain NRS < 3 at M6 and/ or M12 were defined as patients without CPSP. Furthermore, the group of patients with CPSP was subdivided into patients without chronic pain of other reasons before surgery and patient with chronic pain before surgery.Depending on their preferences, patients were contacted via telephone or email after 6 months (M6) and once more after 12 months (M12) with the identical QUIPS questionnaire. If contacted by telephone, the questions of the QUIPS questionnaire were answered by telephone interview. If contacted via email, the patients received an individual code to log into the QUIPS webpage (p < 0.05) were included into multivariate binary logistic regression analyses for analysis of independent predictors for CPSP at M6 and at M12. From the pain parameters, minimal pain was included into the multivariate analyses, because minimal pain showed the largest difference between patients without CPSP and with CPSP. Nominal p values of two-tailed tests are reported. The significance level for the multivariable analyses was also set at p < 0.05.If not indicated otherwise, data is presented with mean values ± standard deviation (SD). All statistical analyses were performed using IBM SPSS, version 25. Pearson’s chi-square test or Fisher’s exact test was used to compare ordinal and nominal data of patients without CPSP and with CPSP. The nonparametric Mann–Whitney-U-test was used to compare metric data. Parameters with significant differences between both groups in univariate testing (Supplementary Information


Consciousness constitutes a fundamental prerequisite in the individual appraisal and experience of pain. In the same way, a person needs to be able to report on pain perception. Patients who suffered a severe brain injury with disorders of consciousness (DOC) represent a spectrum of pathologies affecting patients' capacity to interact with the external world. In these patients, the most relevant aspects in response to pain are physiologic and behavioral. The treatments and management of pain are challenging issues in these patients, arising serious ethical concerns and bringing emotional load among medical staff, caregivers, and relatives. In this review, we report the importance of having a correct pain management in DOC patients, to individuate the best pharmacological treatment that can make the difference in detecting a behavioral response, indicative of a change in the level of consciousness, and in planning a more effective rehabilitative approach. The importance of reporting on the pain sensation is described in a study by Clarke and colleagues on the chronic pain in older adults, recommending the narrative approach to describe and discuss the experience of pain. If this approach could represent an useful tool to assess pain in subjects who are able to refer on it . Typical physiological responses are observable in the cardiovascular reactivity, respiration, skin conductance and pupil dilatation .via spinothalamic tract to reach the thalamus and the cortex  refers to the perception (conscious or not) of nociceptive stimuli  , elicitie cortex . The refe cortex , while pe cortex .Pain Matrix  and the Medial Network (MN). The LNN encompassing S2 cortex, lateral thalamus, and posterior insula  encodes Several studies investigating the dynamics of activation (connectivity) of the pain matrix have shown that nociceptive input is first processed in the posterior insula, wherein it is coded in terms of intensity and anatomical location, and then transmitted to the anterior insula, where the emotional reaction to pain is elaborated .For the "mind-body" theory, the pain experience necessitates of a body and a mental component . The firIn non-communicative patients, the most relevant aspects in response to pain are physiologic  and behavioral .To assess pain in non-communicative patients several behavioral scales were developed, with each of them oriented to assess a specific typology of patients. As an example, the Behavioral Pain Scale  which isDisorders of Consciousness (DOC) represent a spectrum of pathologies affecting the capacity of patients to interact with the external world. It can be either due to a traumatic or a non-traumatic cause and sometime to a combination of both .Among the different definition of consciousness, the most accepted viewpoint refers to the brain's ability to form cognition of the world, by the perception of self and the environment. A requisite for conscious behaviors is the presence of adequate arousal  and awareness of content  . The firThe two possible conditions following the acquired brain injury  are either the Vegetative State/Unresponsive Wakefulness Syndrome (UWS/VS) or the Minimally Conscious State (MCS) . The firThe clinical assessment is based on clinical consensus and behavioral scales such as the Coma Recovery Scale .For the assessment of pain in patients with DOC a specific scale, the Nociception Coma Scale  has beenA study by The treatments and management of pain is a challenging issue in patients with DOC. The condition of suffering in DOC patients is a very controversial question. Generally, caregivers and relatives believe in the possibility that VS/UWS patients might feel pain, influencing end-of-life decisions. However, there is not a unanimous consensus about whether non-responsive patients might have a sufferance condition or might feel pain , implyin2O) PET study, pain induced activation of the midbrain, contralateral thalamus, and primary somatosensory cortex in UWS/VS patients , Galvanik Skin Response (GSR), or Laser Evocated Potential (LEP) have shown the possibility to observe pain processing in UWS/VS patients .HRV is the fluctuation in the time intervals between adjacent heartbeats  and represents the output of a complex brain-heart two-way interaction system . The CenTo describe the sympathovagal modulation, the HRV is generally analyzed in the time and frequency domains . HoweverIn two different LEP studies, authors found that brain-injured UWS/VS patients might process the painful stimuli . In a suThe above-cited results put in evidence two relevant points: firstly, the assessment of nociceptive stimulation as mean to detect possible content of consciousness in patients diagnosed as UWS/VS; secondly, also if not capable of exhibiting oriented behavior to the painful stimuli, UWS/VS patients might perceive pain. In a recent work, Cortese and colleagues  showed tPain could be present in the acute phase and in the successive period of intensive rehabilitation . The cauThe Central Nervous System damage might be the cause of chronic pain . These The presence of painful symptoms might interfere with the rehabilitation processes limiting and/or delaying its effect. It is crucial to intervene with appropriate early measure to prevent the appearance of secondary damage associated with pain and functional limitation such as bedsore or muscle-tendon retraction .In DOC patients, there is no general agreement on pharmacological pain treatment . GeneralBrain lesions in these patients are extensive, affecting the nervous system at the cortical, subcortical, intracortical and spinal level. It is essential to provide basic care, managing the insurgence of the secondary medical complication that could increase the risk of further disability  and compMost of these patients are characterized by spasticity. The spasticity, due to a lesion of the pyramidal tract, is defined as “a motor disorder, characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex as one component of the upper motor neuron syndrome.” . It is pThe symptomatic pain treatment follows the criteria of proportionality and graduality, assessing the interaction with the current therapy . The theA and GABAB receptors and GABAergic neurons are present in spinal cord and brain areas associated with the mediation and perception of pain (A receptors in the parafasciculus thalami (In case of suspected moderate pain and neuropathic pain, it is suggested a high-dose of aspirin or paracetamol, oral NSAIDs, GABAergic agents . GABAerg of pain . Behavio of pain . Both in of pain . Further thalami . The pha thalami .In the case of presumed severe pain, it is advised to consider the use of parenteral opioids, mixed agonists/antagonists, partial agonist opioids, antidepressants, anticonvulsants, and atypical agents . The opiIt is evident the current difficulty for pain treatment in patients with DOC, and the impossibility for the patient to refer on the pain perception makes the choice of the correct pharmacological approach a challenge.At the light of these concerns, the guideline of the physicians should be based on the cost/benefit, intended as to follow the ethical principle of nonmaleficence/beneficence of the treatments.Pain is not only a perceptual phenomenon. The initial injury, cause of the pain, disrupts the body’s homeostatic systems which, in turn, produce stress. Pain involves a dynamic interaction among biological, psychological, and social factors. These components may modulate pain perception and disability .The assessment and management of pain in patients with a DOC remain a challenge. The perception of pain in these patients arises rehabilitative problems with ethical issues extending beyond the boundaries of end-of-life decisions . To dateThe correct pain management and the capability to individuate the best pharmacological treatment can make the difference in detecting a behavioral response indicative of a change in the level of consciousness in DOC patients, and in planning a more effective rehabilitative approach.


Pain associated with sciatica is one of the most common indications for surgery. The annual rate of discectomy has increased over recent years, with a significant number of patients reporting a poor outcome or symptom recurrence after surgery. This study aims to evaluate the predictors of poor outcome for patients undergoing lumbar discectomy for sciatica. A comprehensive search was conducted to find relevant literature published between 1985 and 2019. All literature with a clear methodology were included. Many factors that affect postoperative recovery after lumbar discectomy have been reported. Some evidence suggests that sociodemographic factors, including female gender, smoking, increased age, low socioeconomic status, and low education level may be associated with less favorable outcomes after surgery. Symptom duration does not appear to be associated with a significant difference in long-term outcomes; however, early surgery (within one year) may result in a faster postoperative recovery with better early results. Furthermore, patients who had discectomy for predominant leg pain had better outcomes compared to those who had the surgery for back pain as the main presentation. There was no evidence to suggest a correlation between the size of the herniated disc and long-term outcomes of sciatica; however, a higher anatomical level of herniation  was associated with poorer outcomes compared to the lower level of herniation . A few studies suggested slow postoperative recovery correlates with unemployment and depression. We recommend that the predictors of postoperative outcomes should be taken into consideration when selecting or counseling patients for lumbar disc decompression. Lower-limb nerve root pain caused by lumbar disc herniation is one of the most frequent indications for spinal surgery. The mean annual rate of discectomies in Sweden during the past decade was 24 operations per 1,00,000 . The higPain is usually the most important symptom of patients with sciatica, and also the most important factor when selecting patients for surgery. The severity of pain experienced by patients is usually assessed on a visual analogue scale (VAS). An elimination or reduction of pain is essential for surgical success and improved quality of life . In pracThis study aims to evaluate the predictors of poor outcomes after lumbar disc decompression for sciatica. A literature search was performed in the electronic databases of Web of Science, Pubmed, Science Direct, and Google Scholar. In addition, manual searches and cross-referencing of articles were performed to include related reviews, studies, and reference lists. Different search strategies with different combinations of words related to back pain, sciatica, disc herniation were used had been implemented to retrieve the most relevant literature Table .All studies of predictors of outcomes after lumbar disc herniation surgery published between 1985 and 2019 with a clear description of the methodology were included. Papers discussing the predictors of outcomes after lumbar disc decompression with fusion or stabilisation were excluded. Table Our initial search retrieved 117 papers from the included databases, however, after excluding duplicate records, only 109 papers were subjected for title and abstract review. This review had resulted in the exclusion of another 68 papers. Subsequently, 41 papers were included for full-text review, and only 30 papers out of 41 met the inclusion criteria and were included for this review (Table Background and pathophysiology of sciaticaSciatica is a symptom (rather than diagnosis) characterized by radiating pain below the knee into the leg and foot, which is the area supplied by one or more nerve roots from the lumbar or sacral spine. It may be associated with sensory and/or motor deficits, muscle weakness, reflex alteration, or all of them. The most common cause of sciatica is a herniated disc (90%); however, other possibilities include lumbar canal stenosis and foraminal stenosis, or, rarely, tumors or cysts -8.The natural history of lumbar disc herniation is favorable, and spontaneous resolution of symptoms may occur in the majority of cases -11. SeveMultiple reasons indicate that pure mechanical compression is not enough to explain the symptoms complex of sciatica . Severe Predictors of outcomes of decompressive surgery for lumbar disc herniationThe goal of decompressive surgery is to relieve the pressure on the nerve root thereby decreasing pain. A technically well-performed surgery on the right patient will often result in a good outcome. Therefore, it is important that we identify factors that influence the outcome of surgery as patients who fail to recover are at risk of developing chronic pain syndromes. Over 150 predictor variables have been documented with varying levels of significance . PredictSocio-Demographic VariablesGender: Most studies found female gender to be a risk factor for a poor outcome; whereas one study stated that males were more at risk of a poor outcome -27. A feAge: No consensus exists amongst studies regarding age being a risk factor. A clear line between the young and the elderly has not been drawn. Hurme and Alaranta included 357 patients younger than 55 years and found that at six months' follow-up after surgery the activities of daily living and pain were worse in patients aged 40 and above . Two othSocio-Economic status and education level: Papers have stated that education level correlates with outcome, but the demarcation between the educated and uneducated is not properly defined . SorianoSmoking: Many studies found that smokers had a worse clinical outcome, longer recovery period, and reduced quality of life , 31, 33.Clinical and Surgical VariablesTime to surgery/duration of pain: How the duration of symptoms before surgery influences functional recovery after lumbar discectomy and what the time point for intervention is beyond which postoperative recovery might be compromised are still unanswered. In the absence of red flags and specific causes , there is a general consensus to try conservative treatment for at least six to eight weeks . For patType of Surgery: Whether minimally invasive surgery results in better overall postoperative outcomes compared to conventional open surgery is still a controversial topic, and the literature failed to show any particular technique to be clearly superior to another , 40. TheConservative vs aggressive discectomy: Conservative discectomy results in shorter operative time, quicker return to work, and a decreased incidence of long-term recurrent lower back pain, but also results in an increased incidence of recurrent disc herniation . While sPreoperative level of back and leg pain as a predictor of outcome: Many studies observed that patients with a preponderance of radicular leg pain had better surgical outcomes after decompressive surgery compared to those operated on with back pain as their main complaint , 34, 45.Neurological impairment: Some studies have reported that neurological symptoms improved after decompressive surgery and the recovery was inversely related to the severity of preoperative paresis , 46, 47,Size and type of herniation: Contained discs were associated with the poorest outcomes, significantly worse than either extruded (P < 0.001) or sequestered (P < 0.001) disc types . The besAnatomical level of disc herniation: Some studies observed that the clinical presentation and outcomes of upper lumbar disc herniation  were worse compared to those at lower levels . In a study of 69 patients with herniations at L1-2, L2-3, and L3-4 only, it was seen that when compression was present at L1-L2 or L2-L3, 58% had improvement in radicular pain and 53% patients had improvement in back pain. In comparison, when compression was present at L3-L4, 94% of patients had improvement in leg pain and 87% had improvement in back pain .In another study of 197 patients by Dewing et al., disc herniations at the L5-S1 level were associated with significantly better outcomes on VAS leg (not back) score and ODI score than those at the L4-L5 level. They postulated that lumbo-pelvic ligaments provided inherent stability at the L5-S1 level and also that the neural foramen for the S1 nerve root is larger .Occupation and Satisfaction with WorkVarious factors related to work were predictive of outcomes for patients undergoing surgery or managed conservatively. In a study by Kerr et al., it was seen that patients who were working at the time of presentation had the greatest relative improvements compared to those who were disabled at the time of presentation . FurtherPsychological VariablesThere is evidence supporting the idea that pain-related fear may be more important in predicting disability than the pain itself. It was seen that patients with a higher level of anxiety, pain coping, or pain catastrophizing, had poorer postoperative outcomes , 34. WhiSpontaneous resolution of symptoms can be expected in up to 90% of patients with sciatica. For those who fail conservative treatment, surgery performed at the right point of time for carefully selected patients can provide significant pain relief. Factors to be considered as predictors of poor postoperative outcomes had been described extensively in the literature, with no consensus regarding any of them. There is no evidence to suggest that a longer duration of preoperative symptoms has a significant impact on the long-term results; however, earlier surgery (within one year) was associated with better early postoperative outcomes and a faster recovery. The literature has also suggested that predominant preoperative back pain, as opposed to leg pain as the main presentation, is considered a predictor of poor postoperative outcomes. The level of compression/herniation is another important factor affecting outcomes. Upper lumbar disc herniation (L1-L2 and L2-L3) has a higher incidence of a poor outcome compared to herniation at lower levels . There was no convincing evidence to suggest that surgical technique or type or size of herniation has a significant impact on long-term outcomes. Finally, unemployment and depression were two other factors that predict poor outcomes, and they need to be considered when discussing surgery with patients. We recommend that these factors need to be considered while counseling patients on lumbar decompression surgery for sciatica, as they can predict suboptimal postoperative recovery and outcomes.


Ossification of the posterior longitudinal ligament (OPLL) can occur throughout the entire spine and can sometimes lead to spinal disorder. Although patients with OPLL sometimes develop physical limitations because of pain, the characteristics of pain and effects on activities of daily living (ADL) have not been precisely evaluated in OPLL patients. Therefore, we conducted a multi-center prospective study to assess whether the symptoms of cervical OPLL are different from those of cervical spondylosis (CS). A total of 263 patients with a diagnosis of cervical OPLL and 50 patients with a diagnosis of CS were enrolled and provided self-reported outcomes, including responses to the Japanese Orthopaedic Association (JOA) Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), JOA Back Pain Evaluation Questionnaire (JOABPEQ), visual analog scale (VAS), and SF-36 scores. The severity of myelopathy was significantly correlated with each domain of the JOACMEQ and JOABPEQ. There was a negative correlation between the VAS score for each domain and the JOA score. There were significantly positive correlations between the JOA score and the Mental Health, Bodily Pain, Physical Functioning, Role Emotional, and Role Physical domains of the SF-36. One-to-one matching resulted in 50 pairs of patients with OPLL and CS. Although there was no significant between-group difference in scores in any of the domains of the JOACMEQ or JOABPEQ, the VAS scores for pain or numbness in the buttocks or limbs were significantly higher in the CS group; however, there was no marked difference in low back pain, chest tightness, or numbness below the chest between the two study groups. The scores for the Role Physical and Body Pain domains of the SF-36 were significantly higher in the OPLL group than in the CS group, and the mean scores for the other domains was similar between the two groups. The results of this study revealed that patients with OPLL were likely to have neck and low back pain and restriction in ADL. No specific type of pain was found in patients with OPLL when compared with those who had CS. The posterior longitudinal ligament is the most common site of spinal ligament ossification and has been widely investigated worldwide. Ossification of the posterior longitudinal ligament (OPLL) can result in not only myelopathy but also spinal cord injury in asymptomatic cases following minor head trauma. Clinically, patients with OPLL sometimes develop physical limitations because of pain rather than because of motor dysfunction. Of note, compression of the spinal cord by an ossified lesion appears to be more severe than that caused by spondylosis and might be more painful. Although researchers have investigated several issues related to ossification, including prevalenceThe aims of this study were to investigate the relationship between severity of pain and neurologic status in patients with OPLL and to identify whether there are any specific clinical symptoms in patients with cervical OPLL that are not present in those with cervical spondylosis (CS), which often leads to myelopathy similar to that occurring in cervical OPLL.This multicenter, prospective cross-sectional study included 16 member institutions of the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament formed by the Japanese Ministry of Health, Labour and Welfare. Two hundred and sixty-three Japanese patients with cervical OPLL were enrolled from September 2015 to December 2017. The inclusion criteria were presentation with symptoms including neck pain, numbness in the upper and/or lower extremities, clumsiness, and gait disturbance as well as radiographic confirmation of having cervical OPLL based on X-ray. We excluded patients who had undergone anterior decompression surgery or posterior OPLL surgery and those aged younger than 20 years.To determine if there was any type of pain or ADL impairment specific to patients with OPLL, we compared the data for these patients with data collected for 50 patients with CS who had symptoms of neck pain, numbness in the upper and/or lower extremities, clumsiness, and gait disturbance as well as radiographic confirmation of degenerative CS.The study protocol was approved by the institutional review board of each participating institution and performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all patients before enrollment in the study.11, JOA Cervical Myelopathy Evaluation Questionnaire 13. A visual analog scale (VAS) was used to evaluate the degree of pain or stiffness in the neck or shoulders, tightness in the chest, pain or numbness in the arms or hands, pain or numbness from the chest to the toes, low back pain, and pain or numbness in the buttocks and lower limbs , and presence of neck pain, back pain, and low back pain were collected for each patient. Clinical status was evaluated using the cervical Japanese Orthopedic Association (JOA) score  to compare the physical status of the patients with OPLL with that of those with CS. All the study data are shown as the mean ± standard deviation. A p-value <0.05 was considered statistically significant.The two groups of patients were compared using the Student’s unpaired Written informed consent was obtained from each study participant before enrollment at each institution. The study protocol was approved by the ethics committee at each participating institution i.e., Shiga University of Medical Science, Tokyo Medical and Dental University, Keio University, National Hospital Organization Okayama Medical Center, University of Toyama, Hirosaki University Graduate School of Medicine, Chiba University Graduate School of Medicine, Jichi Medical University, University of Yamanashi, Tokai University School of Medicine, Niigata University Medicine and Dental General Hospital, Tokyo Medical University, Tohoku Medical and Pharmaceutical University Tohoku University School of Medicine, Nagoya University Graduate School of Medicine, Kyoto University, and University of Tsukuba.In total, 263 patients with OPLL  and 50 with CS  were enrolled. The patient demographics are shown in Table The mean JOA cervical myelopathy score was 12.4 in the patients with OPLL and 11.4 in those with CS, indicating more severe myelopathy in the CS group. Neck pain was reported by 61.2% of the patients with OPLL and 94% of those with CS, back pain by 28.5% and 30%, respectively, and low back pain by 52.4% and 78%. The prevalence rates of neck pain and low back pain were higher in the patients with CS.The mean scores for the various JOACMEQ domains were as follows: 65.6 in patients with OPLL and 69.7 in those with CS for cervical function, 80.4 and 73.9, respectively, for upper extremity function, 66.6 and 57.1 for lower extremity function, 75.5 and 74.0 for bladder function, and 50.2 and 46.1 for quality of life. The mean JOABPEQ score was 68.7 in patients with OPLL and 64.7 in those with CS for lumbar function, 56.9 and 53.3 for social participation, 64.5 and 53.3 for walking ability, 70.8 and 70.8 for pain, and 49.2 and 48.4 for mental health. Therefore, the scores were significantly lower for functioning of the upper and lower extremities and walking ability in patients with CS.The mean VAS score was 39.1 in the OPLL group and 49.6 in the CS group for pain or stiffness in the neck or shoulder, 10.2 and 7.9, respectively, for tightness in the chest, 44.2 and 62.6 for pain or numbness in the arms or hands, 37.3 and 41.6 for pain or numbness from the chest to the toes, 27.3 and 33.1 for low back pain, 23.1 and 35.7 for pain in the buttocks and lower limbs, and 30.6 and 33.0 for numbness in the buttocks and lower limbs. The between-group differences in the VAS scores for neck and shoulder pain or numbness, pain or numbness in the upper extremities, and numbness in the lower extremities were statistically significant.The mean scores for each domain of the SF-36 were as follows: 60.8 in patients with OPLL and 54.5 in those with CS for Physical Functioning, 58.0 and 46.5, respectively, for Role Physical, 51.6 and 40.3 for Bodily Pain, 49.3 and 47.7 for General Health, 56.5 and 58.9 for Vitality, 51.5 and 53.0 for Social Functioning, 64.6 and 51.0 for Role Emotional, and 60.2 and 61.5 for Mental Health. These results indicate that patients with CS had significant poorer scores in the Role Physical, Bodily Pain, and Role Emotional domains than those with OPLL.The relationships between the JOA score and patient-reported evaluations were investigated to confirm whether or not neurologic symptoms were associated with body functioning in patients with OPLL. Overall, the JOA score was significantly correlated with the score on each domain of the JOACMEQ Fig.  and JOABOut of 263 cases, radiologic data could be obtained from 239 patients. To investigate whether different types of OPLL have different types of pain or restriction of ADL in OPLL patients, these 239 patients were divided into continuous OPLL (n = 17) and other types of OPLL, namely segmental, mixed, and other (n = 222). Although there were no significant differences in terms of basic data, the prevalence of neck pain and low back pain were significantly lower in patients with continuous OPLL compared with patients with other types . One-to-one matching resulted in 50 pairs of patients with OPLL and CSM Table . The dis14 and is now understood to result from heterotopic bone formation in the posterior longitudinal ligament of the spine and to be a common cause of myelopathy, especially in Asia. Although several researchers have investigated the symptoms of OPLL and the efficacy of surgery, there are few reports on pain and impairment of ADL in patients with this disorder16. Sasaki et al. reviewed a sample (n = 1291) of the general population in Japan and divided it into subjects with and without OPLL15. They found that 86.7% of patients in the female subjects with OPLL group had symptoms and that female subjects in the OPLL group had more severe neck pain than their counterparts without OPLL. Given that the subjects in that study were recruited from the general population, the symptoms in subjects with OPLL might have been milder than those in patients with OPLL who presented to hospital, as in this study, which specifically recruited symptomatic patients with OPLL.OPLL was first described in the 1960sAlthough the JOA cervical score has been validated in patients with myelopathy, the main focus when it has been used in OPLL studies has been on motor dysfunction rather than sensory deficit or pain. However, patients with OPLL often complain of body pain and receive medication for their subjective symptoms. Therefore, it is important to understand the extent of pain and recognize deterioration of ADL in patients with OPLL. We believe that our study is the first multi-institutional investigation of self-reported ADL, quality of life, and pain in this patient population.Our study shows that patients with cervical OPLL and poor neurologic status are more likely to have whole body pain and progression of neuropathic pain as a result of spinal disorder with compression of ossified lesions. Our findings suggest that neurologic dysfunction could worsen in patients with relatively severe body pain, even in the early phase of myelopathy. Therefore, the extent of body pain may be a predictor of deterioration of myelopathy in patients with OPLL.17. However, in this study, we found that patients with cervical OPLL had unsatisfactory scores in all domains of the JOACMEQ. We also found a similar trend in the JOABPEQ. Despite the higher likelihood of those in their 80 s having a worse score, the mean score for each domain, except for mental health, was over 80 in the general population17. In our study, patients with cervical OPLL had poor scores, even for functioning of the lumbar spine. Furthermore, the average score in each section of the SF-36 was 50–65 points.A nationwide survey of the general population reported that the average score for each domain of the JOACMEQ, except for quality of life, was almost 100 pointset al. reviewed 39 patients with OPLL and spinal cord-induced chronic pain and also found that their scores for all items on the SF-36 were significantly lower than the national average18. Therefore, care is needed in patients with OPLL, who have impaired ability to perform ADL because of motor dysfunction and/or pain.The severity of myelopathy in patients with OPLL does not always correlate with scores in the Vitality, Social Functioning, and General Health domains of the SF-36. However, the mean scores for these items were significantly lower in patients with OPLL than in healthy volunteers. Nakajima 17. Our findings indicate that among patients with OPLL, those with severe symptoms likely have more pain. Interestingly, we found a strong association between the severity of myelopathy and low back pain, which was not directly related to the pathology of cervical OPLL and has not been reported before. Takenaka et al. reviewed 205 patients with thoracic myelopathy who underwent surgery and performed multivariate analyses to identify factors that were associated with pain19. They found that anterior compression caused by OPLL was a more significant determinant of low back pain and lower limb pain in the thoracolumbar spine than ossification of the ligament flavum or intervertebral herniation. A retrospective multicenter study that included patients with cervical OPLL reported that OPLL was also present in the thoracolumbar spine in 17.8% of cases and in the lumbar spine in 12.1%20. Furthermore, it has been documented that the prevalence of OPLL in the thoracolumbar spine increases with the number of cervical levels affected by OPLL2. Similarly, patients with CS often have low back pain as well. Yamada et al. demonstrated that cervical spondylotic stenosis in patients without OPLL often coexists with lumbar canal stenosis and sometimes requires decompressive surgery21. Overall, our study finding suggests that patients with and without cervical OPLL may have multiple lesions in the thoracolumbar spine and thus be more likely to develop low back pain and symptoms in the lower extremities.A cross-sectional observational cohort study of healthy volunteers demonstrated that the prevalence rates of both low back pain and neck pain were approximately 10% in the Japanese populationet al. compared a group of patients with OPLL and a group of patients with cervical spondylotic myelopathy and reported that the VAS scores for neck pain and arm symptoms were higher in the group with cervical spondylotic myelopathy22. Nakajima et al. also reported that spontaneous neuropathic pain and paresthesia scores were higher in patients with cervical spondylotic myelopathy than in those with OPLL18. Our results are consistent with their finding that CS is more painful than OPLL. Given that patients with CS have been found to be more likely to have neck and/or upper extremity pain as a result of cervical radiculopathy, we speculate that the mean intensity of neck and upper extremity pain would be greater in patients with CS than in those with cervical OPLL. Interestingly, we found that patients with continuous OPLL were less likely have neck pain or low back pain compared with those with other types of ossification in which the cervical spine has more mobility than in continuous OPLL. It has also been documented that unstable segmental motion in the cervical spine can impair neurologic function and cause pain24, probably because mobility of the cervical spine is likely to be more restricted in patients with OPLL than in those with spondylosis25. These findings and evidence could account for why patients with CS or motion preserved-OPLL have higher pain scores for the neck and all four limbs.In this study, we compared a group of patients with cervical OPLL with a group that had CS to determine whether or not there are specific symptoms or types of pain that occur in patients with OPLL. Propensity score matching was performed before comparing the clinical features of the patients with OPLL and those with CS because of between-group differences in demographic data. Although this analysis revealed no significant difference in neurologic function as evaluated by the JOABPEQ and JOACMEQ between the two arms, the VAS scores indicated that patients in the CS group were more likely to complain of neck pain, numbness in all four limbs, and pain in the lower extremities. Fujimori 28. Further evaluation of imaging features, including the degree of spinal cord compression, mobility of the spinal segment affected, and changes in signal intensity of the cord, will be required to clarify the relationship between pain in patients with cervical OPLL and radiologic findings.Whether or not there is an association between the radiologic severity of the ossified lesion and pain remains unclear. Some studies have reported no significant difference in neck pain and arm pain between cervical OPLL patients with and without intramedullary signal intensity changes on T2-weghted magnetic resonance imaging. However, radiologic findings have been considered to be a significant factor in severe symptoms of myelopathy such as motor and posterior column dysfunctionThis study has several limitations. First, although the study was it was conducted prospectively, it was not population-based. Second, only one-sixth of the patients with OPLL were included in the final analysis after propensity score matching. Third, we did not investigate the relationship between severity of symptoms and detailed radiologic findings, such as occupancy rate or degree of ankylosis, in patients with OPLL or the compressive lesions in those with CS based on computed tomography in the whole spine. Finally, the study had a cross-sectional design, and therefore a longitudinal investigation will be needed to validate the association between severity of myelopathy and body pain. However, despite these limitations, we believe that our findings provide important information and insights concerning the diagnostic features of patients with OPLL and those with spondylosis.This is the first well-powered, multicenter prospective study to identify that patients with OPLL are likely to have neck and low back pain and impairment of ADL. This study also found that there is no specific type of pain in patients with OPLL that distinguishes them from those with cervical spondylosis. More studies are needed to investigate the underlying pathophysiology and reasons for these significant findings to shed further light on the neurologic status of patients with OPLL.Supplementary Information.


Botulinum toxin type A (BTA) injection is considered an available alternative treatment for myofascial pain. However, its efficacy in treating masticatory myofascial pain syndrome (MMPS) remains unclear. The purpose of this study was to evaluate whether the BTA injection into the affected muscles would significantly reduce pain and improve function, and to assess its efficacy, safety, and therapeutic indications in a randomized, single-center clinical trial. Sixty patients with MMPS were randomized into three groups evenly to receive a single session injection of saline solution (SS group), lidocaine (LD group), and BTA (BTA group) in the masseter, temporal, and pterygoid muscles after an electromyographic study. Patients’ pain was classified as localized or referred according to the DC/TMD classification. Assessments were performed on pre-treatment, and subsequently, on days 7, 14, 28, 60, 90, and 180. A significant reduction in pain and improvement of mandibular movements was found in the BTA group compared to the SS and LD groups. The response lasted until day 180 and was more intense in patients with localized myalgia and focused myofascial pain than in referred remote pain. No significant adverse reactions were observed. A single BTA injection can be considered an effective treatment option in patients with localized MMPS by reducing pain and improving mandibular movements, which persisted up to 6 months. Myofascial pain syndrome is a complex disorder of the musculoskeletal system with multifactorial involvement and diverse clinical presentations in several areas of the body . It can In 2014, the National Institute for Dental and Craniofacial Research revised the Research Diagnostic Criteria for Temporo-Mandibular Disorders (RDC/TMD), thus giving rise to a new classification known as Diagnostic Criteria for Temporo-Mandibular Disorders (DC/TMD) . In the MMPS is a one of the main reasons for consultation in maxillofacial surgery clinics . IrrespeBotulinum toxin type A (BTA) is included within the available therapeutic array in these refractory cases. BTA has been used for decades in disorders caused by muscle hyperactivity such as strabismus, blepharospasm, spasmodic torticollis, hemifacial spasm, chronic migraine, or chronic musculoskeletal pain ,10. It iGiven that scientific evidence justifying the use of BTA is based on the treatment of muscle hyperactivity pathology in other anatomical areas, we chose to review and update what is known about this condition and then study the efficacy, safety, and therapeutic use of botulinum toxin in refractory myofascial syndrome with trigger points in masticatory muscles. n = 20 in each group) (Sixty patients were included and randomized to study groups (h group) . The thrPanoramic radiography and magnetic resonance imaging (MRI) did not reveal significant changes. All patients showed normal electromyographic studies (EMG), but 10 patients (77%) in RP subgroup of three treatments groups  showed the presence of myokymic records . These patterns were clearly defined after the clinical examination and the EMG study that was performed before injections. This focal myokymia pattern was not observed in the other subgroups. No pathological spontaneous activity, such as fibrillation potentials or complex repetitive discharges, was detected in any patient .The analysis of the differences between groups in consecutive checkpoints is shown in The analysis of the intragroup differences according to the classification of localized or referred muscle pain is shown in Values obtained in the 100-point questionnaire improved significantly between day 0 and day 180 in the BTA group , as wellVarious therapeutic procedures are available for the management of chronic muscle pain, although no specific treatment has proven to be consistently effective. The primary mode of action of conservative treatments lies in reducing muscle tone and achieving relaxation. In this way, a large percentage of cases can obtain a satisfactory reduction in pain after following one or more conservative treatment modalities. There remains, however, a significant group of refractory cases that must be therapeutically oriented towards minimally invasive treatments, among which are the puncture and injection of different therapeutic substances .MMPS is a common pain syndrome and a comorbidity complicating other diseases. It is characterized by TrPs that are areas of intense tenderness located on a contracted band of masticatory muscles. The local twitch response is a characteristic finding of MMPS; it is activated by pressure, palpation, or needle insertion at TrPs and is manifested by a burst of activity in the muscle band that contains the activated point. Treatment of MMPS involves the inactivation of TrPs. In many cases, repeated inactivation generally reverses central sensitization, so that TrPs no longer form repeatedly. However, in some patients, these points continue to recur despite repeated inactivation. In these patients, additional steps must be taken to inactivate TrPs and prevent their recurrence. It is in these situations that BTA could play an effective role, as it occurred in the patients included in our study, because of its long duration of action. In these cases, BTA decreases the electrical activity of the TrPs and, therefore, should eliminate the taut band that underlies the TrP ,7,14. The neurophysiological mechanisms involved in MMPS are difficult to resolve from clinical studies because of the great variability among patients, which may be originated by different factors such as pain intensity or location of muscle pain. There are different theories that have been proposed to explain the findings observed in TrPs: muscle spindle hyperactivity theory , end-plate hyperactivity theory (when TrPs is due to hyperexcitable motor end-plates), and focal dystonia theory , but no single theory completely explain all the known data concerning TrPs and further research is needed to more accurately understand these neurophysiological findings ,7,14. BTA is a relatively recent treatment for MMPS, but few scientific studies support its use, clearly due to the considerable heterogeneity of the populations studied so far ,21,22,23It seems clear, however, that despite several clinical trials the myofascial pain relief efficacy of the botulinum toxin has not yet been established . We consIn our study, we observed a clear improvement in refractory MMPS, with a significant reduction in pain in the masticatory muscles following the injection of BTA in cases of LM and MP. This positive response, although significant, was not seen with to the same degree in patients with referred myofascial pain with irradiation to areas distant from the masticatory muscles (RP). In addition, in the sub-group of patients with referred pain who received BTA treatment, we observed a slower response in the appearance of reductions in VAS from the first month, while in the sub-groups with localized pain (LM and MP groups), the reduction was already significant after 7 days in 55% of cases and remained stable throughout the study follow-up. In our opinion, the differential aspects of RP are based on central mechanisms, and central sensitization may be involved in the origin of RP; therefore, their management and therapeutic approach must be different. Consequently, it is helpful to use consistent diagnostic criteria for temporo-mandibular disorders and to classify patients with refractory MMPS into subgroups according to pain type and location. This would enable BTA to be used specifically in those patients in whom a better response is expected. As for the other two groups in the study, the first (SS) was clearly a placebo group, since the content of the syringes was saline. For the second group receiving lidocaine (LD), we assumed that the peripheral block can be effective in some patients with facial pain disorders; pain suppression in these cases is based on the therapeutic effect of low concentrations of local anesthetics to selectively block sensory fibers in mixed nerves. In our experience, this can be useful in the differential diagnosis of referred pain conditions. Various authors consider that motor function is preserved or minimally affected in these patients. Of course, the duration of the block depends on the dose and the pharmacokinetics of the anesthetic used, but in clinical practice, a longer than expected duration of benefits is observed in many cases ,28. Howep = 0.001), including localized pain in its two varieties . The reduction, although significant, was not as evident in patients with RP in the BTA group (pain reduction from 6.5 to 4 in VAS).There are studies that favor the use of BTA, such as the one by Sidebottom et al.  who condRetrospective studies, such as that by Stonehouse-Smith et al. , which iWe also found variations in the designs of the analyzed studies, inconsistent reports on assessment tools, and heterogeneous study groups ,25,26,31The onset of pain reduction with BTA is established in a delayed manner after its administration, which in our study, was significant after 7 days, especially in patients with a localized pain pattern, probably due to the analgesic effect of the toxin that accumulates gradually, reaching a peak of effectiveness after a week of continuous muscle relaxation. Similar to the more common conservative treatment modalities, the analgesic effect of BTA appears after a period of continuous and sustained relaxation of pain generated by fatigued muscle fibers. The effect of BTA on MMPS lasts for at least 6 months in duly selected cases, since in our study, most patients in the BTA group reported at the last check-up that they had not reverted to pain levels experienced prior to the administration of BTA. We did not observe a reduction in normal mandibular mobility figures in patients prior to starting our trial, and therefore, the figures obtained after treatment showed few changes except in the BTA group in which a significant improvement in mandibular function was found in maximum interincisal opening (MIO) and laterality and protrusive movements . From thFinally, all of our patients were evaluated concerning the known contraindications for BTA. All adverse effects experienced by patients were temporary and included localized pain, hematoma, and transient headache. We did not observe in our study any form of paralysis of the zygomaticus major muscle, which is characterized as an asymmetric smile, common in other studies. We believe this may be the result of the local diffusion of BTA from the masseter muscle, or due to direct trauma to the muscle aggravated by the usual practice of massaging the injected area. We consider it necessary to avoid this procedure. It is important to consider that the local diffusion of BTA may depend on the dose and the volume used, since large volumes can compromise the integrity of the muscle fasciae, which is another point that must be taken into account to minimize side effects in future studies. The high costs of BTA treatment compared to other conservative measures must also be considered. In a pilot study which analyzed the osteopenic consequences of BTA injections in the masticatory muscles, Raphael et al. found a reduced bone density in all patients who had been exposed to BTA, and a normal density in those who had not . In our This study has some limitations. Treatment review was limited to the effects seen in the mid-term. A study with a larger size sample and a longer follow-up period is required to determine the long-term benefits of BTA injection into masticatory muscles. To improve the validity of the study, it would be interesting to assess the treatment in patients with fibromyalgia or depression, which in this study were excluded.This six-month prospective study has evaluated the efficacy of BTA in the treatment of refractory MMPS and differentiated between two detected patterns of myofascial pain: localized myofascial pain and non-localized, radiated or referred myofascial pain. In our study, these patterns were clearly defined after the clinical examination and the EMG study performed prior to injections. The results obtained show a significant reduction in pain following the injection of BTA in all patients with localized refractory masticatory myofascial pain, which persisted up to 6 months, in its two varieties (LM and MP groups). A decrease in pain intensity, although significant, did not reach very low values in any of the patients with referred pain (RP group). BTA should be thus considered as a safe therapeutic option in patients with localized masticatory myofascial pain where a better response to treatment is expected, and where it has been shown to be more effective. This study protocol was approved by the Institutional Review Board (IRB) of the Virgen del Rocio University Hospital (IRB number: 2013PI/119) with approval date on 7 January 2014, and guidelines of the Declaration of Helsinki were followed. All participants were informed of the nature of the study, and written informed consent was provided by all the subjects participated in the study.A randomized, single-center clinical trial was conducted between July 2015 and June 2016. Patients of both genders, between 18 and 75 years of age, with myofascial pain in the temporo-mandibular area, were recruited after ruling out the presence of other pathologies by means of a panoramic radiography and MRI study. Patients with pain in the temporo-mandibular area with a myogenic component of 6 to 12 months of evolution, without severe limitation in joint mobility or signs of internal damage, and with trigger points in the masticatory muscles were included. Individuals were excluded if they presented one or more of the following conditions: concomitant treatments with aminoglycosides or quinolones, inflammatory processes at the proposed injection area, pregnancy, lactation, internal damage to the TMJ, degenerative joint pathology, dentofacial deformities, previous jaw trauma, chronic degenerative neuromuscular disorders, increased bleeding tendency or if taking anticoagulants, tension or migraine headaches, an infectious-inflammatory history of odontogenic origin, belonephobia, fibromyalgia, uncontrolled metabolic disease, or significant depression. A baseline clinical examination was performed to determine if the pain was of joint or muscle origin. If it was muscle-derived pain, it was classified as localized or referred pain according to the DC/TMD classification ,3, as . ®), where 50 units were diluted in 1.25 mL of saline to obtain 4 units of BTA for every 0.1 mL of injection fluid. The administered dose was 100–150 units distributed among the different muscle masses bilaterally. (4) Prior to muscle puncture, the area was cleaned with 90° alcohol. The puncture was performed manually by pinching the overlying skin with 2 fingers. The injection was performed at 3 points in the temporal muscle , 3 points in the masseter muscle ((0.2–0.25) × 3 = 0.6–0.75 mL), 1 point in the lateral pterygoid muscle (0.2 mL), and 1 point in the medial pterygoid muscle (0.2 mL) on each side; therefore, taking into account the dilution used in the BTA group, injecting doses of 8 units × 3 = 24 units in the temporal muscle, 8–10 units × 3 = 24–30 units in the masseter muscle, 8 units × 1 = 8 units in the lateral pterygoid muscle and 8 units × 1 = 8 units in the medial pterygoid muscle, bilaterally. After the injection, hemostatic compression was applied for one minute. No muscle stretching was performed after the injection. Patients were randomly assigned by a random number generator to one of three treatment groups: SS, LD, and BTA. The treatments were performed in a single session to allow an assessment of the efficacy and safety of the treatment and its therapeutic indications. Clinical evaluations were performed on the pretreatment baseline day (day 0), and subsequently on days 7, 14, 28, 60, 90, and 180. Data were collected at each visit by the same observer. The injection protocol was identical for the three groups: (1) Manual localization of the muscle mass and intramuscular puncture-injection after the EMG study. (2) Selection of 1 mL BD U-100 insulin syringes with a decimal scale graduation and fitted with 30G needles of 13 mm length. (3) Injection material: for the SS group, an injectable 0.9% saline solution; for the LD group, 2% lidocaine with vasoconstrictor; for the BTA group: onabotulinumtoxin A . Signs that were evaluated as indicators of effectiveness were significant reduction in myofascial pain at rest and with mastication, recovery of normal ranges of mandibular opening, lateral and protrusive movements, and improvement in TMJ function. Affectation of the TMJ was evaluated via a questionnaire consisting of a scale of 100 points , assessing pain (40 points), function (45 points), and chewing (15 points) [The main parameters used to evaluate the effectiveness of the treatment were: (1) Pain at rest and when chewing, assessed with a visual analog scale  and 2) range of mandibular movements associated with the opening of the mouth, lateral, and protrusion movements measured with a Therabite range of points) . Secondat-test based on 3 independent series, which gave us 19 necessary cases per tested group. By estimating a possible dropout rate of 2%, the recruitment of 20 individuals was considered necessary for each group undergoing the different therapeutic procedures . The data were first analyzed with a general statistical test (Friedman’s test), using absolute and relative frequencies in the case of qualitative variables and mean values, standard deviation (SD), or the 50th percentile , or P25–P75 interquartile ranges (IQR) for quantitative variables. Comparisons between the three groups were made with the Kruskal-Wallis test for each checkpoint. Before and after comparisons of variables in each group were made with Friedman’s test, while within group differences were analyzed with the Wilcoxon signed rank test (with post hoc Bonferroni correction) to analyze intragroup variations. When differences between the three groups were detected, the Mann-Whitney U test was used to analyze between two groups which groups differed from each other (with post hoc Bonferroni correction). Values of p < 0.05 were considered to indicate statistical significance. Data were analyzed with the IBM SPSS Statistics 20.0.1 , software 2012. The sample size was estimated with a view to identifying a decrease of 2 or more pain points in the visual analog scale (VAS) after the injection of BTA that should be present within 2 weeks of the procedure. Considering 5% as the significance level and 1.35 as the equivalence limit, we performed a triple unilateral equivalence Student’s


The potential paravertebral space includes spinal nerves, dorsal rami, rami communicants, and sympathetic chains. This study evaluated correlations between paravertebral spread of injectate and clinical efficacy in lumbar transforaminal block. We retrospectively analysed the data of 88 patients who received transforaminal blocks for lumbar radicular pain. We categorized patients into two groups: patients with ≥ 50% pain reduction on a numeric rating scale at 30 min following a block (responder group), and patients with < 50% pain reduction (non-responder group). Paravertebral spread of injectate was graded as limited to the anterior, middle, and posterior 1/3 of the anterolateral aspect of vertebral bodies; spread between the posterolateral margins of bodies and the posterior epidural space was considered no spread. Clinical and fluoroscopic data, perfusion index, temperature, and cold sensation were compared between the groups. Among 54 patients analysed, 26 (48.1%) experienced ≥ 50% and 28 (51.9%) < 50% pain reduction. Paravertebral spread occurred in 33 (61.1%) patients; 19 (57.6%) responders and 14 (42.4%) non-responders. On analysis, paravertebral spread, epidural spread patterns, perfusion index change ratios, temperature changes, and cold sensation changes showed no differences between responder and non-responder groups. Paravertebral spread occurred in 61.1%, with no correlation with the clinical efficacy of lumbar transforaminal block. It is known to communicate with the epidural space through intervertebral foramina and with the contralateral PV space through the prevertebral or epidural spaces3. PV blocks are performed on all levels of the roots of nerves or plexuses to provide segmental anaesthetic and analgesic effects in the thorax, abdomen, pelvis, and lower limbs5. Although the PV space is defined as that within transverse process and intervertebral foramen, injectate spread to the PV space and its clinical efficacy has not yet been explored in cases of transforaminal block. In previous reports, epidural and spinal anaesthesia was presumed to attenuate sympathetic response due to PV spread; however, evidence is limited owing to the lack of methods for measuring sympathetic denervation8. Marhofer and colleagues reported that the intended effects of local anaesthetics were unpredictable and the effect was stronger than local anesthetic spread range in thoracic PV injection2. The variability of PV spread was suspected to be related to individual anatomic differences and/or secondary redistribution following injection2. The caudal boundary of the thoracic PV space is connected with the origin of the psoas major muscle9. Lumbar sympathetic ganglia are located on the anterolateral aspects of vertebral bodies L2, L2–3 disc, L3–4 disc, and L511. Lumbar sympathetic block is indicated for the diagnosis and treatment of pain associated with sympathetic dysfunction, and is related to its prognosis13. The possibility of PV spread and subsequent sympathetic effects through transforaminal injection may be an important factor in deciding the indications for these injections in clinical practice. This study evaluated the correlation between the PV spread of injectate and clinical efficacy of lumbar transforaminal block.The paravertebral (PV) space is a potential space on either side of the vertebral body, which contains spinal nerves, spinal dorsal rami, rami communicants, and sympathetic chains14. The exclusion criteria included any history of lumbar surgery; lumbar neuroplasty; neoplastic diseases; peripheral vascular disease affecting pain, perfusion index and/or cold sensation; or use of medications affecting the vascular system14. We also excluded injections at L5, as the clinical response to the lumbar sympatholytic effect is known to be significant above the level of the L4 vertebral body15. The lesion level for transforaminal injections was selected on the basis of clinical manifestations, physical examination, and review of imaging studies14. Lesion severity was categorised as one of three different degrees  by reviewing imaging data14.We retrospectively reviewed the electronic medical records of 88 patients with lumbar radicular pain, who underwent transforaminal blocks between January and September 2019 at a single tertiary care hospital. The patients’ ages ranged from 31 to 85 years. All patients had lower back and radicular pain. The inclusion criteria were as follows: (a) a primary diagnosis of lower back pain radiating to the lower limbs and (b) a cross-sectional imaging study (either computed tomography [CT] or magnetic resonance imaging [MRI]) of the lumbosacral spine in patients diagnosed with spinal stenosis or herniated nucleus pulposus (HNP)-1, GE Healthcare), which confirmed whether the point was well placed in the epidural space14. After confirming that the contrast had spread throughout the epidural space, a total volume of 3 ml  was infused. The spread pattern of 3 ml of injectate was analysed based on the following criteria: posterior or anterior and posterior epidural spread on the lateral view, and extra-foraminal (E), intra-foraminal (I), or extra and intra-foraminal (EI) epidural spread on the AP view, based on a 6 o’clock location of the pedicle , 5 (T5), 15 (T15), and 30 (T30) min following transforaminal injection14. Temperature was assessed at T0, T5, T15, and T30 using a touch thermometer  on the dorsum of the foot of the affected limb14. Room temperature was maintained at 23–25 °C. Pain was scored using a numeric rate scale (NRS), which ranged from 0 = no pain to 10 = absolutely intolerable pain; cold sensation of the affected limb (NRS: ranging from 0 = no cold sensation to 10 = most severe cold) was recorded at T0 and T30. The pain severity, PI, temperature, and cold sensation at T0 were recorded after 5 min of bed rest and before infiltrating the skin with 1% lidocaine14.All procedures were performed under fluoroscopic guidance in a standardised manner by a single experienced pain physician (J.Y.L). Patients were placed in the prone position, and anteroposterior (AP) and lateral view images were obtained using a C-arm  to ensure proper site of entry. Following aseptic preparation and application of 1% lidocaine, a 23-gauge Tuohy needle  was passed through the skin overlying the upper quadrant of the target foramen. Aspirations were routinely performed to assess for the presence of blood or cerebrospinal fluid. On feeling a loss of resistance, the aspiration test was performed, followed by injection of 1–2 ml of contrast medium  analysis14. A P value of less than 0.05 was considered statistically significant.All data were analysed using the SAS 9.4  software package. The data have been presented as the mean ± standard deviation or number (proportion), as appropriate. Demographic data for the two groups were compared using the Chi-square, t-test, or Fisher’s exact tests. The injection level, injection side, epidural spread, and PV spread were compared using Fisher’s exact and Chi-square tests. For PV spread analysis, we compared spread with no spread, and graded spread as A, B, or C. Fisher’s exact test with a 5% two-sided significance level was performed to calculate the difference in response according to the presence or absence of PV spread. To minimise individual variance in PI absolute values, we calculated PI change ratios (PI at each time point—PI at T0/PI at T0) and temperature changes (temperature at each time point—temperature at T0) at T5, T15, and T30https://cris.nih.go.kr/cris/index.jsp, KCT0004405). The need for individual consent was waived by the IRB, as this was a retrospective study involving medical record review. All methods were performed in accordance with the relevant guidelines and regulations. All medical data were collected by a standardized protocol, and only analyzed after anonymisation.This retrospective cohort study was approved by the Institutional Review Board (IRB) of Samsung Medical Center  and was registered with CRIS  also did not differ between the two groups (Table P = 0.082) and PV spread grade  (P = 0.312). Overall, PV spread was seen in 61.1% of patients, with 73.1% in responders and 50.0% in non-responders. In the PV spread analysis, 19 of 33 patients in the spread group were responders (57.6%) compared to 7 of 21 in the no spread group (33.0%). The post hoc power was 66.8% and the probability of type II error was 0.332. No differences were observed between the two groups in terms of PV spread status (P = 0.082), and grade  (P = 0.312). In both groups, the change in PI ratio differed significantly over time (from T5 to T30) (P = 0.002), but it was not different with respect to time and differing group (P = 0.821) (Table P = 0.139) or with respect to time and differing group (P = 0.328). The pain severity at T30 was different between the groups (P < 0.001)  and distorted anatomy (n = 1). Finally, a total 54 patients were analysed. We defined responders as patients who showed a reduction of ≥ 50% on a NRS for pain at 30 min following block, and non-responders as those who showed a reduction of less than 50%. The demographic and clinical data are summarised in Table  and dist16. We found that PV spread of the injectate did not correlate with the clinical efficacy in lumbar transforaminal block.In the present study, we aimed to evaluate whether PV spread correlates with clinical efficacy in lumbar transforaminal block. Although the incidence of PV spread was higher in responders, there was no significant difference between the groups in terms of the evaluated parameters, including epidural spread pattern. We evaluated the clinical efficacy based on the PI change ratio and changes in temperature and cold sensation. In case of deactivation of the sympathetic nervous system, the PI may increase owing to decreased vasomotor tone and peripheral vasodilation17. It is caused by narrowed neural foramina consequent to disc herniation, spinal stenosis, and degenerative spinal changes, resulting in a direct mass effect on the nerve root, as well as by inflammatory reactions18. The transforaminal approach provides more direct access into the neurotransforaminal space, and anterior epidural injection has been associated with superior analgesic outcomes for lumbosacral radicular pain20. PV block was first introduced in 1905 by Sellheim, and has gained popularity for acute and chronic pain in the thoracolumbar region21. The PV space is bounded by the vertebral body medially and by the transverse process posteriorly. The thoracic PV space continues caudally to the retroperitoneal space, which contains the lumbar plexus5. PV blocks may produce simultaneous somatic and sympathetic blockade by forwarding flow of injectate to the sympathetic chain22. The distance between the tip of the transverse process and lateral border of the intervertebral foramen in the thoracic PV space is approximately 1.5–2 cm; however, this may decrease to 1 cm or less at the T11 and T12 levels5. However, corresponding distances have not been reported in the lumbar area. We suspect that because of the proximity of the transverse processes and foramina, transforaminal injection may provide an opportunity for injectate spread to the PV space; however, this is subject to variations in patient anatomy or status of surrounding tissues. We speculate that, in our cohort, narrowed and/or distorted foraminal structures and consequent increases in intra-foraminal pressure may have affected injectate spread to the extra-foraminal space; however, as there was no difference in lesion severity between the groups, the incidence of PV spread was similar. Radicular pain may have several aetiologies, such as neural dysfunction, vascular compromise, inflammation, and biochemical influences, and it does not merely arise from neural compression due to foraminal narrowing24. Since the injectate may mostly flow around the dorsal root ganglion via the foramen, PV spread is unlikely to impact clinical efficacy. Morishita and colleagues reported that bony foraminal stenosis on imaging does not reflect the severity of clinical symptoms25.Lumbar radicular pain is caused by irritation or compression of the affected nerve root27; yet we used 4–5 ml in our study. Second, we only planned approaches through the sub-pedicle area; therefore, we could not evaluate the extent of PV spread via other approaches, including retro-neural or retro-discal routes. Third, the lumbar sympathetic ganglia vary in number, size, and location, and presumably aggregate above L410. In our study, the injection site was mostly at L4; therefore, the sympatholytic response may not have been expressed sufficiently. Fourth, our sample size was small, where the power was 66.8% and a risk of type II error was present. Further studies with larger sample sizes, improved power, and lower risk of type II errors are required to confirm our findings. Fifth, the follow-up period of 30 min was considerably inadequate for evaluating block efficacy. Sixth, we evaluated PV spread with 1–2 ml of contrast medium, and then by subsequent injection of 3 ml of local anesthetics and contrast medium. The two subsequent injections and differing viscosities between the contrast medium and other injectates may bias the evaluation of injectate spread. Finally, all patients had either received various analgesics, such as acetaminophen, ibuprofen, paracetamol, NSAIDs, opioids, and anticonvulsant28, or had received other interdisciplinary management protocols, which may have affected the severity of the pain after the block.This study had several limitations. First, we did not compare the volumes of injectate; therefore, the effect of volume on injectate spared could not be excluded. For lumbar transforaminal block, the reported injectate volume ranges from 0.2 to 9 mlIn our cohort, PV injectate spread did not correlate with successful pain relief following lumbar transforaminal block. Future prospective randomized studies are needed to determine whether larger volumes, different approach techniques, or injection at upper lumbar levels may affect PV spread during transforaminal block.