Background: Though multidisciplinary pain treatment (MPT) is considered the gold standard for managing chronic pain, it is unclear which patients benefit most from this high-cost treatment approach.Aims: The goals were to identify subgroups of patients sharing similar pain severity trajectories over time and predictors of MPT responsiveness.Methods: Participants were 1894 patients  enrolled in the Quebec Pain Registry with moderate to severe baseline pain severity. Patients completed validated questionnaires on pain and related constructs before initiating treatment and 6, 12, and 24 months later.Results: Trajectory analyses of pain severity (intensity and interference) showed that a three-class model best fit the data. Two of the trajectories, which included 24.5% of patients, showed significant improvement in pain severity levels over time (improvers). Compared to patients in the nonimproving trajectory (non-improvers), improvers were younger and more likely to suffer from neuropathic pain and had pain of shorter duration, lower worst pain intensity, lower sleep disturbances and depression scores at baseline, a lower tendency to catastrophize, and better physical health–related quality of life (QOL). This predictive model had a specificity of 96.2% and a sensitivity of 23.6%.Conclusions: Only a minority of patients exhibited an improvement in their pain severity with MPT. Several patients’ characteristics were significantly associated with pain trajectory membership. Early identification of nonimprovers, through examination of baseline characteristics and rates of change in pain scores, can provide valuable information about prognosis and open the doors for evaluation of different cost-effective treatment approaches.Abbreviations: CP = chronic pain; MPT = multidisciplinary pain treatment; QPR = Quebec Pain Registry; QOL = quality of life. MPT is considered to be the optimal standard of care for CP10; however, the waiting time to access such specialized services can be as long as 2 years.12The prevalence of chronic pain (CP), namely, pain that persists beyond normal tissue healing time or is associated with a chronic medical disorder (>3–6 months),10 has shown that patients report (1) a reduction in their pain intensity varying between 14% and 60%, with an average reduction of 20%–30%, (2) a significant improvement (65%) in physical activity, and (3) an average return to work rate of 66% following treatment. In addition, decreased health care utilization in the year following attendance at an MPT clinic has been reported; studies have shown that between 60% and 90% of patients do not seek additional health care in the first year following treatment completion whereas costs associated with treating CP decrease by 68% after treatment.10A review of published reports on the effectiveness of MPT in specialized clinics13 Research has repeatedly shown methodological issues with using such a measurement approach and recommended that multiple time points be used to increase accuracy and take into account interindividual variability in predicting prognosis.18These statistics provide strong evidence as to the effectiveness of MPT for a large proportion of patients, yet little is known about which patients will respond most to treatment. The current literature on MPT is limited by the fact that methodological approaches examining treatment effectiveness typically use average pain scores across patient groups, resulting in the loss of between- and within-individual variations in pain experience.The overall aim of this study was to examine pain severity trajectories over a period of 24 months among patients suffering from moderate to severe pain who attended an MPT clinic. The specific objectives of this study were to (1) examine inter- and intra-individual variations in pain severity (pain intensity and interference) trajectories over a 2-year period; (2) identify baseline pain and psychological characteristics that predicted trajectory membership; and (3) determine whether types of pain trajectories can predict patient outcomes at 24 months.19  who provided written consent for their QPR data to be used for research purposes (91.4% of patients). The QPR was developed and implemented to monitor the condition of patients suffering from various types of pain syndromes who were referred to large MPT clinics (dedicated centers of expertise) in the province of Quebec (Canada) using common demographics, identical clinical descriptors, and uniform outcome measures. Patients were enrolled in the QPR if they were (1) scheduled for a first visit at the pain clinic for multidisciplinary treatment considerations, (2) aged 18 years or older, (3) fluent in spoken and written French and/or English, and (4) physically or cognitively able to complete questionnaires. Patients were excluded if they were eligible for recruitment in the preexisting Fibromyalgia Registry at one of the participating sites. Patients seen at an MPT clinic were offered different treatment options based on their clinical profile. Treatment was thus individualized to patient needs. Treatments could include one or a combination of the following treatments: pharmacotherapy, physiotherapy, psychotherapy, chiropractic care, and interventions .Study participants were selected from patients enrolled in the Quebec Pain Registry20; Brief Pain Inventory [BPI-10] mean score ≥ 4 on the pain interference scales) were included in the present study. Patients with mild pain intensity and interference were excluded from the analyses. Due to floor effects, these patients could not show an improvement in their pain severity to the same extent as those who started with higher pain levels.Patients suffering from chronic non-cancer pain (≥3 months), reporting baseline pain intensity and/or interference scores in the moderate to severe range  and March 2011. Patients entering the QPR after March 2011 were excluded because follow-up data were no longer collected at 12 and 24 months starting in April 2012 (patients enrolled after March 2011 did not reach the 12-month follow-up before these changes were made and thus did not complete any of the 12- and 24-month follow-ups). Participants attended one of the three designated tertiary clinics of the Quebec Pain Centres of Expertise located at the Centre hospitalier de l’Université de Montréal (CHUM), McGill University Health Centre (MUHC), and Centre hospitalier de l’Université de Sherbrooke (CHUS).The QPR project was approved by the institutional research ethics boards of the CHUM, MUHC, and CHUS. Successive patients who came for a first appointment at one of the participating pain clinics were enrolled in the QPR. They were informed that the information collected as part of the QPR had both clinical  and administrative  purposes. Patients were invited to sign the research ethics board–approved consent form if they agreed to the use of their QPR data for research purposes.Biopsychosocial data  were collected with a self-report questionnaire (patient self-administered questionnaire) and medical/clinical data  were gathered by the QPR nurses using a structured interview protocol (nurse-administered questionnaire) prior to the patient’s first appointment at the pain clinic (baseline). Participants answered the patient and the nurse questionnaires at baseline and 6 months later. Additional follow-up measures were collected at 12 and 24 months but only in patients who had not been discharged from the pain clinic in the meantime. If a patient was discharged within the first 6 months following her or his first appointment, follow-up ended at 6 months. If this was the case between 6 and 12 months, follow-up was carried out at 12 months but not at 24 months to minimize participant burden.21 is a self-administered scale that measures pain intensity and ranges from 0  to 10 (worst possible pain). The NRS has been shown to have good reliability, validity, and sensitivity to change.21 Participants were asked to rate their current pain intensity, average pain intensity in the past 7 days, and worst pain intensity during the same period.The NRS22 is a screening diagnostic tool that assesses the presence of neuropathic pain through self-report and physical examination. Each of the 10-item is answered yes (score 1) or no (score 0). A total score is computed by summing all 10 items and a score ≥ 4 is indicative of the presence of neuropathic pain. The DN4 has good sensitivity (82.9%) and specificity (89.9%), as well as good construct validity and reliability.22Douleur Neuropathique 4 Questions (DN4)22 that suggested the presence of neuropathic pain and received a neuropathic pain diagnosis from the treating doctor. Patients were categorized as having nonneuropathic pain if they had a score < 4 on the DN4 and a medical nonneuropathic pain diagnosis. Last, patients were categorized as having a mixed evidence of neuropathic pain when there were conflicting results between the DN4 score and the physician’s pain diagnosis .Patients were categorized as having neuropathic pain if they had a score ≥ 4 on the DN423 is a modified version of the seven-item BPI26 and contains a total of 10 items assessing pain interference on various aspects of daily living. Participants are asked to rate on a scale from 0 (does not interfere) to 10 (completely interferes) the extent to which pain has interfered in the past 7 days with general activity, mood, mobility, normal work, relationships with others, sleep, enjoyment of life, self-care, recreational activities, and social activities. Items are summed and averaged to create a mean score, with higher scores indicating greater pain interference. The BPI has been shown to have good validity and sensitivity to change in CP patients receiving MPT.27 The BPI has been translated into French using a forward–backward translation method.28The BPI-1029 is a five-item questionnaire that assesses sleep quality in patients with CP. The first four items assess sleep onset, need for sleep medication, wake after sleep, and early morning awakening; participants are asked to rate each item on a scale from 0 (never) to 10 . The last item assesses subjective global sleep quality and participants rate this item on a scale from 0 (very bad) to 10 (excellent). Three of the sleep items  can be summed to compose a sleep quality index,29 with higher scores indicating worse sleep quality. The CPSI has excellent internal consistency (α = 0.90), adequate convergent validity (r ≥ 0.50) between CPSI items, discriminant validity , and adequate sensitivity to change.29 This questionnaire has been translated into French in the context of the QPR project using a forward–backward translation method by native French and English speakers.The Chronic Pain Sleep Inventory (CPSI)31 is a 21-item scale that assesses depressive symptomology . For each question, patients are asked to select one of four statements (rated from 0 to 3) that best describe the way they are feeling. Total score is computed by summing all items, with higher scores indicating higher levels of depressive symptomology. The BDI-I has excellent reliability and validity in a wide range of medical populations.33The Beck Depression Inventory-I (BDI-I)35 is a valid and reliable 13-item scale measuring pain-related rumination, magnification, and helplessness. Participants rate each item on a scale from 0  to 4 , for a total score of 52. Higher total scores indicate greater tendency to catastrophize about pain. Cronbach’s alpha of 0.87 for the total scale is satisfactory. The scale also has good convergent validity with measures of anxiety (r = 0.32) and negative affect (r = 0.32). Ten-week test–retest reliability showed good reliability (r = 0.70).37The Pain Catastrophizing Scale (PCS)38 is a valid and reliable 12-item scale that assesses quality of life (QOL) in terms of physical health and mental health. For each item, patients are asked to check the box that best describes their condition; answer options vary from one question to the next. The SF-12v2 generates norm-based scores for eight different domains as well as two composite summary scores representing physical health– and mental health–related QOL. Higher scores indicate better QOL. The SF-12v2 has good test–retest reliability (r = 0.76–0.89) and internal consistency (α = 0.81–0.84).The Short-Form-12 Health Survey Version 2 (SF-12v2)t tests and Fisher’s exact tests were employed to compare the baseline characteristics of patients who did and did not complete any follow-up time points. Considering that even small differences can reach statistical significance in large sample sizes,40 effect sizes of group differences were also calculated using Cohen’s d for continuous variables41 and the phi (φ) statistic for dichotomous variables.42 Only differences that reached a d value ≥ ±0.4 or a φ value ≥ ±0.3 were considered meaningful and clinically important.40Means and standard deviations along with frequency tables were used to describe participants’ characteristics. Independent Student’s 45) was used to carry out pain trajectory analyses. This longitudinal data analysis method uses latent class membership to estimate discrete trajectories based on multivariate outcomes. R (Ver. i386 3.1.246) was used to empirically examine several models that differed in terms of number of trajectories and model structure using the latent class mixed models (lcmm) package.47 The multivariate dependent variables were pain intensity and pain interference. Scores on the NRS-11 representing average pain intensity on the previous 7 days and scores on the BPI-10 (average score on the 10 interference items), both collected at each time point , were used to estimate pain severity trajectories. Models varied based on the number of trajectories being tested (number of classes was not predetermined and increased until either the fit indices stopped decreasing or the interpretation of data was no longer plausible) and time effects . The Akaike information criterion (AIC) and Bayesian information criterion  were used to determine the best model fit. Model selection was also based on interpretability of trajectories50 and favored a parsimonious model.Pain severity trajectory analyses were conducted in patients who completed the patient questionnaire at baseline and at least one of the follow-ups—that is, at 6, 12, and/or 24 months. Growth mixture modeling for multivariate latent classes , trajectories were merged into two groups—improvers vs. non-improvers—based on the slope of their pain trajectory . Logistic regression analysis was used to identify baseline characteristics that differentiate improvers from nonimprovers. The following baseline characteristics were considered in the logistic regression model using a forward conditional procedure: age, sex, type of pain , worst pain intensity (NRS-11), depression (BDI-I), sleep quality , pain catastrophizing (PCS), and physical and mental health–related quality of life (SF-12v2).A multivariate general linear model (GLM) was conducted in order to examine how belonging to the improvers vs. non-improvers classes of pain severity predicted patient outcomes at 24 months in terms of depression, sleep quality, and physical and mental health–related QOL.51 The estimation was made for measurements at four time points with an estimated moderate slope correlation effect size (r = 0.50) and a growth curve reliability > 0.85. With these conditions met, a sample size of 500 patients generates a power level > 0.80.Given that no data are currently available on means, standard deviations, and rates of change between group slopes and intercepts, sample size was estimated based on relevant simulations for growth curve models.Y = 1│X = 1) H0 = 0.2, and alpha = 0.05. A sample size of 244 participants is required to achieve power = 80% with effect size f2 = 0.05, alpha = 0.05, with two groups and four response variables.Using G*Power (Ver. 3.1.2), a sample size of 721 participants is required to achieve power = 80% with odds ratio = 1.3 and Pr(n = 1894) and those who did not (n = 756) revealed no clinically significant difference in age, sex, pain duration, baseline measures of average or worst pain intensity, pain interference, sleep quality, depression, and physical and mental health–related QOL .A final sample of 1894 participants was retained for this study ; these pn = 1894) was 53.18 years (SD = 14.0) and 60.3% were female. Average pain duration was 6.72 years (SD = 8.4). Mean age of the participants . Their scores then slightly decreased at the 6-month follow-up  and remained stable on the average at the 12- and 24-month follow-ups. The same was true for the interference scores .52 A three-trajectory model with linear and quadratic terms was thus retained to improve fit and interpretability while offering a more parsimonious solution. The additional three models that were run to control for local maxima returned parameters values identical to the final model parameter estimates to the first or second decimal value . As such, this confirmed that the final solution was not due to local maxima.Eighteen different GMM models were evaluated; they varied from one another based on the number of classes being tested (between one and six classes were tested) and on the use of a linear constant, mixed linear and quadratic, or mixed linear and asymptotic terms. 2 (df = 4) = 18.84, P = 0.001, but not clinically significant (Cramér’s V = 0.07) difference in trajectory membership and clinic site.n = 17) and thus they were discharged from the MPT clinic. These patients were more likely to be classified in trajectories 2 (n = 5) and 3  and less likely to be represented in trajectory 1 (n = 3). Results of Pearson’s chi-square test showed no clinically significant differences in trajectory membership across the three MTP clinics .As shown in n < 5), it was not possible to assess statistical significance of pain diagnosis differences across trajectories. There were no significant sex  or age, F = 2.49, P = 0.083, differences across pain trajectories.2 = 264.00, P < 0.001, percentage of correct prediction = 80.1%) showed that seven baseline characteristics were significant predictors of pain severity trajectory, namely, age, type of pain , worst pain intensity, depression, physical health–related quality of life, sleep, and pain catastrophizing  at 24 months. Results of the multivariate GLM showed an overall significant model, Pillai’s trace = 0.305; F = 48.54, Results of this study, which used real-world data and latent trajectory analysis, suggest that responses to tertiary care multidisciplinary pain treatment clearly vary considerably in patients suffering from chronic non-cancer pain. One quarter of patients showed a significant improvement in their pain severity levels, a composite of pain intensity and interference. Compared to patients in the non-improving trajectory, patients in the improving trajectories were younger, were more likely to suffer from neuropathic pain, had lower worst pain intensity, had lower sleep disturbances and depression scores at baseline, had a lower tendency to catastrophize, and had better physical health–related QOL at baseline. Patients were correctly classified as improvers or non-improvers 80% of the time. Improvers also reported better pain-related outcomes at 24 months compared to non-improvers in terms of other dimensions of the pain experience .14 This is even more important in the context where the health care system is moving toward a patient-oriented approach as recommended by the Institute of Medicine53; treatment guidelines, and recommendations should more appropriately be based on patient-centered empirical evidence.Overall, patients experienced on average a small decrease in pain intensity and interference within the first 6 months of attending an MPT clinic. The reported pain intensity and interference remained relatively the same over the following 18 months. However, results suggest that looking only at the overall sample trajectory leads to an inaccurate interpretation of treatment effectiveness, whereas looking at underlying latent subgroup trajectories allows for a more comprehensive view of how pain evolves over time. Exploration of inter- and intra-individual variability in pain severity trajectories revealed the presence of three distinct groups of patients that differed in terms of initial level of pain severity and rates of improvement over time. This pain trajectory model showed that only one quarter of patients (24.5 %) experienced a significant decline in pain severity over 24 months. One third of these patients who reported an improvement in their pain severity did not successfully maintain their gains over time. In fact, this specific subgroup (early improvers) significantly benefited from MPT over the first year, but their pain severity started to gradually worsen beyond that time. It is possible that for a subgroup of patients, either the interventions lost their effect  or they did not persist in using the learned skills . The most important subgroup in terms of proportion of patients reported constantly high levels of pain severity during the same period. Three quarters of patients reported an elevated pain severity that remained stable over time. The obtained results with the pain trajectory analysis point to the importance of considering patient heterogeneity and intra-individual differences when examining treatment efficacy and effectiveness. From a methodological point of view, these results are consistent with other studies suggesting that averaging pain scores across groups or samples results in the loss of accuracy and within-individual variations.Compared to patients in the non-improving trajectory, patients in the improving trajectories were younger and tended to suffer from neuropathic pain; they also had lower worst pain intensity at baseline, fewer sleep disturbances and lower depression scores, lower tendency to catastrophize, and better physical health–related QOL. These results are important in that they suggest that in addition to pain severity, these characteristics measured at baseline can help predict which pain trajectory patients are most likely to belong to (improving vs. non-improving trajectories). The model suggests that as early as the first visit, specific criteria can be used to identify patients who might not respond to conventional MPT approaches. It is also possible to use these criteria to identify patients who are more likely to benefit from an MPT and prioritize these patients in terms of access to care. Additional research aimed at identifying other factors that would improve the predictive value of the model is required before such approaches are implemented. These results also open the door to the elaboration and evaluation of alternative treatments that might be more cost-effective for this subgroup. Early identification of these patients offers the opportunity to adjust treatment plan and design interventions that best fit their clinical presentation.54 leading to different analgesic prescription regimens).Age is an important factor in determining treatment responses such that younger age offers a more optimistic prospect in terms of treatment response. It is possible that younger adults are offered different treatment approaches compared to older ones because of the specific characteristics of the elderly population  might show better treatment responsiveness. It has also been shown that pain recall is influenced by peak pain intensity and recent pain intensity.57 and it has been shown that reduction in levels of pain catastrophizing is associated with better treatment outcomes.58 Similarly, a negative relation has been found between the presence of depression and decreased pain treatment responses,59 whereas sleep disturbances are associated with hyperalgesia through descending modulatory systems.60 The presence of pain catastrophizing and depression is often associated with increased disability and physical functioning,57 thus resulting in lower physical health–related QOL. As such, results from this study are consistent with the existing literature, but they go further in showing that despite similar pain severity at baseline between patients in trajectories 1 and 3, the presence of depression, pain catastrophizing, sleep disturbances, and QOL predicted poor treatment response. In other words, these results suggest that factors other than pain severity predict poor treatment responses. Knowing that patient condition deteriorates while waiting for treatment,61 it would be interesting for future research to examine whether these psychological characteristics should be taken into account at triage to determine whether earlier interventions in high pain severity and psychologically distressed patients would allow them to move to an improving pain severity trajectory.Pain catastrophizing has been associated with both experimental and clinical pain experiences,62 Results in the literature are also mixed regarding the presence of sex differences in response to pharmacologic and nonpharmacologic pain treatments.63 Though in this study males and females were not differently assigned to trajectories, it would be interesting to compare treatment assignation; that is, whether males and females are being prescribed different treatments for the same symptom presentation. Depression, but not mental health–related QOL, was associated with treatment response. It is possible that specific features of depression  or accompanying features  are directly contributing to the pain experience through common maintaining factors or are indirectly influencing treatment response by decreasing one’s ability to fully comply with treatment. It would be interesting in future research to examine what mechanisms associated with depressive episodes but not part of overall mental health QOL are associated with treatment response.These two factors were not significantly associated with treatment response (improvers vs. non-improvers). The absence of sex differences is consistent with a study of CP patients on waitlist for MPT that found that women and men do not differ in terms of their pain experience .Being an improver or non-improver was significantly associated with patient outcomes at 24 months. More specifically, results showed that improvers had lower levels of depressive symptomology, as well as better sleep quality and QOL  at follow-up. These results are consistent with those observed at baseline, suggesting that patients’ pain and psychological characteristics play an important role in treatment responsiveness. This raises the possibility that these factors are influencing each other and covary across time. It would be interesting to examine this issue in future studies.This study uses a real-world data set of nearly 2000 patients attending one of the dedicated centers of expertise in the multidisciplinary treatment of CP in Quebec. The results thus contribute to our knowledge of the effectiveness of multidisciplinary pain management by stressing the importance of the heterogeneity of treatment responses. Nonetheless, there are some limitations to this study. First, drop-out rates at 12 and 24 months were high; however, the majority of the drop-outs were systematic . It is possible, however, that this might have influenced the results. Second, pain scores were obtained at baseline as well as 6, 12, and 24 months after initiating treatment. Though these scores sufficiently informed the pain trajectory model, they did not capture the pain severity changes that might have occurred acutely between the time points (within the first 6 months and at later times). It would be interesting for future studies to collect real-time data at closer time points during treatment. Third, it was not possible to examine distribution of precise pain diagnoses across pain trajectories given the too-small sample size of some diagnostic categories. Fourth, the statistics presented here represent the characteristics of patients who are long-term users of MPT, which might limit the generalizability of the results to all patients attending an MPT clinic . Finally, it was not possible within this study to control for variations in MPT approaches across participating sites. However, our results revealed no significant differences in pain trajectory membership across participating centers, suggesting that the observed latent trajectories are not an artefact of treatment centers.Despite its limitations, this study is the first to our knowledge to examine pain severity trajectories in a large heterogeneous sample of patients with CP attending an MPT clinic. The results revealed the presence of subgroups of patients that differed in terms of their clinical evolution over a 2-year period as well as in terms of their baseline and 24-month pain and psychological characteristics . These results are important in that they identified several subgroups of patients who did not improve over the course of treatment. Early identification of these patients, through examination of characteristics such as worst pain intensity, sleep disturbances, depression, pain catastrophizing, and QOL, can provide valuable information about prognosis. Future research directions include the examination of different treatment approaches that could best fit the patients’ pain trajectories.


Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Methods: Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian–parafascicular (CM–Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores . Results: The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM–Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3–180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM–Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain , or brachial plexus injury, while patients with thalamic lesions had the least benefit. Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain. The treatment of chronic pain syndromes has been a focus of functional neurosurgery since its inception ,2. A varThe thalamus has been recognized early to be involved in pain processing via its relay function for various sensory and pain conducting pathways and its wide connectivity with cortical regions involved in nociceptive neural transmission, including primary sensory, limbic and cognitive-associative domains ,11. A vaIn the 1970s, DBS was first applied for the treatment of nociceptive and neuropathic pain, before it became popular as a therapeutic option for movement disorders . The tarWe have reintroduced the CM–Pf as a target for the treatment of chronic pain in the late 1990s in patients with refractory neuropathic pain in order to address the affective component of pain perception and processing ,44,45. SThis is a study with retrospective analysis of long-term follow-up. All patients underwent bifocal implantation of DBS electrodes in the CM–Pf and the VPL or the VPM  contralateral to the side of pain. Surgical procedures were performed or supervised by the senior author (JKK) in the Departments of Neurosurgery in Berne (Switzerland), Mannheim and Hannover (Germany) between December 1997 and December 2014.After thorough interdisciplinary screening of inclusion and exclusion criteria (see below), bifocal thalamic DBS was offered to patients with chronic neuropathic pain syndromes. All patients underwent preoperative standard assessment including MR imaging, evaluation of the pain syndrome with regard to site of pain, and pain intensity according to a visual analogue scale (VAS) from 0 (no pain) to 10  as defined for specific pain determinants, and administration of the Mini Mental State Examination (MMSE) and the Hamilton Depression Rating Scale (HDRS).The determinants for the specific VAS scores for the intensity of pain were: maximum, minimum and average intensity of pain during the past week, pain at the time of the presentation, and allodynia upon clinical examination.Inclusion criteria. To be considered for surgery, patients suffered from medically-refractory chronic neuropathic pain syndromes. A defined cause or lesion in the central or peripheral nervous system underlying the development and the maintenance of the pain syndrome was required. Trials with various analgetic medications including non-steroidal anti-inflammatory drugs, opioids, antidepressants, and gabapentinoids did not yield sufficient relief or were not tolerated because of side effects. Before 2005, patients needed to have at least one trial of medication with gabapentin, and after 2005 a trial with pregabalin. The minimum duration of severe pain was at least one year with a profound negative impact on well-being.Exclusion criteria. Patients who had a VAS maximum pain score of less than 7 or a VAS average pain score of less than 4 were excluded. Also, a prevalent nociceptive pain type disqualified patients from participation in the study. Patients with dementia, substance abuse, a history of psychiatric comorbidities, ongoing litigation, fibromyalgia, or a short life expectancy were excluded as well.Patients with neuropathic pain syndromes seeking operative pain therapy who seemed to be better suited for less invasive surgery were offered spinal cord stimulation, dorsal root ganglionectomy or more recently also dorsal ganglion stimulation, and other options ,47.The study was conducted according to the guidelines of the Declaration of Helsinki. All subjects provided informed consent. Institutional review board approval was obtained for LFP recording , but was not required for this study because of its retrospective nature.The surgical procedure and the temporary externalization of electrodes after confirmation of electrode positioning for test stimulation and for recording of local field potentials investigating the role of the CM–Pf complex in attentional processing and goal-oriented behavior selection has been described in detail elsewhere ,49,50.Implantation of DBS electrodes. All procedures were performed as awake surgeries without analgosedation. For the stereotactic procedure a Riechert–Mundinger frame with the Zamorano–Dujovny semi-arc was used. The thalamic targets were determined by CT-stereotactic planning guided by preoperative MR imaging. The average stereotactic coordinates for the CM–Pf target were x = 8 mm lateral to the intercommissural line, y = 8 mm posterior to the midcommissural point, and z = 0 at the level of the intercommissural plane. Target coordinates for the VPL were: x = 14, y = −10, and z = 0; and for the VPM: x = 12, y = −10, and z = 0.During surgery, patients were in the supine position with slight upper body elevation. The stereotactic frame was secured to the operating table. After a C-shaped incision under local anesthesia, two burr holes were made, oriented in an oblique axis just anterior to the coronal suture. A single microelectrode  was inserted along the CM–Pf trajectory in most instances. It was gradually advanced through a guiding cannula with a microdrive, starting from 10 mm above the target with recordings made until 5 mm below target to detect low threshold calcium spikes (LTS) bursts neurons. The length of the DBS electrode along the trajectory was then adjusted according to the microelectrode findings. Thereafter, the quadripolar DBS electrode  was inserted. Macrostimulation was performed to look for the occurrence of stimulation-induced side effects or a sensation of warmth in the CM–Pf. The VPL and the VPM targets were approached, in general, without microelectrode recording. Macrostimulation was used to determine the site and the threshold of stimulation-induced paresthesias. The DBS electrodes were fixed to the skull with the burr hole ring and cap method. After connection of the DBS electrodes to extension wires these were tunneled to the parietal region and externalized. After skin closure, a stereotactic CT was performed to determine the location of the implanted electrodes and to rule out hemorrhagic complications.Test Phase. Test stimulation of either target was performed via the externalized extension cables for a period of several days (4–10 days) postoperatively. Each target was stimulated at least for a period of two days. Patients were asked daily to rate the intensity of their pain with different stimulation settings according to the specific VAS pain scores. During the test phase, patients received intravenous antibiotic prophylaxis with a cephalosporine, usually cefazolin. After completion of the test phase, the results were discussed extensively with the patient. Whenever improvement of pain was rated greater than 30% on one of the specific VAS scores, and this improvement was considered useful by the individual patient, implantation of a pacemaker for chronic stimulation was suggested choosing the DBS electrode for chronic stimulation which had yielded the better results during test stimulation. Otherwise, in case of limited stimulation response, explantation of the electrodes was proposed.Pacemaker Implantation. Surgery for implantation of the pacemaker and the extension cables was performed under general anesthesia. First, the extension cables were cut and removed. Via a subclavicular incision, usually on the left side, a subcutaneous or subfascial pocket was created for the implantable pulse generator (IPG). In general, a single channel IPG was implanted, only more recently dual channel IPGs were reimbursed by health care providers . Then, both DBS electrodes were tunneled via a retroauricular incision. In the early phase of the study a single extension cable was tunneled from the incision site down to the pocket and connected to the IPG, while the other electrode was isolated locally. In the latter phase, two extension cables were tunneled down to the IPG.Initial DBS programming. The IPG was programmed on the first postoperative day after a monopolar review of impedances. For the initial programming a bipolar configuration was chosen using either the two lowest or the two middle contacts setting the pulse width at 210 µs and the frequency at 130 Hz. The voltage was set below the threshold evoking persistent paresthesias at the VPL or the VPM target, usually between 0.5 and 1.5 V, while it was set between 2.0 and 3.0 V at the CM–Pf target.Follow-up and Outcome Assessment. Patients were followed with clinical appointments at regular intervals postoperatively for adjustment of stimulation settings and assessment of outcome according to a standard protocol. In the early phase patients were seen at 3-month intervals, and then yearly thereafter. Assessment of outcome included rating of the five specific VAS pain scores, the MMSE and the HDRS. In addition, patients determined their subjective perception of benefit according to a self-rating scale as excellent, marked, moderate, minor or none. All changes in medication were noted.In order to assess long term efficacy follow-up periods were summarized as follows: FU I: early postoperative, 3–11 months; FU II: 12–23 months, FU III: 24–47 months, and FU IV: 48 months and longer.Adjustments of stimulation settings were made with regard to clinical response. IPGs were replaced preemptively when possible. At the time of IPG replacement, patients were offered the possibility to switch to the other target in case the effect of stimulation had waned. In single instances, a dual channel IPG was offered.® 15 software . p-values < 0.05 were considered statistically significant and indicated by stars: * indicates p < 0.05, ** p < 0.01, *** p < 0.001 by default.Statistical analysis. Demographic data of patients were summarized using average values and their standard deviations as were the results of the visual analogue scale (VAS). Categorical data were given as frequencies with proportions. Statistical tests were used according to the measurements’ level, including the Kruskal–Wallis test and chi2 test. Statistical analyses were performed using JMPForty patients were included in the study. Demographic and clinical data are shown in The mean specific VAS pain scores of all 40 patients before DBS electrode implantation were: 9.0 ± 1.1 (maximum pain), 4.8 ± 2.6 (minimum pain), 7.1 ± 1.6 (average pain), 7.5 ± 1.7 (pain at time of presentation), and 6.9 ± 3.9 . The mean MMSE was 27.8 ± 2.3, and the mean HDRS 11.5 ± 5.6.DBS electrodes were implanted on the right side in 22 patients, on the left side in 17 patients, and one patient  had bilateral surgery. LTS neurons could be recorded in the CM–Pf in 28/30 instances. Upon test stimulation of VPL or VPM, contralateral paresthesias could be evoked at a threshold between 0.5 V and 2.0 V in all patients. There were no intraoperative or early postoperative complications. Postoperative imaging confirmed appropriate location of the DBS electrodes in the target structures. There were no instances of postoperative intracranial hemorrhage.p < 0.01). Likewise, VPL or VPM test stimulation yielded similar reductions in the five specific VAS pain scores (p < 0.01). The maximum pain score, for example, was reduced from 9.0 ± 1.1 to 5.0 ± 3.0 (44%) on average during CM–Pf test stimulation, while it was reduced from 9.0 ± 1.1 to 6.3 ± 3.0 (34%) on average with VPL or VPM stimulation. There were no statistically significant differences when the stimulation effects of the two different targets were compared for all five specific VAS pain scores.CM–Pf stimulation during the test phase resulted in a highly significant reduction of all five specific VAS pain scores  indicated that they had a clear benefit during test stimulation and were thus scheduled for IPG implantation for chronic DBS. The benefit of test stimulation in the 33 responders was thought to be more pronounced in 20 patients with CM–Pf test stimulation, and in 13 patients with VPL or VPM stimulation.The etiologies of pain syndromes in the seven patients who did not achieve benefit during test stimulation were: central thalamic pain (three), trigeminal neuropathic/atypical facial pain (one), postherpetic pain (one), deafferentation pain due to spinal cord injury (one), and CRPS (one). The highest number of primary non-responders vs. responders was found in the subset of patients with central thalamic pain (three of four patients). All three patients with central thalamic pain who did not respond to test stimulation had thalamic lesions which, however, were not localized in the target areas.The mean follow-up of the 33 patients who underwent subsequent IPG implantation was 62.8 months . The number of patients who were available for the different follow-up periods and the reasons for attrition are shown in the flowchart in Secondary surgeries apart from IPG replacement were performed in a total of 11/33 patients (33%) because of hardware-related complications (eight instances) or for connection of the second implanted electrode because of decline of efficacy with stimulation of the target which had been chosen initially (three instances). As indicated above, 5/33 patients (15.2%) had their complete systems explanted due to infection between one and five years after the primary surgery despite several attempts in three of them to preserve components of the neurostimulation system. Three other patients had lead revisions because of electrode fracture or discomfort because of bowstringing.The mean stimulation settings at the last follow-up for the CM–Pf target were: 2.5 ± 0.8 V, 131 ± 4.2 Hz, 210 ± 0 µs; and for the VPL or the VPM target: 2.1 ± 1.0 V, 129 ± 5.5 Hz, 207 ± 45 µs.The development of the five specific VAS pain scores over time for the whole study population when available for the different follow-up periods is shown in VAS maximum pain score in the 33 available patients at FU I was improved by ≥50% in 15/33, and by ≥30% in 22/33; in the 30 patients at FU II it was improved by ≥50% in 13/30, and by ≥30% in 18/30; in the 25 patients at FU III it was improved by ≥50% in 12/25, and by ≥30% in 17/25; and in the 18 patients at FU IV it was improved by ≥50% in 8/18, and by ≥30% in 11/18.The VAS average pain score in the 33 patients at FU I was improved by ≥50% in 17/33, and by ≥30% in 21/33; in the 30 patients at FU II it was improved by ≥50% in 15/30, and by ≥30% in 20/30; in the 25 patients at FU III it was improved by ≥50% in 13/25, and by ≥30% in 17/25; and in the 18 patients at FU IV it was improved by ≥50% in 10/18, and by ≥30% in 16/18. The number of patients who improved by ≥50% and ≥30% classified with regard to the different pain syndromes in the different follow-up periods is shown in The The overall outcome with regard to the five specific VAS pain scores for the whole group (CM–Pf and VPL or VPM) during follow-up is shown in The degree of improvement differed between patients with different pain etiologies, as outlined above. The overall outcome with regard to the five specific VAS pain scores for the three largest groups of patients during follow-up is shown in p < 0.01, respectively).There were no differences between the preoperative MMSE score (27.8 ± 2.3), and the scores at the different follow-up periods: FU I 27.7 ± 1.5, FU II 27.9 ± 2.3, FU III 28.5 ± 1.1, and FU IV 28.4 ± 1.1. The HDRS, however, was improved significantly at all follow-up periods as compared to preoperatively: preoperative 11.5 ± 5.6, FU I 7.4 ± 6.6, FU II 8.2 ± 4.9, FU III 7.4 ± 4.4, and FU IV 5.3 ± 2.6 .The scores of patients’ self-rating of overall benefit according to their subjective perception at the different periods of follow-up is shown in Our study shows that thalamic DBS can result in sustained improvement of chronic neuropathic pain due to different etiologies at long term follow-up beyond four years. The best results were achieved in patients with brachial plexus injury, facial pain or poststroke/central pain , while DBS produced more inconsistent and less favorable outcome in patients with CRPS, FBSS, postherpetic pain, peripheral nerve lesions or phantom limb pain, and was generally disappointing in those with spinal cord injury or thalamic lesions. Stimulation of the CM–Pf complex was not superior to stimulation of the somatosensory thalamus neither in the acute setting nor upon chronic stimulation. Overall, results of CM–Pf stimulation, however, appear to be comparable to those reported for PVG stimulation ,36,51,52While several reviews on various aspects of DBS for chronic pain identifying gaps and controversies have been published ,61,62,63The overall results for the different indications and the various targets used for DBS in chronic pain have been covered well in the published literature reviews ,61,62,63In the study with the largest number of patients published thus far, the group from Oxford summarized the outcome of 85 patients who underwent thalamic DBS for various pain syndromes . Of thesIn addition to the various thalamic targets which have been used for the modulation of neuropathic pain, other areas within central pain circuitries have been introduced both regarding the primary and the secondary processing of chronic pain ,68,69. WMany of the thalamic targets which had been used for thalamotomy in the past were adopted for DBS after its introduction in clinical practice by early pioneers in the 1970s ,73,74. CThe CM–Pf complex constitutes the major portion of the intralaminar thalamus in primates and it is considered to be a central node in the thalamus–basal ganglia–cortex loop ,80. It iGiven the inter- but also intraindividual variability, it remains largely unknown which thalamic nucleus would represent the optimal target for chronic stimulation. With regard to the proximity of the PVG and the CM–Pf, it has to be considered that stimulation of one of these targets might also affect the other structure, in particular in patients with wide third ventricles. Another structure that might be stimulated with DBS electrodes in the CM–Pf is the neighboring CL .Currently, there are two new but divergent developments which spike interest in thalamic targets for treatment of chronic pain again. First, the recording of local field potentials from target regions used for DBS in movement disorders has allowed not only a better understanding of the underlying pathophysiology of several disorders, but also of the mechanisms involved in the efficacy of DBS ,87. ReceWhile the strengths of our study are the relatively high patient numbers as compared to previous studies, the inclusion of patients with various etiologies, and the long follow-up, there are also several limitations. First of all, we did not have the option to compare systematically the effect of CM–Pf versus somatosensory stimulation over the course of our study in individual patients. To achieve this, it would have been necessary to implant dual channel pacemakers in all patients which, however, was not possible because of lack of reimbursement from health insurance carriers for such a policy. Second, we did not include a sham stimulation protocol to control for placebo effects. While this would have been feasible for CM–Pf stimulation, it would have been difficult to achieve with somatosensory thalamic stimulation. On the other hand, the prolonged benefit of responders on long-term chronic stimulation after four years and argues against a strong placebo effect.Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory neuropathic pain. Bifocal implantation of DBS electrodes is helpful to select the stimulation target in an individual patient. To further determine the role of thalamic DBS, randomized placebo-controlled studies are highly warranted. In view of the heterogeneity of central and neuropathic pain syndromes, we advocate for the conceptualization of multicenter studies applying the same surgical and stimulation protocol and uniform outcome measures.


To confirm the validity of coblation nucleoplasty in reduction of cervical discogenic nature.In a monocentric prospective clinical observational study recruiting 20 patients, treated with percutaneous coblation for cervical discogenic pain in 16 months in our hospital, we have clinically evaluated 18 patients. The pain was scored with the Visual Analogic Scale (VAS) in a pre-procedural questionary, 3/4 monthly follow-up from treatment and, finally, in a long-term follow-up 2 years after procedure.a < 50% VAS reduction, three did not have any variation of VAS; after 2 years, six patients had a total pain resolution, eight had a > 50% VAS reduction, two hada < 50% VAS reduction, two did not have any benefit. No peri- and post-procedural complication has been observed.The mean pre-procedural VAS score was 7.9 ± 1.6 , while the mean post-procedural score after 3–4 months has been 2.5 ± 3.1  and 2.5 ± 2.5  after 2 years. Among 18 patients, in the shortly post-treatment follow-up, nine had a complete pain relief, four had a > 50% VAS reduction, two hadIn a spite of a little sample, our results showed coblation as a valid therapeutic option to reduce cervical discogenic pain in medicine-refractory patients, as an alternative or a previous choice before a more invasive surgical treatment. Neck and upper limb pain are a common problem, which often results in functional disabilities and loss of productivity at work. Its prevalence is estimated at between 20 and 45% in industrialized countries,  with a hAll body structures with a sensory nerve supply may be potential sources of neck pain and include muscles, ligaments, bones, zygapophysial joints and intervertebral discs , 4.Among these, it is thought that the pain induced by the stress of the disc, called “discogenic pain”, is one of the most important causes and its prevalence has been reported between 16 and 20% , 6.In 90% of cervical hernias, conservative treatment is sufficient and consists of rest, orthotic treatment with collar, physical therapy, medical therapy with NSAIDs and corticosteroids. Only hernias that are more refractory to conservative therapy are treated with discectomy surgery .Recently, spinal surgery is shifting towards minimally invasive and lower cost procedures such as nucleoplasty; this technique is a minimally invasive procedure, used since 2000 .Coblation consists in the application of radiofrequency energy using a conductive medium, such as a saline solution, to create a precisely focused plasma. The aim is to dissolve soft tissue using relatively low temperatures , preserving the integrity of surrounding healthy tissue. Nucleoplasty generates small holes in the nucleus of intervertebral discs by combining coagulation and tissue ablation (Coblation technology) through the tip of the Perc-D Spine Wand, and this leads to a decompression of the herniated disc .Chen et al. proved that the decompression using the Coblation technique decreased the pressure in the disc with an experiment in a cadaveric specimen .The main advantage of the coblation technique used in nucleoplasty, versus surgical discectomy, is that exceptionally precise and targeted removal is possible while minimizing the thermal injury to the surrounding tissue .So far, only a few studies evaluated the validity of coblation, in terms of cervical discogenic pain reduction, conferred by the reduction of the disc core volume, reduction of intradiscal pressure, alteration of the expression of inflammatory agents and interruption of nociceptive nerve endings –14.Therefore, the goal of this study is to clinically evaluate the efficacy, side effects and patient satisfaction with cervical nucleoplasty performed on patients with cervical disc disorders that were unresponsive to conservative treatment.In a monocentric, prospective, clinical and observational study recruiting 20 patients, treated with percutaneous coblation for cervical discogenic pain, 18 patients have been clinically evaluated in 16 months . Two patients refused recruiting in the study.All patients had previously performed a radiological imaging exam (CT: Computed Tomography or MRI: Magnetic Resonance Imaging) and a specialized orthopaedic or neurological examination, proving the discal source of the pain.Any necessary ethics committee approval was secured for the study reported.The main inclusion criterion for the nucleoplasty treatment was discogenic pain without motor and sensory deficits not responsive to at least three months of medical treatment and physiotherapy. CT or MRI images should show a discal protrusion, bulging or a little migrated soft herniations.Exclusion criteria for the procedure included large discal herniations, severe spinal stenosis due to osteophytosis, presence of muscular or ligamentous pain issues, gait disorders depending on different neurological or orthopaedic pathologies. Before the procedures is necessary to know the entire medical history of the patient and carefully investigate clinical and instrumental data; a radiological consultation was carried out before the procedure, to identify therapeutic strategies, to explain to the patients the procedure and the technical approach, to obtain informed consent and to exclude some risk factors, especially the haemorrhagic one: coagulation balance is necessary 1 or 2 days before procedure in order to avoid, though rare, uncontrolled bleeding problems. Benefits and potential risks must always be discussed between the interventional radiologist and the patient or referral doctor.Percutaneous disc decompression using coblation technology was performed under local anaesthesia by an experienced interventionist radiologist in angiographic room. Antibiotic prophylaxis therapy was administered prior to procedure. A pillow was placed under patient’s shoulders to maintain neck hyperextension. Vital signs were monitored throughout the procedure.The correct spinal level to be treated was previously chosen by the results of imaging and clinical evaluation.Before starting the procedure, anterior cervical spine was palpated with fingertips and larynx and trachea were displaced medially, while the carotid artery was displaced laterally. Under fluoroscopic guidance, the puncture angle was confirmed using a lateral–lateral view. To reach the target disc at the juncture of anulus and nucleus the needle was introduced with a single-sided anterior approach. The exact position of the needle tip was confirmed on the anterior–posterior and lateral–lateral views, as shown in Fig. The procedure results in tissue removal (via plasma dissociation) able to guarantee both disc decompression and chemical denaturation of sensitive nerve fibres whose growing within the disc nucleus.We observed patients at least 6 h after procedure and patients were advised to stay in bed for the 1st day following the procedure. If necessary, non-steroidal anti-inflammatory drugs and myorelaxant drugs may be prescribed to the patients but it is an option to be assessed in relation to the patient’s condition. No lifting of weights, bending, or stooping was permitted for 2 weeks following percutaneous disc decompression. Patients were returned to sedentary or light work after two weeks and were provided with home exercise instructions by a qualified physical therapist.Once the discogenic cause of the pain has been recognized, the pain symptomatology has been evaluated by Visual Analogic Scale (VAS): the patient had compiled it immediately before the procedure and after, respectively, 3/4 months and 2 years from the treatment, when they came back for a clinical follow-up.VAS scale is a standardized tool to measure pain. Patients assessed the intensity of their subjective pain on a 10 cm long scale, with values from 0 (no pain) to 10 (the greatest pain imaginable) with a space of one centimetre between the individual values .The results obtained by 18 patients  with discogenic cervicobrachialgia treated with nucleoplasty procedure, using the coblation technique, were analysed.Four of the 18 patients received treatment at the level of two distinct discs, of which three during the same session and one in two separate moments.Coblation was therefore performed on a total of 22 intervertebral discs: three at the level of the C3–C4 disc (13.63%), three at the level of the C4–C5 disc (13.63%), in 13 cases for the disc between C5–C6 (59.09%) and finally in another three cases for the disc between C6-C7 (13.63%).The characteristics of the patients regarding the distribution by age, sex and level of the treated pathology were presented in Table The pre-operative baseline mean VAS score was 7.9 ± 1.6 , while the mean post-operative score was 2.5 ± 3.1 after 3/4 months  and 2.5 ± 2.5  after 2 years.The variation of the VAS scale in the pre-operative and post-operative phases, divided for each individual patient, is illustrated in Fig.  a > 50% VAS reduction (44.44%), two hada < 50% VAS reduction (11.11%), two did not have any change (11.11%).In the short follow-up of the 18 patients, nine (50%) showed a total remission of symptoms, four (22.22%) a reduction of more than 50%, two (11.11%) a reduction of less than 50%, while in three cases (16.67%) the VAS value was unchanged; in the later follow-up after 2 years, six patients had a complete pain relief (33.33%), eight hadThese data are summarized in Fig. All our patients had failed pain medications prior the procedure: 15/18 had only medical treatment with NSAIDs and corticosteroids, 2/18 had medical treatment with NSAIDs and corticosteroids and physio kinesitherapy and 1/18 had medical treatment with NSAIDs and corticosteroids and spinal injection.Two years after treatment, we noticed a clear reduction in the use of drugs: 2/18 use NSAIDs just in the acute phases, 1/18 has only occasional sessions of physio kinesitherapy and 2/18 underwent to open discectomy.There were no severe peri and post-procedural complications, as bleeding, paresthesia and infections. Three patients complained of pain immediately after treatment, while in another two patients a small hematoma was observed at the puncture site; both conditions regressed in about 1 week, without long-term discomfort.In this study, it was evaluated the efficacy of nucleoplasty that is a minimally invasive technique for the treatment of discogenic neck pain. Already in 2003, Chen et al. demonstrated that the application of RF energy on the disc material results in breakdown of molecular bonds of the tissue into elementary molecules and low molecular gases. The whole procedure results in removal of the disc material and reduction in intradiscal pressure .The etiopathogenesis of the discal stress is a sum of micro-traumatic and degenerative factors of the disc leading to a change in the chemical composition of the nucleus pulposus and the fibrous anulus, resulting in a progressive reduction of the viscoelastic properties , 17 for Disc degeneration and its reduction in height, determines a posterior dislocation in the medullary canal and intervertebral foramen, inducing a potential radicular conflict; also, arthrosis-related damage like osteophytes contributes to increase extrinsic pressure on the nerve root as well as on the spinal cord, leading to both sensory and motor deficits , 17.In clinical practice, the terms "soft hernia" and "hard hernia" are commonly used to describe and distinguish different disease that may affect cervical spinal tract; soft hernia is used to define discal material recently herniated while hard hernia refers to earlier discal material, partly dehydrated and replaced by calcified tissue. No significant clinical differences are found, even if soft hernias may have a more acute onset .In most cases, the hernia is placed in a posterolateral position and conflicts with the root emergency, giving a radicular discogenic pain typified by painful symptomatology radiated to the upper limb , disabling, often present even during the night, accompanied by disorders of the tactile sensitivity and pain due to motor deficit and modification of the osteo-tendon reflexes .In the most severe cases and in a smaller percentage of patients, the hernia may instead take a more central position and cause direct compression on the anterior portion of the spinal cord. We will have a different symptomatology, involving both the upper and lower limbs: the so-called cervical myelopathy modifying osteo-tendon reflexes, with absence or reduced grip strength at the level of compression and hyper-reflex below it; appearance of pathological reflexes; hypo-amyotrophy of muscle groups innervated by fibres from the anterior horns cells of the damaged spinal cord; fasciculations and fibrillations; sensitivity disorders that travel along the posterior cords (most compromised in the stenosis on a degenerative basis) .So, the symptoms can lead to a presumed diagnosis about the discal level involved by pathology, as describes by Stephen A. Grubb et al. in 2000: they analysed the results of 12 years of study and described the various pain patterns that were triggered by the stimulation, by cervical discography, of each cervical disc from C2 to C7 .First, in our study, we had to consider the selection of a suitable patient in proceeding with cervical nucleoplasty. Nardi et al.  argued tIn our study, the selected patients were suffering for a discogenic pain, not associated to significant motor or sensitive deficit, refractory to upto 3 months conventional therapy, with a discal protrusion or a little migrated soft herniations on CT or MRI images. We preferred to treat hard hernias using a mechanical disc decompression, disintegrating the calcified intradiscal components.Exclusion criteria included large discal herniations, spinal stenosis with osteophytosis and an underlying neurological or orthopaedic disease.Secondarily, we can notice that in our study the most involved disc has been C5–C6, as in the analysis of Suzuki et al. . This huThe main consideration of our study is about the significant reduction of algo-dysfunctional cervical pain due to discogenic degeneration, with a significant lifestyle improvement of treated patients.Regarding the mean VAS score, we noticed a substantial reduction from a presurgical score of 7.9 to a post-surgical value of 2.5 after 3–4 months and after 2 years from coblation. Our results are according to values of Birnbaum et all in 2009 [a > 50% VAS reduction (44.44%), two a < 50% VAS reduction (11.11%), two didn’t have any change (11.11%).Moreover, we detected in the first 3/4 months after procedure a total pain resolution in 50% of patients, a more than 50% reduction in 22.22%, a less than 50% decrease in 11.11%, while in 16.67% we did not obtained any variation of symptoms. We also noticed a slight worsening of results after 2 years, six patients had a complete resolution of pain (33.33%), eight had Even in this case, our results are according to a 2007 study of Calisaneller et al. , 93.1% oRegarding the limited long-term decline in results, it is possible that coblation may cause some degenerative effects on the treated levels which may result in an increased discogenic pain.One important result of our study was to notice a clear reduction using drug therapies: before treatment, all 18 patients had medical treatment with NSAIDs and corticosteroids, 2/18 had also physio kinesitherapy and 1/18 moreover had spinal injection.After treatment 13/18 report no longer using drugs, 2/18 use NSAIDs just in the acute phases, 1/18 has only occasional sessions of physio kinesitherapy but 2/18 underwent to open discectomy.Just 3 patients had MRI study after treatment: an intervertebral disc volumetric reduction was seen but no substantial signal changes are registered if compared with the baseline survey. We decided not to extend MRI evaluation protocol to all Patients, in order to emphasize post-procedural clinical changes and drugs taken. In the Fig. These results of cervical nucleoplasty appear to be much better than the results of lumbar nucleoplasty. However, the reasons that the nucleoplasty treatment may be more effective at the cervical level than at the lumbar level are not clear. One possible explanation could be anatomic: the cervical nerve root is confined to a relatively smaller space than its lumbar counterpart, so the cervical nerve root responds more sensitively to even a minute reduction. For this reason, even if the pressure of the disc is reduced slightly, the decompression on the nerve root and reduction in clinical symptoms can be easily obtained. Another reason could be the topography of the lesion and direction from which it is approached for treatment. In lumbar nucleoplasty, we use a posterolateral approach from the lesion. But in cervical nucleoplasty, we use antero-lateral approach to the disc, and so, the SpineW and TM could be accurately positioned in the lesion site posteriorly located. In other words, since symptomatic herniation is directed posterior, cervical nucleoplasty can effectively approach the lesion site because it uses the anterior approach , 27, 28.On the other hand, there's a study of our group  that obtIn the end, we can argue about side effects or complications of this procedure.Few side effects concerning the cervical nucleoplasty have been reported and no serious side effects have been known; potential serious complications of nucleoplasty are neurovascular injury to adjacent structures or post-operative spondylodiscitis.Side effects reported in literature included cases of infectious discitis, temporary side effects related to local anaesthetic  and retrosternal and retropharyngeal pain, but they responded well to conservative treatment , 29.We too did not encounter any serious complications in our study, moreover in none of our patients a pain raise was noticed also. Three patients complained pain soon after the procedure, while other two developed a little hematoma in the puncture site.Surgical technique has been widely accepted as the standard treatment for more than five decades. However, this procedure is associated with a small risk of serious complications such as perforation of the oesophagus, injuries to the carotid or vertebral arteries and severe neurological complications. However, the results of surgery are not always satisfactory, and the overall outcome may be similar to conservative treatment .Many minimally invasive spinal surgical (MISS) alternatives using microscopy, laser technology, endoscopy, and video and image guidance systems have been proposed in the past decades to reduce the morbidity of surgical procedure, to minimize the risk of iatrogenic injury resulting from open discectomy and, consequently, to decrease health care costs .In this perspective, even if actual literature data regarding coblation technique are poor and incomplete, some studies exalted its results so that coblation can be considered as intermediate option between a conservative treatment and a surgical one, especially in patients with degenerated and protruded disc, not responsive to a standard medical-rehabilitative therapy patients and not-surgical-eligible patients.Coblation benefit is due to its ability to remove part of nucleus pulposus with minimal invasiveness, through its volume reduction, intradiscal pression reduction and biochemical status change –34.Among percutaneous treatments, great results have been reached in chemiodiscolysis performed by administration of intradiscal oxygen–ozone (O2–O3) evaluating the Oswestry Disability Index (ODI) and pain intensity (0–5) scale ; moreoveHowever, there are some limits in all these studies, due to poor literature, few sample sizes, absence of control group, short follow-up, limited clinical indications, poor imaging-clinical correlation.In the future, it will be important to increase sample sizes, to create clinical randomized studies and long-term follow-up, to define inclusion/exclusion criteria, to promote multidisciplinary approaches, to improve executive technique.According to our experience, disc decompression using the Coblation technique has proved to be one of the best MISS, but it is essential to strictly adhere to his indications and to choose the best therapeutic approach for each patient.The results of our study have shown that coblation is a satisfactory, safe and minimally invasive procedure, and is a valid therapeutic alternative to surgical discectomy in reducing allergic symptoms for the treatment of cervicobrachialgia of a discogenic nature, with a more than acceptable response in the short and medium–long terms.Small cohorts and the absence of a control group, although perhaps unfeasible, are the weak points of this study; therefore, further randomized placebo-controlled studies and large recruitment are necessary to clarify the effects of nucleoplasty on discogenic neck pain.Datasets analysed during the current study are available from the corresponding author on reasonable request.


Intravenous haloperidol has been shown to decrease milligram morphine equivalents (MME) of analgesia and reduce hospital admissions for diabetic gastroparesis. The objective of this study was to evaluate whether haloperidol decreases MME for the treatment of non-specific abdominal pain diagnoses in the emergency department (ED), including gastroparesis, cyclic vomiting, cannabinoid hyperemesis syndrome, and unspecified abdominal pain. The primary outcome compared the difference in MME between encounters. Secondary outcomes included admission rate, pain scores, length of stay, rescue therapy administration, and adverse effects.This retrospective chart review included patients ≥ 18 years old who presented to the ED. Patients must have had ≥ 2 ED encounters for abdominal pain, one in which they received conventional therapy with opioids (C-encounter), and the other in which they received haloperidol (H-encounter). Agitated patients were excluded. Seventy-five patients were needed to detect a 3 MME difference with 80% power and two-sided alpha of 0.05.We analyzed 107 patients with self-matched encounters. The median dose of haloperidol administered was 5.0 milligrams (mg) (interquartile range [IQR] 2.0 – 5.0). C-encounters had significantly more MME administered than H-encounters . These results remained significant despite route of haloperidol administration. C-encounters had higher rates of rescue therapy administration than H-encounters, . There were higher rates of ketorolac administration in the H-encounter (P = 0.02).Encounters in which patients received haloperidol and ketorolac for abdominal pain had a statistically significant reduction in MME administered and lower rates of rescue therapy administration than encounters in which patients were treated with opioids. Pain accounts for 45.4% of all emergency department (ED) visits in the United States. Abdominal pain accounts for up to 8% of those visits.Haloperidol, a first-generation antipsychotic, antagonizes a variety of neurotransmitters in the central nervous system.11P ≤ 0.001), and nausea scores, 2.70 vs 0.72 (P = 0.05), at one hour.P = 0.009) morphine equivalents used, and a decreased admission rate of 10% vs 27% (P = 0.002) when compared to conventional therapy alone.13Several recent studies have examined the analgesic effect of haloperidol. In 2017, Roldan and colleagues conducted a randomized, double-blind, placebo-controlled trial comparing haloperidol 5 milligrams (mg) intravenously (IV) plus conventional therapy vs placebo plus conventional therapy for the treatment of gastroparesis. They found a significant difference in their primary outcome, mean reduction in pain scores, 5.37 vs 1.11  – ANALGESIA.” Indications for therapy were included in the order instructions and the dose of 5 milligrams intravenously (mg IV) was auto-selected, with the option of changing dose and route based on provider preference. A reference link to the full protocol was included in the medication record. In this study we sought to examine the opioid-sparing effect of haloperidol when used for abdominal pain and to determine whether the effect was dependent on route of haloperidol administration.What do we already know about this issue?Non-specific abdominal pain is a common emergency department presentation, and its treatment has been complicated by drug shortages and the opioid epidemic.What was the research question?Does haloperidol administration for the treatment of unspecified abdominal pain spare morphine equivalents?What was the major finding of the study?Haloperidol, in conjunction with ketorolac, spares approximately 6 milligram morphine equivalents.How does this improve population health?Haloperidol can reduce opioid exposure and is a safe and effective means of managing unspecified abdominal pain in a population with high healthcare utilization.-encounter).This was a retrospective cross-over chart-review of an electronic health record within an integrated health system. The health system is composed of large academic medical centers, regional hospitals, and freestanding EDs, accounting for approximately 700,000 patient encounters annually. This study, number 19–122, was reviewed and exempted by the institutional review board. Included patients were 18 years of age and older admitted to an ED between July 1–December 1, 2018, and administered haloperidol 2 mg-5 mg intramuscular (IM) or IV for abdominal pain  codes associated with abdominal pain were analyzed, including, but not limited to the following: non-specific abdominal pain; peptic ulcer disease; cyclic vomiting; cannabinoid hyperemesis syndrome; and reflux disease. Abdominal pain was confirmed within the ED provider note with a positive reference in “review of systems.” Patient charts were then audited for qualifying comparison encounters in which the patient received opioids as conventional therapy (C-encounter) for abdominal pain. Encounters did not qualify as a comparator if the patient was administered antipsychotics. All comparison encounters must have been separated by a minimum of three days from other hospital encounters requiring analgesia to allow for treatment washout, and a maximum of 365 days of the haloperidol encounter to minimize variability in patient presentation between encounters. We excluded the following patients from the study: allergy or sensitivity to haloperidol; chronic use of haloperidol as a prior-to-admission medication; urgent abdominal surgery; and administration of haloperidol for acute agitation secondary to delirium, psychosis, or for sedation.Encounters with Baseline demographic data included age, gender, time and date of ED encounter, resulting inpatient stay if applicable, ED location, repeat ED encounter within 30 days, and death. We classified EDs according to number of annual encounters. Dose, route, and resultant pain scores were also collected. Pain was documented as a 0–10 visual analogue scale and was included if the patient had a score before and at least 15 minutes after analgesic administration. If patients had more than two qualifying comparison encounters, the most recent qualifying encounter to the haloperidol encounter was used.The primary outcome was to analyze the difference in milligram morphine equivalent (MME) administration between the self-matched H- and C-encounters. Any opioids, NSAIDs, acetaminophen, ketamine, lidocaine, and haloperidol administered during the encounters were documented and considered to be concurrent analgesia. Secondary outcomes included disposition, adverse events, difference in pain scores, ED length of stay, repeat ED encounters within 30 days, and use of rescue medications.The “interventions” of this review were haloperidol and opioid use for the treatment of abdominal pain. We defined rescue therapy as any analgesic or antiemetic administered 30 minutes after initial haloperidol or opioid administration. Any acetaminophen, ketorolac, or antiemetic use prior to administration of the intervention was not analyzed as rescue therapy. We selected 30 minutes to allow for initial onset of medications administered and to provide a realistic time frame for symptom reassessment in ED patients. The following antiemetics were considered rescue therapy: diphenhydramine; metoclopramide; ondansetron; promethazine; and prochlorperazine. All routes of rescue therapy administration were included for analysis. Additional agents were not included due to formulary restrictions. We calculated MMEs based on an equianalgesic dosing chart.Seventy-five patients with self-matched encounters were needed to detect a difference of three MMEs with 80% power and a two-sided alpha of 0.05.A total of 504 patients qualified for chart review based on diagnosis audit and haloperidol administration. Breakdown of excluded patients was as follows: 218 patients lacked a qualifying comparison encounter; 160 patients had documented agitation or altered mental status; 15 patients lacked documentation of abdominal pain in their review of systems; and four patients were admitted for urgent abdominal surgery. The remaining 107 patients were included for review. Patients were administered haloperidol for the following diagnoses: cyclic vomiting; colitis/diverticulitis; gastroparesis; pancreatitis; gastroesophageal reflux disease (GERD); and unspecified abdominal pain. The diagnoses attached to the encounters were not mutually exclusive and no diagnosis predominated significantly, although many patients had concurrent diagnoses of GERD and unspecified abdominal pain.Seventy percent of patients were women and mean age was 41 years old. The median haloperidol dose administered in the H-encounter was 5.0 mg (IQR 2.0 – 5.0). More patients were administered haloperidol IV than IM, 81.3% vs 18.7%, respectively. Seventy-nine patients, or 73.8%, had their H-encounter chronologically after their C-encounter. Encounters at ED locations with greater than 50,000 annual visits accounted for 46% and 45% of the H-encounters and C-encounters, respectively. Encounters at locations with 20,000–50,000 annual visits accounted for 40% and 39%, respectively. Encounters at locations with less than 20,000 annual visits accounted for 14% and 16%, respectively.P < 0.001). This opioid-sparing effect remained significant despite route of haloperidol administration. The median MME given with IV haloperidol was 0.00 mg (IQR 0.0–4.0) vs 5.8 mg (IQR 4.0–8.0); P < 0.001 in the comparison C-encounter. The median MME given with IM haloperidol was 0.0 mg (IQR 0.0–0.0) vs 5.0 (IQR 3.3–8.0) in the comparison C-encounter; P < 0.001. H-encounters were associated with significantly lower rates of rescue therapy administration than C-encounters. This remained significant when separately analyzing rescue antiemetic and analgesic use. Six patients who received haloperidol for abdominal pain required a repeat dose. Haloperidol was not used as rescue therapy for any of the C-encounters.H-encounters had a statistically significant reduction in MME administered when compared to C-encounters,  but received significantly more ketorolac, 38.9% vs 14.0%; (P = 0.02). Mean dose of ketorolac administered in these H-encounters was 17.1 mg (CI 15.1 – 19.2). We conducted a post-hoc analysis of IM and IV ketorolac administration in H-encounters. Twenty-five percent of patients received haloperidol > 30 minutes before ketorolac, 25% of patients had concurrent administration of haloperidol and ketorolac, and 50% of patients received haloperidol > 30 minutes after the administration of ketorolac.Patients had significantly less opioid use in the H-encounter than in the C-encounter, 47.2% vs 100% (There were no statistically significant differences in ED length of stay, admission rate, mean pain score difference between encounters, adverse events, and 30-day repeat encounters. There were no adverse events in the H-encounters and one adverse event of mental status change in the C-encounter. Although 30-day repeat encounters related to abdominal pain were lower with patients who received haloperidol, the difference was not significant .In this study, haloperidol was associated with a greater opioid-sparing effect than previous literature had demonstrated. Prior studies showed that patients who received haloperidol for abdominal pain were spared approximately 4 MME, while patients in this study were spared approximately 6 MME. Unlike what was reported in previous literature, haloperidol was not associated with a significant decrease in admission rate or pain scores when compared to conventional therapy with opioids. This is likely because previous studies did not use paired comparators, while in this study we used McNemar’s test to analyze paired, nonparametric data.Patients who were administered haloperidol for abdominal pain needed significantly less rescue analgesia and rescue antiemetics than patients who were treated with opioids. This may be correlated to the inherent antiemetic properties of haloperidol. No patients administered concurrent lidocaine or ketamine met inclusion criteria for data analysis. Because haloperidol is not a first-line agent for acute analgesia, it is typically administered to patients who are refractory to other agents. This may explain the significant decrease in rescue therapy after haloperidol administration; many of the other agents were given prior. Although ketorolac was administered more frequently in the H-encounter, 50% of these patients received haloperidol greater than 30 minutes after the administration of ketorolac, which may suggest their pain was refractory to NSAID therapy. Another 25% of these patients had concurrent administration of ketorolac and haloperidol.This study was multicenter, with sites varying from large academic institutions to freestanding EDs, which increases generalizability of the results. Other strengths of the study include a large patient population, a wide variety of emergent settings, and the fact that all patients were self-matched. Data was collected by a single researcher, and primary endpoints are objective and well-defined, which minimizes variability in documentation. Self-matching patients decreases variability in comorbid conditions, prior to admission medications, and perception of pain. Lastly, the time frame selected for patient presentation allowed complete treatment washout between encounters.Although the time frame for qualifying comparison encounters was selected to minimize variability in presentation, diagnosis, and prior to admission medications, patients may have had differences between encounters. Several secondary outcomes relied on nursing documentation in the electronic health record, including pain score changes and adverse effects. Documentation of pain scores was sporadic. Only 21 out of 107 patients in the H-encounter had pre- and post-analgesic pain scores recorded, compared to 101 out of 107 in the C-encounter. This disparity is likely due to lack of a best practice alert prompting nursing staff to document pain scores after haloperidol administration, unlike when they administer opioids. Because adverse drug events were identified with nursing notes, their occurrence may be under-reported in this study. Repeat encounters within 30 days may have been underestimated, as only repeat encounters within the health system are visible. Higher rates of administration of ketorolac in the H-encounter may have confounded the opioid-sparing effect and need for rescue analgesia.This is the largest study to date analyzing haloperidol for the treatment of abdominal pain. It demonstrates that both IM and IV haloperidol, in conjunction with ketorolac, significantly reduces the amount of MMEs used for the treatment of abdominal pain and significantly decreases the need for rescue therapy when compared to conventional opioid therapy. These findings allows us to reduce opioid exposure, treat acute pain despite drug shortages, and demonstrate the safety and efficacy of managing chronic abdominal pain in a population with baseline high healthcare utilization.